Hitomi observation of radio galaxy NGC 1275: The first X-ray microcalorimeter spectroscopy of Fe-Kα line emission from an active galactic nucleus

NASA Astrophysics Data System (ADS)

Hitomi Collaboration; Aharonian, Felix; Akamatsu, Hiroki; Akimoto, Fumie; Allen, Steven W.; Angelini, Lorella; Audard, Marc; Awaki, Hisamitsu; Axelsson, Magnus; Bamba, Aya; Bautz, Marshall W.; Blandford, Roger; Brenneman, Laura W.; Brown, Gregory V.; Bulbul, Esra; Cackett, Edward M.; Chernyakova, Maria; Chiao, Meng P.; Coppi, Paolo S.; Costantini, Elisa; de Plaa, Jelle; de Vries, Cor P.; den Herder, Jan-Willem; Done, Chris; Dotani, Tadayasu; Ebisawa, Ken; Eckart, Megan E.; Enoto, Teruaki; Ezoe, Yuichiro; Fabian, Andrew C.; Ferrigno, Carlo; Foster, Adam R.; Fujimoto, Ryuichi; Fukazawa, Yasushi; Furuzawa, Akihiro; Galeazzi, Massimiliano; Gallo, Luigi C.; Gandhi, Poshak; Giustini, Margherita; Goldwurm, Andrea; Gu, Liyi; Guainazzi, Matteo; Haba, Yoshito; Hagino, Kouichi; Hamaguchi, Kenji; Harrus, Ilana M.; Hatsukade, Isamu; Hayashi, Katsuhiro; Hayashi, Takayuki; Hayashida, Kiyoshi; Hiraga, Junko S.; Hornschemeier, Ann; Hoshino, Akio; Hughes, John P.; Ichinohe, Yuto; Iizuka, Ryo; Inoue, Hajime; Inoue, Yoshiyuki; Ishida, Manabu; Ishikawa, Kumi; Ishisaki, Yoshitaka; Iwai, Masachika; Kaastra, Jelle; Kallman, Tim; Kamae, Tsuneyoshi; Kataoka, Jun; Katsuda, Satoru; Kawai, Nobuyuki; Kelley, Richard L.; Kilbourne, Caroline A.; Kitaguchi, Takao; Kitamoto, Shunji; Kitayama, Tetsu; Kohmura, Takayoshi; Kokubun, Motohide; Koyama, Katsuji; Koyama, Shu; Kretschmar, Peter; Krimm, Hans A.; Kubota, Aya; Kunieda, Hideyo; Laurent, Philippe; Lee, Shiu-Hang; Leutenegger, Maurice A.; Limousin, Olivier O.; Loewenstein, Michael; Long, Knox S.; Lumb, David; Madejski, Greg; Maeda, Yoshitomo; Maier, Daniel; Makishima, Kazuo; Markevitch, Maxim; Matsumoto, Hironori; Matsushita, Kyoko; McCammon, Dan; McNamara, Brian R.; Mehdipour, Missagh; Miller, Eric D.; Miller, Jon M.; Mineshige, Shin; Mitsuda, Kazuhisa; Mitsuishi, Ikuyuki; Miyazawa, Takuya; Mizuno, Tsunefumi; Mori, Hideyuki; Mori, Koji; Mukai, Koji; Murakami, Hiroshi; Mushotzky, Richard F.; Nakagawa, Takao; Nakajima, Hiroshi; Nakamori, Takeshi; Nakashima, Shinya; Nakazawa, Kazuhiro; Nobukawa, Kumiko K.; Nobukawa, Masayoshi; Noda, Hirofumi; Odaka, Hirokazu; Ohashi, Takaya; Ohno, Masanori; Okajima, Takashi; Ota, Naomi; Ozaki, Masanobu; Paerels, Frits; Paltani, Stéphane; Petre, Robert; Pinto, Ciro; Porter, Frederick S.; Pottschmidt, Katja; Reynolds, Christopher S.; Safi-Harb, Samar; Saito, Shinya; Sakai, Kazuhiro; Sasaki, Toru; Sato, Goro; Sato, Kosuke; Sato, Rie; Sawada, Makoto; Schartel, Norbert; Serlemitsos, Peter J.; Seta, Hiromi; Shidatsu, Megumi; Simionescu, Aurora; Smith, Randall K.; Soong, Yang; Stawarz, Łukasz; Sugawara, Yasuharu; Sugita, Satoshi; Szymkowiak, Andrew; Tajima, Hiroyasu; Takahashi, Hiromitsu; Takahashi, Tadayuki; Takeda, Shin'ichiro; Takei, Yoh; Tamagawa, Toru; Tamura, Takayuki; Tanaka, Takaaki; Tanaka, Yasuo; Tanaka, Yasuyuki T.; Tashiro, Makoto S.; Tawara, Yuzuru; Terada, Yukikatsu; Terashima, Yuichi; Tombesi, Francesco; Tomida, Hiroshi; Tsuboi, Yohko; Tsujimoto, Masahiro; Tsunemi, Hiroshi; Tsuru, Takeshi Go; Uchida, Hiroyuki; Uchiyama, Hideki; Uchiyama, Yasunobu; Ueda, Shutaro; Ueda, Yoshihiro; Uno, Shin'ichiro; Urry, C. Megan; Ursino, Eugenio; Watanabe, Shin; Werner, Norbert; Wilkins, Dan R.; Williams, Brian J.; Yamada, Shinya; Yamaguchi, Hiroya; Yamaoka, Kazutaka; Yamasaki, Noriko Y.; Yamauchi, Makoto; Yamauchi, Shigeo; Yaqoob, Tahir; Yatsu, Yoichi; Yonetoku, Daisuke; Zhuravleva, Irina; Zoghbi, Abderahmen; Kawamuro, Taiki

2018-03-01

The origin of the narrow Fe-Kα fluorescence line at 6.4 keV from active galactic nuclei has long been under debate; some of the possible sites are the outer accretion disk, the broad line region, a molecular torus, or interstellar/intracluster media. In 2016 February-March, we performed the first X-ray microcalorimeter spectroscopy with the Soft X-ray Spectrometer (SXS) on board the Hitomi satellite of the Fanaroff-Riley type I radio galaxy NGC 1275 at the center of the Perseus cluster of galaxies. With the high-energy resolution of ˜5 eV at 6 keV achieved by Hitomi/SXS, we detected the Fe-Kα line with ˜5.4 σ significance. The velocity width is constrained to be 500-1600 km s-1 (FWHM for Gaussian models) at 90% confidence. The SXS also constrains the continuum level from the NGC 1275 nucleus up to ˜20 keV, giving an equivalent width of ˜20 eV for the 6.4 keV line. Because the velocity width is narrower than that of the broad Hα line of ˜2750 km s-1, we can exclude a large contribution to the line flux from the accretion disk and the broad line region. Furthermore, we performed pixel map analyses on the Hitomi/SXS data and image analyses on the Chandra archival data, and revealed that the Fe-Kα line comes from a region within ˜1.6 kpc of the NGC 1275 core, where an active galactic nucleus emission dominates, rather than that from intracluster media. Therefore, we suggest that the source of the Fe-Kα line from NGC 1275 is likely a low-covering-fraction molecular torus or a rotating molecular disk which probably extends from a parsec to hundreds of parsecs scale in the active galactic nucleus system.

NRA: First Multiwavelength, Multiple Layer Doppler Imaging of an Active Binary

NASA Technical Reports Server (NTRS)

Dempsey, Robert C.

1998-01-01

In this final report, grantee reports on data obtained from 26 orbits of continuous observing time with the Hubble Space Telescope's Goddard High Resolution Spectrograph in order to produce a comprehensive 2-D image of the RSCVn V824 Ara at MgII, CIV and for the first time ever, the coronal diagnostic line of FeXXI 1356A.

Divergent selection on home pen locomotor activity in a chicken model: Selection program, genetic parameters and direct response on activity and body weight

PubMed Central

2017-01-01

General locomotor activity (GLA) in poultry has attracted attention, as it negatively influences production costs (energy expenditure and feed consumption) and welfare parameters (bone strength, litter quality, feather pecking and cannibalism). Laying hen lines diverging in the average level of spontaneous locomotor activity in the home pen were developed by genetic selection using the founder New Hampshire line. Activity was recorded using RFID technology at around five weeks of age during four to five days in the home pen. After initial phenotyping, the least active birds were selected for the low activity line and the most active for the high activity line, with no gene transfer between lines. In each of six generations, approximately ten sires were mated to twenty dams producing 158 to 334 offspring per line per generation. The response to selection was rapid and of a considerable magnitude. In sixth generation, the level of GLA was approximately halved in the low and doubled in the high line compared to the control (7.2, 14.9 and 28.7 recordings/h). Estimated heritability of locomotor activity in the low and high line was 0.38 and 0.33, respectively. Males, in general, were more active than females. High line birds were significantly heavier than low line birds. In fourth, fifth, and sixth generation, low as well as high line birds were lighter than control line birds. This selection experiment demonstrates variation in heritability for GLA and, as a result, genetically diverged lines have been developed. These lines can be used as models for further studies of underlying physiological, neural and molecular genetic mechanisms of spontaneous locomotor activity. PMID:28796792

Divergent selection on home pen locomotor activity in a chicken model: Selection program, genetic parameters and direct response on activity and body weight.

PubMed

Kjaer, Joergen B

2017-01-01

General locomotor activity (GLA) in poultry has attracted attention, as it negatively influences production costs (energy expenditure and feed consumption) and welfare parameters (bone strength, litter quality, feather pecking and cannibalism). Laying hen lines diverging in the average level of spontaneous locomotor activity in the home pen were developed by genetic selection using the founder New Hampshire line. Activity was recorded using RFID technology at around five weeks of age during four to five days in the home pen. After initial phenotyping, the least active birds were selected for the low activity line and the most active for the high activity line, with no gene transfer between lines. In each of six generations, approximately ten sires were mated to twenty dams producing 158 to 334 offspring per line per generation. The response to selection was rapid and of a considerable magnitude. In sixth generation, the level of GLA was approximately halved in the low and doubled in the high line compared to the control (7.2, 14.9 and 28.7 recordings/h). Estimated heritability of locomotor activity in the low and high line was 0.38 and 0.33, respectively. Males, in general, were more active than females. High line birds were significantly heavier than low line birds. In fourth, fifth, and sixth generation, low as well as high line birds were lighter than control line birds. This selection experiment demonstrates variation in heritability for GLA and, as a result, genetically diverged lines have been developed. These lines can be used as models for further studies of underlying physiological, neural and molecular genetic mechanisms of spontaneous locomotor activity.

RF tuning element

NASA Technical Reports Server (NTRS)

McGrath, William R. (Inventor); Lubecke, Victor M. (Inventor)

1992-01-01

A device for tuning a circuit includes a substrate, a transmission line on the substrate that includes first and second conductors coupled to a circuit to be tuned, and a movable short-circuit for varying the impedance the transmission line presents to the circuit to be tuned. The movable short-circuit includes a dielectric layer disposed atop the transmission line and a distributed shorting element in the form of a conductive member that is configured to be slid along at least a portion of the transmission line atop the dielectric layer. The conductive member is configured to span the first and second conductors of the transmission line and to define at least a first opening that spans the two conductors so that the conductive member includes first and second sections separated by the first opening. The first and second sections of the conductive member combine with the first and second conductors of the transmission line to form first and second low impedance sections of transmission line, and the opening combines with the first and second conductors of the transmission line and the dielectric layer to form a first high impedance section of transmission line intermediate the first and second low impedance sections. Each of the first low impedance section and the first high impedance section have a length along the transmission line of approximately one-quarter wavelength, thus providing a periodic variation of transmission line impedance. That enhances reflection of rf power.

Chicken lines divergently selected for antibody responses to sheep red blood cells show line-specific differences in sensitivity to immunomodulation by diet. Part I: Humoral parameters.

PubMed

Adriaansen-Tennekes, R; de Vries Reilingh, G; Nieuwland, M G B; Parmentier, H K; Savelkoul, H F J

2009-09-01

Individual differences in nutrient sensitivity have been suggested to be related with differences in stress sensitivity. Here we used layer hens divergently selected for high and low specific antibody responses to SRBC (i.e., low line hens and high line hens), reflecting a genetically based differential immune competence. The parental line of these hens was randomly bred as the control line and was used as well. Recently, we showed that these selection lines differ in their stress reactivity; the low line birds show a higher hypothalamic-pituitary-adrenal (HPA) axis reactivity. To examine maternal effects and neonatal nutritional exposure on nutrient sensitivity, we studied 2 subsequent generations. This also created the opportunity to examine egg production in these birds. The 3 lines were fed 2 different nutritionally complete layer feeds for a period of 22 wk in the first generation. The second generation was fed from hatch with the experimental diets. At several time intervals, parameters reflecting humoral immunity were determined such as specific antibody to Newcastle disease and infectious bursal disease vaccines; levels of natural antibodies binding lipopolysaccharide, lipoteichoic acid, and keyhole limpet hemocyanin; and classical and alternative complement activity. The most pronounced dietary-induced effects were found in the low line birds of the first generation: specific antibody titers to Newcastle disease vaccine were significantly elevated by 1 of the 2 diets. In the second generation, significant differences were found in lipoteichoic acid natural antibodies of the control and low line hens. At the end of the observation period of egg parameters, a significant difference in egg weight was found in birds of the high line. Our results suggest that nutritional differences have immunomodulatory effects on innate and adaptive humoral immune parameters in birds with high HPA axis reactivity and affect egg production in birds with low HPA axis reactivity.

First Line Treatment Response in Patients with Transmitted HIV Drug Resistance and Well Defined Time Point of HIV Infection: Updated Results from the German HIV-1 Seroconverter Study

PubMed Central

zu Knyphausen, Fabia; Scheufele, Ramona; Kücherer, Claudia; Jansen, Klaus; Somogyi, Sybille; Dupke, Stephan; Jessen, Heiko; Schürmann, Dirk; Hamouda, Osamah; Meixenberger, Karolin; Bartmeyer, Barbara

2014-01-01

Background Transmission of drug-resistant HIV-1 (TDR) can impair the virologic response to antiretroviral combination therapy. Aim of the study was to assess the impact of TDR on treatment success of resistance test-guided first-line therapy in the German HIV-1 Seroconverter Cohort for patients infected with HIV between 1996 and 2010. An update of the prevalence of TDR and trend over time was performed. Methods Data of 1,667 HIV-infected individuals who seroconverted between 1996 and 2010 were analysed. The WHO drug resistance mutations list was used to identify resistance-associated HIV mutations in drug-naïve patients for epidemiological analysis. For treatment success analysis the Stanford algorithm was used to classify a subset of 323 drug-naïve genotyped patients who received a first-line cART into three resistance groups: patients without TDR, patients with TDR and fully active cART and patients with TDR and non-fully active cART. The frequency of virologic failure 5 to 12 months after treatment initiation was determined. Results Prevalence of TDR was stable at a high mean level of 11.9% (198/1,667) in the HIV-1 Seroconverter Cohort without significant trend over time. Nucleotide reverse transcriptase inhibitor resistance was predominant (6.0%) and decreased significantly over time (OR = 0.92, CI = 0.87–0.98, p = 0.01). Non-nucleoside reverse transcriptase inhibitor (2.4%; OR = 1.00, CI = 0.92–1.09, p = 0.96) and protease inhibitor resistance (2.0%; OR = 0.94, CI = 0.861.03, p = 0.17) remained stable. Virologic failure was observed in 6.5% of patients with TDR receiving fully active cART, 5,6% of patients with TDR receiving non-fully active cART and 3.2% of patients without TDR. The difference between the three groups was not significant (p = 0.41). Conclusion Overall prevalence of TDR remained stable at a rather high level. No significant differences in the frequency of virologic failure were identified during first-line cART between patients with TDR and fully-active cART, patients with TDR and non-fully active cART and patients without TDR. PMID:24788613

High-resolution digital movies of emerging flux and horizontal flows in active regions on the sun

NASA Astrophysics Data System (ADS)

Topka, K.; Ferguson, S.; Frank, Z.; Tarbell, T.; Title, A.

1988-11-01

High-resolution observations of active regions in many wavelength bands obtained at the Vacuum Tower Telescope of NSO/Sunspot (Sacramento Peak) are presented. The SOUP tunable filter, HRSO 1024 x 1024 CCD camera, and a sunspot tracker for image stabilization were used. Subarrays of 512 x 512 pixels were processed digitally and recorded on videodisk in movie format. The movies with 0.5 to 1 arcsecond resolution of the following simultaneous observations were shown: green continuum, longitudinal magnetogram, Doppler velocity, Fe I 5576 A line center, H alpha wings, and H alpha line center. The best set of movies show a 90 x 90 arcsecond field-of-view of an active region at S29, W11. When viewed at speeds of a few thousand times real-time, the photospheric movies clearly show the active region fields being distorted by a remarkable combination of systematic flows and small eruptions of new flux. Flux emergence is most easily discovered in line center movies: an elongated dark feature appears first, followed soon after by bright points at one or both ends. A brief, strong upflow is seen when the dark feature first appears; downflow in the bright points persists much longer. The magnetic flux appears to increase gradually over this extended period. Some of the flux emergence events were studied in detail, with measurements of horizontal and vertical velocities and magnetic flux versus time within one footpoint of the loop.

High-resolution digital movies of emerging flux and horizontal flows in active regions on the sun

NASA Technical Reports Server (NTRS)

Topka, K.; Ferguson, S.; Frank, Z.; Tarbell, T.; Title, A.

1988-01-01

High-resolution observations of active regions in many wavelength bands obtained at the Vacuum Tower Telescope of NSO/Sunspot (Sacramento Peak) are presented. The SOUP tunable filter, HRSO 1024 x 1024 CCD camera, and a sunspot tracker for image stabilization were used. Subarrays of 512 x 512 pixels were processed digitally and recorded on videodisk in movie format. The movies with 0.5 to 1 arcsecond resolution of the following simultaneous observations were shown: green continuum, longitudinal magnetogram, Doppler velocity, Fe I 5576 A line center, H alpha wings, and H alpha line center. The best set of movies show a 90 x 90 arcsecond field-of-view of an active region at S29, W11. When viewed at speeds of a few thousand times real-time, the photospheric movies clearly show the active region fields being distorted by a remarkable combination of systematic flows and small eruptions of new flux. Flux emergence is most easily discovered in line center movies: an elongated dark feature appears first, followed soon after by bright points at one or both ends. A brief, strong upflow is seen when the dark feature first appears; downflow in the bright points persists much longer. The magnetic flux appears to increase gradually over this extended period. Some of the flux emergence events were studied in detail, with measurements of horizontal and vertical velocities and magnetic flux versus time within one footpoint of the loop.

Design, synthesis and in vitro evaluation of 18β-glycyrrhetinic acid derivatives for anticancer activity against human breast cancer cell line MCF-7.

PubMed

Yadav, Dharmendra Kumar; Kalani, Komal; Singh, Abhishek K; Khan, Feroz; Srivastava, Santosh K; Pant, Aditya B

2014-01-01

In the present work, QSAR model was derived by multiple linear regression method for the prediction of anticancer activity of 18β-glycyrrhetinic acid derivatives against the human breast cancer cell line MCF-7. The QSAR model for anti-proliferative activity against MCF-7 showed high correlation (r(2)=0.90 and rCV(2)=0.83) and indicated that chemical descriptors namely, dipole moment (debye), steric energy (kcal/mole), heat of formation (kcal/mole), ionization potential (eV), LogP, LUMO energy (eV) and shape index (basic kappa, order 3) correlate well with activity. The QSAR virtually predicted that active derivatives were first semi-synthesized and characterized on the basis of their (1)H and (13)C NMR spectroscopic data and then were in-vitro tested against MCF-7 cancer cell line. In particular, octylamide derivative of glycyrrhetinic acid GA-12 has marked cytotoxic activity against MCF-7 similar to that of standard anticancer drug paclitaxel. The biological assays of active derivative selected by virtual screening showed significant experimental activity.

Stimulated Brillouin scatter and stimulated ion Bernstein scatter during electron gyroharmonic heating experiments

NASA Astrophysics Data System (ADS)

Fu, H.; Scales, W. A.; Bernhardt, P. A.; Samimi, A.; Mahmoudian, A.; Briczinski, S. J.; McCarrick, M. J.

2013-09-01

Results of secondary radiation, Stimulated Electromagnetic Emission (SEE), produced during ionospheric modification experiments using ground-based high-power radio waves are reported. These results obtained at the High Frequency Active Auroral Research Program (HAARP) facility specifically considered the generation of Magnetized Stimulated Brillouin Scatter (MSBS) and Stimulated Ion Bernstein Scatter (SIBS) lines in the SEE spectrum when the transmitter frequency is near harmonics of the electron gyrofrequency. The heater antenna beam angle effect was investigated on MSBS in detail and shows a new spectral line postulated to be generated near the upper hybrid resonance region due to ion acoustic wave interaction. Frequency sweeping experiments near the electron gyroharmonics show for the first time the transition from MSBS to SIBS lines as the heater pump frequency approaches the gyroharmonic. Significantly far from the gyroharmonic, MSBS lines dominate, while close to the gyroharmonic, SIBS lines strengthen while MSBS lines weaken. New possibilities for diagnostic information are discussed in light of these new observations.

ANOMALOUS RELATIVE AR/CA CORONAL ABUNDANCES OBSERVED BY THE HINODE/EUV IMAGING SPECTROMETER NEAR SUNSPOTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doschek, G. A.; Warren, H. P.; Feldman, U.

2015-07-20

In determining the element abundance of argon (a high first ionization potential; FIP element) relative to calcium (a low FIP element) in flares, unexpectedly high intensities of two Ar xiv lines (194.40, 187.96 Å) relative to a Ca xiv line (193.87 Å) intensity were found in small (a few arcseconds) regions near sunspots in flare spectra recorded by the Extreme-ultraviolet Imaging Spectrometer on the Hinode spacecraft. In the most extreme case the Ar xiv line intensity relative to the Ca xiv intensity was 7 times the value expected from the photospheric abundance ratio, which is about 30 times the abundancemore » of argon relative to calcium in active regions, i.e., the measured Ar/Ca abundance ratio is about 10 instead of 0.37 as in active regions. The Ar xiv and Ca xiv lines are formed near 3.4 MK and have very similar contribution functions. This is the first observation of the inverse FIP effect in the Sun. Other regions show increases of 2–3 over photospheric abundances, or just photospheric abundances. This phenomenon appears to occur rarely and only over small areas of flares away from the regions containing multi-million degree plasma, but more work is needed to quantify the occurrences and their locations. In the bright hot regions of flares the Ar/Ca abundance ratio is coronal, i.e., the same as in active regions. In this Letter we show three examples of the inverse FIP effect.« less

Reverberation Mapping of Optical Emission Lines in Five Active Galaxies

DOE PAGES

Fausnaugh, M. M.; Grier, C. J.; Bentz, M. C.; ...

2017-05-10

We present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a “changing look” AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He II λ4686 lags for all objects except 3C 382. The He II λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. Themore » relative responsivities of these lines are also in qualitative agreement with photoionization models. Finally, these spectra have extremely high signal-to-noise ratios (100–300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.« less

Reverberation Mapping of Optical Emission Lines in Five Active Galaxies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fausnaugh, M. M.; Denney, K. D.; Peterson, B. M.

2017-05-10

We present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a “changing look” AGN and a broad-line radio galaxy. Based on continuum-H β lags, we measure black hole masses for all five targets. We also obtain H γ and He ii λ 4686 lags for all objects except 3C 382. The He ii λ 4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines aremore » in general agreement. The relative responsivities of these lines are also in qualitative agreement with photoionization models. These spectra have extremely high signal-to-noise ratios (100–300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.« less

A pharmacovigilance study of adults on highly active antiretroviral therapy, South Africa: 2007 - 2011.

PubMed

Dube, Nomathemba Michell; Summers, Robert; Tint, Khin-San; Mayayise, Guistee

2012-01-01

Of the 1.6 million South African people infected with human immunodeficiency virus (HIV), approximately 970,000 (55%) have been initiated on HAART. Despite these numbers, very little has been published about the safety profile of antiretroviral (ARV) medicines in the country. This study was performed at the Medunsa National Pharmacovigilance Centre and aimed to describe the demographic characteristics of patients enrolled in the pharmacovigilance surveillance study; highly active antiretroviral therapy (HAART) initiation regimen patterns; reasons for regimen changes; and adverse effects of ARV medicines. A cohort study of HIV-infected individuals aged 15 years or older who were on ARV medicines was conducted at four sentinel sites. After HAART initiation, with an average lapse of 17.8 months (range: 0 - 83.8 months), 2,815 patients were enrolled into the study. Results show that patients were observed for 1,606.2 person-years for pharmacy visits (collection of ARV medicines) and 817.1 person-years for clinical visits (consultation with the doctor). Females constituted 69.6% (1,958/2,815) of the study population. Almost all patients initiated HAART on first-line regimens (2,801/2,815). Some patients (6.7%, 190/2,815) dropped out of the study after HAART initiation. Reasons for regimen changes were not recorded for 2.5% (22/891) of the patients who changed regimens. The primary reason for regimen changes was drug-related toxicity (76.1%, 678/891), mostly evident in patients taking first-line regimens. Adverse effects experienced by patients were polyneuropathy (24.0%, 163/678); lipodystrophy (23.9%, 162/678); neuropathy (10.6%, 72/678); and suspected lactic acidosis (3.8%, 26/678). The majority of prescribers complied with the HAART guidelines and initiated most patients on first-line regimens. However, adverse effects are evident in patients taking first-line regimens. We recommend that the Department of Health should introduce less toxic first-line ARV regimens. Future efforts will aim to initiate patients on HAART and enrol them into the study simultaneously to determine early risk profiles of ARV medicines.

Development of propidium iodide as a fluorescence probe for the on-line screening of non-specific DNA-intercalators in Fufang Banbianlian Injection.

PubMed

Niu, Yanyan; Li, Sensen; Lin, Zongtao; Liu, Meixian; Wang, Daidong; Wang, Hong; Chen, Shizhong

2016-09-09

Fufang Banbianlian Injection (FBI) has been widely used as an anti-inflammatory and anti-tumor prescription. To understand the relationships between its bioactive ingredients and pharmacological efficacies, our previous study has been successfully identified some DNA-binding compounds in FBI using an established on-line screening system, in which 4',6-diamidino-2-phenylindole (DAPI) was developed as a probe. However, DAPI can be only used to screen ATT-specific DNA minor groove binders, leaving the potential active intercalators unknown in FBI. As a continuation of our studies on FBI, here we present a sensitive analytical method for rapid identification and evaluation of DNA-intercalators using propidium iodide (PI) as a fluorescent probe. We have firstly established the technique of high-performance liquid chromatography-diode-array detector-multistage mass spectrometry-deoxyribonucleic acid-propidium iodide-fluorescence detector (HPLC-DAD-MS(n)-DNA-PI-FLD) system. As a result, 38 of 58 previously identified compounds in FBI were DNA-intercalation active. Interestingly, all previously reported DNA-binders also showed intercalative activities, suggesting they are dual-mode DNA-binders. Quantitative study showed that flavonoid glycosides and chlorogenic acids were the main active compounds in FBI, and displayed similar DNA-binding ability using either DAPI or PI. In addition, 13 active compounds were used to establish the structure-activity relationships. In this study, PI was developed into an on-line method for identifying DNA-intercalators for the first time, and thus it will be a useful high-throughput screening technique for other related samples. Copyright © 2016 Elsevier B.V. All rights reserved.

First direct comparison of high and low ionization line kinematics in active galactic nuclei

NASA Technical Reports Server (NTRS)

Sulentic, J. W.; Marziani, P.; Dultzin-Hacyan, D.; Calvani, M.; Moles, M.

1995-01-01

We present first results of a comparison of emission line shift properties for the high (HILs) and low (LILs) ionization lines in 43 low-reshift quasars. We identify a core sample of C IV lambda 1549 and hydrogen beta profiles with a wide distribution of red- and blueshifts (less than or equal to +/- 1000 km/sec). We also identify two tails in this distribution: one with large hydrogen beta redshifts (greater than or equal to 2000 km/sec) and another with large C IV blueshifts (greater than or equal to 1500 km/sec). The tails are mutually exclusive. All objects with extreme hydrogen beta redshift are radio loud, and all objects with extreme C IV blueshift are radio quiet. The core samples of smaller shifts can be most simply divided into: (1) hydrogen beta - a redshifted radio-loud population (related to the tail) and a radio-quiet population with mean shift near zero, and (2) C IV - a blueshifted radio-quiet population (related to the tail) and a radio-loud population with mean shift near zero. The results suggest fundamentally different kinematics for the HILs and LILs. They also suggest very different kinematics for radio-loud and radio-quiet active galactic nuclei. They also favor a predominance of radial motion in a large fraction of the sample.

First-line therapy for advanced non-small cell lung cancer with activating EGFR mutation: is combined EGFR-TKIs and chemotherapy a better choice?

PubMed

Wang, Shuyun; Gao, Aiqin; Liu, Jie; Sun, Yuping

2018-03-01

As the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the median progression-free survival (PFS) up to 18.9 months. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, which limits the first-line PFS. To overcome the resistance and improve overall survival, researchers have tried to identify the resistance mechanisms and develop new treatment strategies, among which a combination of EGFR-TKIs and cytotoxic chemotherapy is one of the hotspots. The data from preclinical and clinical studies on combined EGFR-TKIs and chemotherapy have shown very interesting results. Here, we reviewed the available preclinical and clinical studies on first-line EGFR-TKIs-chemotherapy combination in patients with advanced NSCLC harboring activating EGFR mutation, aiming to provide evidences for more potential choices and shed light on clinical treatment.

First Detection of the [O(sub III)] 88 Micrometers Line at High Redshifts: Characterizing the Starburst and Narrow-Line Regions in Extreme Luminosity Systems

NASA Technical Reports Server (NTRS)

Ferkinhoff, C.; Hailey-Dunsheath, S.; Nikola, T.; Parshley, S. C.; Stacey, G. J.; Benford, D. J.; Staguhn, J. G.

2010-01-01

We have made the first detections of the 88 micrometers [O(sub III)] line from galaxies in the early universe, detecting the line from the lensed active galactic nucleus (AGN)/starburst composite systems APM 08279+5255 at z 3.911 and SMM J02399-0136 at z = 2.8076. The line is exceptionally bright from both systems, with apparent (lensed) luminosities approx.10(exp 11) Solar Luminosity, For APM 08279, the [O(sub III)] line flux can be modeled in a star formation paradigm, with the stellar radiation field dominated by stars with effective temperatures, T(sub eff) > 36,000 K, similar to the starburst found in M82. The model implies approx.35% of the total far-IR luminosity of the system is generated by the starburst, with the remainder arising from dust heated by the AGN. The 881,tm line can also be generated in the narrow-line region of the AGN if gas densities are around a few 1000 cu cm. For SMM J02399, the [O(sub III)] line likely arises from HII regions formed by hot (T(sub eff) > 40,000 K) young stars in a massive starburst that dominates the far-IR luminosity of the system. The present work demonstrates the utility of the [O(sub III)] line for characterizing starbursts and AGN within galaxies in the early universe. These are the first detections of this astrophysically important line from galaxies beyond a redshift of 0.05.s

Line intensity measurements and analysis in the ν3 band of ruthenium tetroxide

NASA Astrophysics Data System (ADS)

Vander Auwera, J.; Reymond-Laruinaz, S.; Boudon, V.; Doizi, D.; Manceron, L.

2018-01-01

Ruthenium tetroxide (RuO4) is a heavy tetrahedral molecule characterized by an unusual volatility near ambient temperature. Because of its chemical toxicity and the radiological impact of its 103Ru and 106Ru isotopologues, the possible remote sensing of this compound in the atmosphere has renewed interest in its spectroscopic properties. The present contribution is the first investigation dealing with high-resolution line-by-line intensity measurements for the strong fundamental band observed near 10 μm, associated with the excitation of the infrared active stretching mode ν3. It relies on new, high resolution FTIR spectra recorded at room temperature, using a specially constructed cell and an isotopically pure sample of 102Ru16O4. Relying on an effective Hamiltonian and associated effective dipole moment [S Reymond-Laruinaz et al, J Mol Spectrosc 2015;315:46-54], the measured line intensities were assigned and dipole moment parameters determined. A HITRAN-formatted frequency and intensity line list was generated.

Busulfan is effective second-line therapy for older patients with Philadelphia-negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea.

PubMed

Douglas, Genevieve; Harrison, Claire; Forsyth, Cecily; Bennett, Michael; Stevenson, William; Hounsell, John; Ratnasingam, Sumita; Ritchie, David; Ross, David M; Grigg, Andrew

2017-01-01

Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.

A vigorous activity cycle mimicking a planetary system in HD 200466

NASA Astrophysics Data System (ADS)

Carolo, E.; Desidera, S.; Gratton, R.; Martinez Fiorenzano, A. F.; Marzari, F.; Endl, M.; Mesa, D.; Barbieri, M.; Cecconi, M.; Claudi, R. U.; Cosentino, R.; Scuderi, S.

2014-07-01

Stellar activity can be a source of radial velocity (RV) noise and can reproduce periodic RV variations similar to those produced by an exoplanet. We present the vigorous activity cycle in the primary of the visual binary HD 200466, a system made of two almost identical solar-type stars with an apparent separation of 4.6 arcsec at a distance of 44 ± 2 pc. High precision RV over more than a decade, adaptive optics (AO) images, and abundances have been obtained for both components. A linear trend in the RV is found for the secondary. We assumed that it is due to the binary orbit and once coupled with the astrometric data, it strongly constrains the orbital solution of the binary at high eccentricities (e ~ 0.85) and quite small periastron of ~21 AU. If this orbital motion is subtracted from the primary radial velocity curve, a highly significant (false alarm probability <0.1%) period of about 1300 d is obtained, suggesting in a first analysis the presence of a giant planet, but it turned out to be due to the stellar activity cycle. Since our spectra do not include the Ca II resonance lines, we measured a chromospheric activity indicator based on the Hα line to study the correlation between activity cycles and long-term activity variations. While the bisector analysis of the line profile does not show a clear indication of activity, the correlation between the Hα line indicator and the RV measurements identify the presence of a strong activity cycle. Based on observations made with the Italian Telescopio Nazionale Galileo (TNG) operated on the island of La Palma by the Fundación Galileo Galilei of the Istituto Nazionale di Astrofisica (INAF) at the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias.Tables 5 and 6 are available in electronic form at http://www.aanda.org

X-Ray Evidence for the Accretion Disc-Outflow Connection in 3C 111

NASA Technical Reports Server (NTRS)

Tombesi, Frank; Sambruna, R. M.; Reeves, J. N.; Reynolds, C. S.; Braito, V.

2011-01-01

We present the spectral analysis of three Suzaku X-ray Imaging Spectrometer observations of 3C III requested to monitor the predicted variability of its ultrafast outflow on approximately 7 d time-scales. We detect an ionized iron emission line in the first observation and a blueshifted absorption line in the second, when the flux is approximately 30 per cent higher. The location of the material is constrained at less than 0.006 pc from the variability. Detailed modelling supports an identification with ionized reflection off the accretion disc at approximately 20-100rg from the black hole and a highly ionized and massive ultrafast outflow with velocity approximately 0.1c, respectively. The outflow is most probably accelerated by radiation pressure, but additional magnetic thrust cannot be excluded. The measured high outflow rate and mechanical energy support the claims that disc outflows may have a significant feedback role. This work provides the first direct evidence for an accretion disc-outflow connection in a radio-loud active galactic nucleus, possibly linked also to the jet activity.

Adoptive transfer of Epstein-Barr virus-specific cytotoxic T-lymphocytes for the treatment of angiocentric lymphomas.

PubMed

Cho, Hyun-Il; Hong, Young Seon; Lee, Myung Ah; Kim, Eun-Kyung; Yoon, Sung-Hee; Kim, Chun-Choo; Kim, Tai-Gyu

2006-01-01

Angiocentric lymphoma, known as natural killer (NK)/T-cell non-Hodgkin's lymphoma, has been reported to be associated with the Epstein-Barr virus (EBV). We performed adoptive transfer of EBV-specific polyclonal T-cell lines in 3 patients with extranodal NK/T-cell lymphoma, nasal type, and evaluated the treatment for safety, immunologic reconstitution, and clinical outcomes. The tissue samples collected from the 3 patients were confirmed by polymerase chain reaction analysis to be EBV positive. In the cases of the first and second patients, EBV-transformed B-lymphoblastoid cell lines (LCLs) and T-cell lines were generated from peripheral lymphocytes of HLA-matched sibling donors. The third patient's T-cell lines were induced with autologous lymphocytes. Polyclonal T-cell infusion was carried out after high-dose radiotherapy because active relapsed disease remained in all of the patients. The first patient received 4 weekly infusions of 2 3 10(7) cells/m(2), and the second and third patients underwent treatment with 2 cycles of infusions of the same dosage. All T-cell lines showed >60% NK activity, cytotoxic T-lymphocyte (CTL) responses of >40% against autologous LCLs, and no CTL activity against patient-derived lymphoblasts. The level of cytotoxicity increased substantially in all patients after cell infusion. The 2 patients who received T-cell therapy twice had stabilized disease for more than 3 years. These safe treatments exhibited no severe inflammatory response, and no serious toxicity developed during T-cell therapy. Our findings demonstrate that adoptively transferred cells may provide reconstitution of EBV-specific CTL responses in patients with active relapsed angiocentric lymphoma. These results provide a rationale for the immunotherapy of angiocentric lymphoma.

Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors.

PubMed

Sgambato, Assunta; Casaluce, Francesca; Maione, Paolo; Gridelli, Cesare

2018-01-01

Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition. Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC. After initial response to crizotinib, tumors inevitably relapse. Next-generation ALK inhibitors, more potent and brain-penetrable than crizotinib, may be effective in re-inducing remissions when cancers are still addicted to ALK. Ceritinib and alectinib are approved for metastatic ALK positive NSCLC patients, while brigatinib received granted accelerated approval by the United States Food and Drug Administration. Regarding ROS1 rearrangement, to date crizotinib is the only ALK-tyrosine kinase inhibitor receiving indication as treatment of ROS1 positive advanced NSCLC. Expert commentary: Although novel ALK-inhibitors are under clinical investigation compared to crizotinib as front-line treatment for ALK-positive NSCLC, nowadays the current standard first-line therapy for these patients is crizotinib. Further research will clarify the best management of ALK-positive NSCLC, above all who progress on first-line crizotinib.

First Detections of the [N II] 122 micron Line at High Redshift: Demonstrating the Utility of the Line for Studying Galaxies in the Early Universe

NASA Technical Reports Server (NTRS)

Ferkinhoff, Carl; Brisbin, Drew; Nikola, Thomas; Parshley, Stephen C.; Stacey, Gordon J.; Phillips, Thomas G.; Falgarone, Edith; Benford, Dominic J.; Staguhn, Johannes G.; Tucker, Carol E.

2011-01-01

We report the first detections of the [N II] 122 micron line from a high-redshift galaxy. The line was strongly (>6(sigma)) detected from SMMJ02399-0136, and H1413 + 117 (the Cloverleaf QSO) using the Redshift (zeta) and Early Universe Spectrometer on the Caltech Submillimeter Observatory. The lines from both sources are quite bright with line to far-infrared (FIR) continuum luminosity ratios that are approx.7.0 x 10(exp -4) (Cloverleaf) and 2.1 x 10(exo -3) (SMMJ02399). With ratios 2-10 times larger than the average value for nearby galaxies, neither source exhibits the line to continuum deficits seen in nearby sources. The line strengths also indicate large ionized gas fractions, approx.8%-17% of the molecUlar gas mass. The [O III]/[N II] line ratio is very sensitive to the effective temperature of ionizing stars and the ionization parameter for emission arising in the narrow-line region (NLR) of an active galactic nucleus (AGN). Using Our previous detection of the [O III] 88 micron line, the [O III]/[N II]line ratio for SMMJ02399-0136 indicates that the dominant source of the line emission is either stellar H II regions ionized by O9.5 stars, or the NLR of the AGN with ionization parameter log(U) = -3.3 to -4.0. A composite system, where 30%-50% of the FIR lines arise in the NLR also matches the data. The Cloverleaf is best modeled by a superposition of approx.200 M82-like starbursts accounting for all of the FIR emission and 43% of the [N II]line. The remainder may come from the NLR. This war!< demonstrates the utility of the [N II] and [O III] lines in constraining properties of the ionized medium.

Printed circuit dispersive transmission line

DOEpatents

Ikezi, Hiroyuki; Lin-Liu, Yuh-Ren; DeGrassie, John S.

1991-01-01

A printed circuit dispersive transmission line structure is disclosed comprising an insulator, a ground plane formed on one surface of the insulator, a first transmission line formed on a second surface of the insulator, and a second transmission line also formed on the second surface of the insulator and of longer length than the first transmission line and periodically intersecting the first transmission line. In a preferred embodiment, the transmission line structure exhibits highly dispersive characteristics by designing the length of one of the transmission line between two adjacent periodic intersections to be longer than the other.

Synthesis and Anticancer Activity of Epipolythiodiketopiperazine Alkaloids

PubMed Central

Boyer, Nicolas; Morrison, Karen C.; Kim, Justin; Hergenrother, Paul J.; Movassaghi, Mohammad

2013-01-01

The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure–activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo. PMID:23914293

Force-free field modeling of twist and braiding-induced magnetic energy in an active-region corona

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thalmann, J. K.; Tiwari, S. K.; Wiegelmann, T., E-mail: julia.thalmann@uni-graz.at

2014-01-01

The theoretical concept that braided magnetic field lines in the solar corona may dissipate a sufficient amount of energy to account for the brightening observed in the active-region (AR) corona has only recently been substantiated by high-resolution observations. From the analysis of coronal images obtained with the High Resolution Coronal Imager, first observational evidence of the braiding of magnetic field lines was reported by Cirtain et al. (hereafter CG13). We present nonlinear force-free reconstructions of the associated coronal magnetic field based on Solar Dynamics Observatory/Helioseismic and Magnetic Imager vector magnetograms. We deliver estimates of the free magnetic energy associated withmore » a braided coronal structure. Our model results suggest (∼100 times) more free energy at the braiding site than analytically estimated by CG13, strengthening the possibility of the AR corona being heated by field line braiding. We were able to appropriately assess the coronal free energy by using vector field measurements and we attribute the lower energy estimate of CG13 to the underestimated (by a factor of 10) azimuthal field strength. We also quantify the increase in the overall twist of a flare-related flux rope that was noted by CG13. From our models we find that the overall twist of the flux rope increased by about half a turn within 12 minutes. Unlike another method to which we compare our results, we evaluate the winding of the flux rope's constituent field lines around each other purely based on their modeled coronal three-dimensional field line geometry. To our knowledge, this is done for the first time here.« less

Simultaneous observations of Ca II K and Mg II k in T Tauri stars

NASA Technical Reports Server (NTRS)

Calvet, N.; Basri, G.; Imhoff, C. L.; Giampapa, M. S.

1985-01-01

The first simultaneous, calibrated observations of the Ca II K and Mg II k resonance lines in T Tauri stars are presented. It is found that for T Tauri stars with mass greater than 1.5 solar mass, which have radiative cores and tend to be fast rotators, the k line seems to arise in an extended region (probably also responsible for the H-alpha emission), whereas the K line apparently originates closer to the highly inhomogeneous stellar surface. The lower mass stars, which are fully convective and tend to be slow rotators, are more easily described by a largely chromospheric model, consistent with main-sequence activity structures but at greater values of the nonradiative flux. The strongest emission-line stars in the low-mass group, however, are also likely to have extended k line regions.

Heavy metal incorporated helium ion active hybrid non-chemically amplified resists: Nano-patterning with low line edge roughness

NASA Astrophysics Data System (ADS)

Reddy, Pulikanti Guruprasad; Thakur, Neha; Lee, Chien-Lin; Chien, Sheng-Wei; Pradeep, Chullikkattil P.; Ghosh, Subrata; Tsai, Kuen-Yu; Gonsalves, Kenneth E.

2017-08-01

Helium (He) ion lithography is being considered as one of the most promising and emerging technology for the manufacturing of next generation integrated circuits (ICs) at nanolevel. However, He-ion active resists are rarely reported. In this context, we are introducing a new non-chemically amplified hybrid resist (n-CAR), MAPDSA-MAPDST, for high resolution He-ion beam lithography (HBL) applications. In the resist architecture, 2.15 % antimony is incorporated as heavy metal in the form of antimonate. This newly developed resists has successfully used for patterning 20 nm negative tone features at a dose of 60 μC/cm2. The resist offered very low line edge roughness (1.27±0.31 nm) for 20 nm line features. To our knowledge, this is the first He-ion active hybrid resist for nanopatterning. The contrast (γ) and sensitivity (E0) of this resist were calculated from the contrast curve as 0.73 and 7.2 μC/cm2, respectively.

Underground waste barrier structure

DOEpatents

Saha, Anuj J.; Grant, David C.

1988-01-01

Disclosed is an underground waste barrier structure that consists of waste material, a first container formed of activated carbonaceous material enclosing the waste material, a second container formed of zeolite enclosing the first container, and clay covering the second container. The underground waste barrier structure is constructed by forming a recessed area within the earth, lining the recessed area with a layer of clay, lining the clay with a layer of zeolite, lining the zeolite with a layer of activated carbonaceous material, placing the waste material within the lined recessed area, forming a ceiling over the waste material of a layer of activated carbonaceous material, a layer of zeolite, and a layer of clay, the layers in the ceiling cojoining with the respective layers forming the walls of the structure, and finally, covering the ceiling with earth.

High-voltage isolation transformer for sub-nanosecond rise time pulses constructed with annular parallel-strip transmission lines.

PubMed

Homma, Akira

2011-07-01

A novel annular parallel-strip transmission line was devised to construct high-voltage high-speed pulse isolation transformers. The transmission lines can easily realize stable high-voltage operation and good impedance matching between primary and secondary circuits. The time constant for the step response of the transformer was calculated by introducing a simple low-frequency equivalent circuit model. Results show that the relation between the time constant and low-cut-off frequency of the transformer conforms to the theory of the general first-order linear time-invariant system. Results also show that the test transformer composed of the new transmission lines can transmit about 600 ps rise time pulses across the dc potential difference of more than 150 kV with insertion loss of -2.5 dB. The measured effective time constant of 12 ns agreed exactly with the theoretically predicted value. For practical applications involving the delivery of synchronized trigger signals to a dc high-voltage electron gun station, the transformer described in this paper exhibited advantages over methods using fiber optic cables for the signal transfer system. This transformer has no jitter or breakdown problems that invariably occur in active circuit components.

High Redshift Quasars

NASA Technical Reports Server (NTRS)

Elvis, Martin S.

1996-01-01

The report for this period includes three papers: 'Associated Absorption at Low and High Redshift'; 'Strong X-ray Absorption in a Broad Absorption Line Quasar: PHL5200'; and 'ASCA and ROSAT X-ray Spectra of High-Redshift Radio-Loud Quasars'. The first gives examples from both low and high redshift for combining information on absorbing material in active galactic nuclei from both x-ray and the UV. The second presents ASCA observations of the z = 1.98 prototype broad absorption line quasar (BALQSO): PHL 5200, detected with both the solid-state imaging spectrometers and the gas imaging spectometers. The third paper presents results on the x-ray properties of 9 high-redshift radio-loud quasars observed by ASCA and ROSAT, including ASCA observations of S5 0014+81 (z = 3.38) and S5 0836+71 (z = 2.17) and ROSAT observations of PKS 2126-158.

Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data.

PubMed

Fornaro, Lorenzo; Vivaldi, Caterina; Cereda, Stefano; Leone, Francesco; Aprile, Giuseppe; Lonardi, Sara; Silvestris, Nicola; Santini, Daniele; Milella, Michele; Caparello, Chiara; Musettini, Gianna; Pasquini, Giulia; Falcone, Alfredo; Brandi, Giovanni; Sperduti, Isabella; Vasile, Enrico

2015-12-23

After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far. We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings. A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months). The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

Printed circuit dispersive transmission line

DOEpatents

Ikezi, H.; Lin-Liu, Y.R.; DeGrassie, J.S.

1991-08-27

A printed circuit dispersive transmission line structure is disclosed comprising an insulator, a ground plane formed on one surface of the insulator, a first transmission line formed on a second surface of the insulator, and a second transmission line also formed on the second surface of the insulator and of longer length than the first transmission line and periodically intersecting the first transmission line. In a preferred embodiment, the transmission line structure exhibits highly dispersive characteristics by designing the length of one of the transmission line between two adjacent periodic intersections to be longer than the other. 5 figures.

High-Resolution Infrared Spectroscopy and Analysis of the ν_2/ν_4 Bending Dyad and ν_3 Stretching Fundamental of Ruthenium Tetroxide

NASA Astrophysics Data System (ADS)

Faye, Mbaye; Reymond-Laruinaz, Sébastien; Vander Auwera, Jean; Boudon, Vincent; Doizi, Denis; Manceron, Laurent

2017-06-01

RuO_4 is a heavy tetrahedral molecule which has practical uses for several industrial fields. Due to its chemical toxicity and the radiological impact of its 103 and 106 isotopologues, the possible remote sensing of this compound in the atmosphere has renewed interest in its spectroscopic properties. We investigate here for the first time at high resolution the bending dyad region in the far IR and the line intensities in the ν_3 stretching region. Firstly, new high resolution FTIR spectra of the bending modes region in the far infrared have been recorded at room temperature, using a specially constructed cell and an isotopically pure sample of {}^{102}RuO_4. New assignments and effective Hamiltonian parameter fits for this main isotopologue have been performed, treating the whole ν_2/ν_4 bending mode dyad. We provide precise effective Hamiltonian parameters, including band centers and Coriolis interaction parameters. Secondly, we investigate the line intensities for the strongly infrared active stretching mode ν_3, in the mid infrared window near 10 μm. New high resolution FTIR spectra have also been recorded at room temperature, using the same cell and sample. Using assignments and effective Hamiltonian parameter for {}^{102}RuO_4, line intensities have been retrieved and the dipole moment parameters fitted for the ν_3 fundamental. A frequency and intensity line list is proposed.

EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer

PubMed Central

Nan, Xueli; Xie, Chao; Yu, Xueyan; Liu, Jie

2017-01-01

After the discovery of activating mutations in EGFR, EGFR tyrosine kinase inhibitors (TKIs) have been introduced into the first-line treatment of non-small-cell lung cancer (NSCLC). A series of studies have shown that EGFR TKI monotherapy as first-line treatment can benefit NSCLC patients harbouring EGFR mutations. Besides, combination strategies based on EGFR TKIs in the first line treatment have also been proved to delay the occurrence of resistance. In this review, we summarize the scientific literature and evidence of EGFR TKIs as first-line therapy from the first-generation EGFR TKIs to conceptually proposed fourth-generation EGFR TKI, and also recommend the application of monotherapy and combination therapies of the EGFR-based targeted therapy with other agents such as chemotherapy, anti-angiogenic drugs and immunecheckpoint inhibitors. PMID:29088904

At-line hyphenation of high-speed countercurrent chromatography with Sephadex LH-20 column chromatography for bioassay-guided separation of antioxidants from vine tea (Ampelopsis grossedentata).

PubMed

Ma, Ruyi; Zhou, Rongrong; Tong, Runna; Shi, Shuyun; Chen, Xiaoqing

2017-01-01

Vine tea (Ampelopsis grossedentata), a widely used healthy tea, beverage and herbal medicine, exhibited strong antioxidant activity. However, systematic purification of antioxidants, especially for those with similar structures or polarities, is a challenging work. Here, we present a novel at-line hyphenation of high-speed countercurrent chromatography with Sephadex LH-20 column chromatography (HSCCC-Sephadex LH-20 CC) for rapid and efficient separation of antioxidants from vine tea target-guided by 1,1-diphenyl-2-picryl-hydrazyl radical-high performance liquid chromatography (DPPH-HPLC) experiment. A makeup pump, a six-port switching valve and a trapping column were served as interface. The configuration had no operational time and mobile phase limitations between two dimensional chromatography and showed great flexibility without tedious sample-handling procedure. Seven targeted antioxidants were firstly separated by stepwise HSCCC using petroleum ether-ethyl acetate-methanol-water (4:9:4:9, v/v/v/v) and (4:9:5:8, v/v/v/v) as solvent systems, and then co-eluted antioxidants were on-line trapped, concentrated and desorbed to Sephadex LH-20 column for further off-line purification by methanol. It is noted that six elucidated antioxidants with purity over 95% exhibited stronger activity than ascorbic acid (VC). More importantly, this at-line hyphenated strategy could sever as a rapid and efficient pathway for systematic purification of bioactive components from complex matrix. Copyright © 2016 Elsevier B.V. All rights reserved.

By Klee Inspired.

ERIC Educational Resources Information Center

Grimes, Linda

1999-01-01

Discusses two activities based on the paintings of Paul Klee who used simple lines, bright colors, and happy subjects within his artwork. Explains that in the kindergarten activity, the students practice line drawing and looking at tree forms as well as painting; the first grade activity focuses on the abstract cubist style. (CMK)

Sub-Millimeter Heterodyne Focal-Plane Arrays for High-Resolution Astronomical Spectroscopy

NASA Astrophysics Data System (ADS)

Goldsmith, Paul F.

2017-09-01

Spectral lines are vital tools for astronomy, particularly for studying the interstellar medium, which is widely distributed throughout the volume of our Milky Way and of other galaxies. Broadband emissions, including synchrotron, free-free, and thermal dust emissions give astronomers important information. However, they do not give information about the motions of, for example, interstellar clouds, the filamentary structures found within them, star-forming dense cores, and photon-dominated regions energized by massive young stars. For study of the interstellar medium, spectral lines at sub-millimeter wavelengths are particularly important, for two reasons. First, they offer the unique ability to observe a variety of important molecules, atoms, and ions, which are the most important gas coolants (fine-structure lines of ionized and neutral carbon, neutral oxygen), probes of physical conditions (high-J transitions of CO, HF, fine-structure lines of ionized nitrogen), and of obvious biogenic importance (H2O). In addition, high-resolution observations of spectral lines offer the unique ability to disentangle the complex motions within these regions and, in some cases, to determine their arrangement along the line of sight. To accomplish this, spectral resolution high enough to resolve the spectral lines of interest is required. We can measure the resolution of the spectrometer in terms of its resolution, R = f/δf, where f is the rest frequency of the line, and δJ is the frequency resolution of the spectrometer. More-active sources can be advantageously studied with R = 3 × 10^5, while more quiescent sources require R as high as 10^7.

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.

PubMed

Zhang, Sen; Anjum, Rana; Squillace, Rachel; Nadworny, Sara; Zhou, Tianjun; Keats, Jeff; Ning, Yaoyu; Wardwell, Scott D; Miller, David; Song, Youngchul; Eichinger, Lindsey; Moran, Lauren; Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Wang, Yihan; Mohemmad, Qurish; Jang, Hyun Gyung; Ye, Emily; Narasimhan, Narayana; Wang, Frank; Miret, Juan; Zhu, Xiaotian; Clackson, Tim; Dalgarno, David; Shakespeare, William C; Rivera, Victor M

2016-11-15

Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK + ) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined. Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK + cell lines, brigatinib inhibited native ALK (IC 50 , 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK + tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK + , crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527-38. ©2016 AACR. ©2016 American Association for Cancer Research.

PSYCHOTHERAPY VERSUS PHARMACOTHERAPY FOR POSTTRAUMATIC STRESS DISORDER: SYSTEMIC REVIEW AND META-ANALYSES TO DETERMINE FIRST-LINE TREATMENTS.

PubMed

Lee, Daniel J; Schnitzlein, Carla W; Wolf, Jonathan P; Vythilingam, Meena; Rasmusson, Ann M; Hoge, Charles W

2016-09-01

Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking. Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment. Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed. © 2016 Wiley Periodicals, Inc.

The Evolution of SINEs and LINEs in the genus Chironomus (Diptera).

PubMed

Papusheva, Ekaterina; Gruhl, Mary C; Berezikov, Eugene; Groudieva, Tatiana; Scherbik, Svetlana V; Martin, Jon; Blinov, Alexander; Bergtrom, Gerald

2004-03-01

Genomic DNA amplification from 51 species of the family Chironomidae shows that most contain relatives of NLRCth1 LINE and CTRT1 SINE retrotransposons first found in Chironomus thummi. More than 300 cloned PCR products were sequenced. The amplified region of the reverse transcriptase gene in the LINEs is intact and highly conserved, suggesting active elements. The SINEs are less conserved, consistent with minimal/no selection after transposition. A mitochondrial gene phylogeny resolves the Chironomus genus into six lineages (Guryev et al. 2001). LINE and SINE phylogenies resolve five of these lineages, indicating their monophyletic origin and vertical inheritance. However, both the LINE and the SINE tree topologies differ from the species phylogeny, resolving the elements into "clusters I-IV" and "cluster V" families. The data suggest a descent of all LINE and SINE subfamilies from two major families. Based on the species phylogeny, a few LINEs and a larger number of SINEs are cladisitically misplaced. Most misbranch with LINEs or SINEs from species with the same families of elements. From sequence comparisons, cladistically misplaced LINEs and several misplaced SINEs arose by convergent base substitutions. More diverged SINEs result from early transposition and some are derived from multiple source SINEs in the same species. SINEs from two species (C. dorsalis, C. pallidivittatus), expected to belong to the clusters I-IV family, branch instead with cluster V family SINEs; apparently both families predate separation of cluster V from clusters I-IV species. Correlation of the distribution of active SINEs and LINEs, as well as similar 3' sequence motifs in CTRT1 and NLRCth1, suggests coevolving retrotransposon pairs in which CTRT1 transposition depends on enzymes active during NLRCth1 LINE mobility.

Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS

PubMed Central

Kalincik, Tomas; Jokubaitis, Vilija; Zhang, Annie; Pellegrini, Fabio; Wiendl, Heinz; Belachew, Shibeshih; Hyde, Robert; Verheul, Freek; Lugaresi, Alessandra; Havrdová, Eva; Horáková, Dana; Grammond, Pierre; Duquette, Pierre; Prat, Alexandre; Iuliano, Gerardo; Terzi, Murat; Izquierdo, Guillermo; Hupperts, Raymond M.M.; Boz, Cavit; Pucci, Eugenio; Giuliani, Giorgio; Sola, Patrizia; Spitaleri, Daniele L.A.; Lechner-Scott, Jeannette; Bergamaschi, Roberto; Grand'Maison, François; Granella, Franco; Kappos, Ludwig; Trojano, Maria; Butzkueven, Helmut

2016-01-01

Abstract Background: We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score–matched cohorts from observational multiple sclerosis registries. Methods: The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. Results: First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28–0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58–0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale–time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. Conclusions: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. Classification of evidence: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA. PMID:27104064

Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer.

PubMed

Marmorino, Federica; Salvatore, Lisa; Barbara, Cecilia; Allegrini, Giacomo; Antonuzzo, Lorenzo; Masi, Gianluca; Loupakis, Fotios; Borelli, Beatrice; Chiara, Silvana; Banzi, Maria Chiara; Miraglio, Emanuela; Amoroso, Domenico; Dargenio, Francesco; Bonetti, Andrea; Martignetti, Angelo; Paris, Myriam; Tomcikova, Daniela; Boni, Luca; Falcone, Alfredo; Cremolini, Chiara

2017-01-01

Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23-0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74-1.64)). Consistent results were reported in overall survival (OS; P=0.075). As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted.

Induction of the high-affinity Na(+)-dependent glutamate transport system XAG- by hypertonic stress in the renal epithelial cell line NBL-1.

PubMed Central

Ferrer-Martinez, A; Felipe, A; Nicholson, B; Casado, J; Pastor-Anglada, M; McGivan, J

1995-01-01

The high-affinity Na(+)-dependent glutamate transport system XAG- is induced (threefold increase in Vmax. with no change in Km) by hypertonicity in the renal epithelial cell line NBL-1. This effect is dependent on protein synthesis and glycosylation and is accompanied by an increase in EAAC1 mRNA levels. Other Na(+)-dependent transport systems in this cell line do not respond to hypertonic stress. In contrast to recent findings [Ruiz-Montasell, Gomez-Angelats, Casado, Felipe, McGivan and Pastor-Anglada (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 9569-9573] showing that increased system A activity after hyperosmotic shock results from induction of a regulatory protein, this is the first demonstration that hypertonicity may increase the expression of the gene for an amino acid transport protein itself. Images Figure 4 PMID:7654212

Establishment of a Transgenic Zebrafish Line for Superficial Skin Ablation and Functional Validation of Apoptosis Modulators In Vivo

PubMed Central

Chen, Chi-Fang; Chu, Che-Yu; Chen, Te-Hao; Lee, Shyh-Jye; Shen, Chia-Ning; Hsiao, Chung-Der

2011-01-01

Background Zebrafish skin is composed of enveloping and basal layers which form a first-line defense system against pathogens. Zebrafish epidermis contains ionocytes and mucous cells that aid secretion of acid/ions or mucous through skin. Previous studies demonstrated that fish skin is extremely sensitive to external stimuli. However, little is known about the molecular mechanisms that modulate skin cell apoptosis in zebrafish. Methodology/Principal Findings This study aimed to create a platform to conduct conditional skin ablation and determine if it is possible to attenuate apoptotic stimuli by overexpressing potential apoptosis modulating genes in the skin of live animals. A transgenic zebrafish line of Tg(krt4:NTR-hKikGR)cy17 (killer line), which can conditionally trigger apoptosis in superficial skin cells, was first established. When the killer line was incubated with the prodrug metrodinazole, the superficial skin displayed extensive apoptosis as judged by detection of massive TUNEL- and active caspase 3-positive signals. Great reductions in NTR-hKikGR+ fluorescent signals accompanied epidermal cell apoptosis. This indicated that NTR-hKikGR+ signal fluorescence can be utilized to evaluate apoptotic events in vivo. After removal of metrodinazole, the skin integrity progressively recovered and NTR-hKikGR+ fluorescent signals gradually restored. In contrast, either crossing the killer line with testing lines or transiently injecting the killer line with testing vectors that expressed human constitutive active Akt1, mouse constitutive active Stat3, or HPV16 E6 element displayed apoptosis-resistant phenotypes to cytotoxic metrodinazole as judged by the loss of reduction in NTR-hKikGR+ fluorescent signaling. Conclusion/Significance The killer/testing line binary system established in the current study demonstrates a nitroreductase/metrodinazole system that can be utilized to conditionally perform skin ablation in a real-time manner, and provides a valuable tool to visualize and quantify the anti-apoptotic potential of interesting target genes in vivo. The current work identifies a potential use for transgenic zebrafish as a high-throughput platform to validate potential apoptosis modulators in vivo. PMID:21655190

DISCOVERY OF RELATIVISTIC OUTFLOW IN THE SEYFERT GALAXY Ark 564

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, A.; Mathur, S.; Krongold, Y.

2013-07-20

We present Chandra High Energy Transmission Grating Spectra of the narrow-line Seyfert-1 galaxy Ark 564. The spectrum shows numerous absorption lines which are well modeled with low-velocity outflow components usually observed in Seyfert galaxies. There are, however, some residual absorption lines which are not accounted for by low-velocity outflows. Here, we present identifications of the strongest lines as K{alpha} transitions of O VII (two lines) and O VI at outflow velocities of {approx}0.1c. These lines are detected at 6.9{sigma}, 6.2{sigma}, and 4.7{sigma}, respectively, and cannot be due to chance statistical fluctuations. Photoionization models with ultra-high velocity components improve the spectralmore » fit significantly, providing further support for the presence of relativistic outflow in this source. Without knowing the location of the absorber, its mass and energy outflow rates cannot be well constrained; we find E-dot (outflow)/L{sub bol} lower limit of {>=}0.006% assuming a bi-conical wind geometry. This is the first time that absorption lines with ultra-high velocities are unambiguously detected in the soft X-ray band. The presence of outflows with relativistic velocities in active galactic nuclei (AGNs) with Seyfert-type luminosities is hard to understand and provides valuable constraints to models of AGN outflows. Radiation pressure is unlikely to be the driving mechanism for such outflows and magnetohydrodynamic may be involved.« less

A survey of X-ray line emission from the supernova remnant Puppis A

NASA Technical Reports Server (NTRS)

Winkler, P. F.; Clark, G. W.; Markert, T. H.; Kalata, K.; Schnopper, H. W.; Canizares, C. R.

1981-01-01

Initial results from the first high-resolution study of the X-ray spectrum of a supernova remnant are reported. The spectrum of Puppis A between 500 and 1100 eV has been surveyed with the Focal Plane Crystal Spectrometer on the Einstein Observatory and the flux in eight lines and three line blends from various transitions of highly ionized nitrogen, oxygen, neon, and iron has been measured. The spectrum resembles that of active regions in the solar corona, but the neon lines seem enhanced relative to the oxygen lines, and both are enhanced relative to iron. The observed line strengths serve as diagnostics of the physical conditions in the emitting material. Without a priori assumptions, the ionization temperatures of O (2.2 million K) and Ne (4 million K) and the dominant ionization stage of Fe (Fe XVII) are deduced. Isothermal equilibrium plasmas or homogeneous nonequilibrium plasmas as descriptions of the source are ruled out. It is concluded that Puppis A must contain plasma over a temperature range 2-million to 5-million K with an intervening absorption column of 4 x 10 to the 21st/sq cm.

First Results from Faint Infrared Grism Survey (Figs): First Simultaneous Detection of Ly Alpha Emission and Lyman Break From a Galaxy at Z =7.51

NASA Technical Reports Server (NTRS)

Tilvi, V.; Pirzkal, N.; Malhotra, S.; Finkelstein, S. L.; Rhoads, J. E.; Windhorst, R.; Grogin, N. A.; Koekemoer, A.; Zakamska, N. L.; Ryan, R.;

The Mechanosensory Lateral Line System Mediates Activation of Socially-Relevant Brain Regions during Territorial Interactions.

PubMed

Butler, Julie M; Maruska, Karen P

2016-01-01

Animals use multiple senses during social interactions and must integrate this information in the brain to make context-dependent behavioral decisions. For fishes, the largest group of vertebrates, the mechanosensory lateral line system provides crucial hydrodynamic information for survival behaviors, but little is known about its function in social communication. Our previous work using the African cichlid fish, Astatotilapia burtoni, provided the first empirical evidence that fish use their lateral line system to detect water movements from conspecifics for mutual assessment and behavioral choices. It is unknown, however, where this socially-relevant mechanosensory information is processed in the brain to elicit adaptive behavioral responses. To examine for the first time in any fish species which brain regions receive contextual mechanosensory information, we quantified expression of the immediate early gene cfos as a proxy for neural activation in sensory and socially-relevant brain nuclei from lateral line-intact and -ablated fish following territorial interactions. Our in situ hybridization results indicate that in addition to known lateral line processing regions, socially-relevant mechanosensory information is processed in the ATn (ventromedial hypothalamus homolog), Dl (putative hippocampus homolog), and Vs (putative medial extended amygdala homolog). In addition, we identified a functional network within the conserved social decision-making network (SDMN) whose co-activity corresponds with mutual assessment and behavioral choice. Lateral line-intact and -ablated fight winners had different patterns of co-activity of these function networks and group identity could be determined solely by activation patterns, indicating the importance of mechanoreception to co-activity of the SDMN. These data show for the first time that the mechanosensory lateral line system provides relevant information to conserved decision-making centers of the brain during territorial interactions to mediate crucial behavioral choices such as whether or not to engage in a territorial fight. To our knowledge, this is also the first evidence of a subpallial nucleus receiving mechanosensory input, providing important information for elucidating homologies of decision-making circuits across vertebrates. These novel results highlight the importance of considering multimodal sensory input in mediating context-appropriate behaviors that will provide broad insights on the evolution of decision-making networks across all taxa.

The Second Flight of the Sunrise Balloon-borne Solar Observatory: Overview of Instrument Updates, the Flight, the Data, and First Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Solanki, S. K.; Riethmüller, T. L.; Barthol, P.

The Sunrise balloon-borne solar observatory, consisting of a 1 m aperture telescope that provides a stabilized image to a UV filter imager and an imaging vector polarimeter, carried out its second science flight in 2013 June. It provided observations of parts of active regions at high spatial resolution, including the first high-resolution images in the Mg ii k line. The obtained data are of very high quality, with the best UV images reaching the diffraction limit of the telescope at 3000 Å after Multi-Frame Blind Deconvolution reconstruction accounting for phase-diversity information. Here a brief update is given of the instruments andmore » the data reduction techniques, which includes an inversion of the polarimetric data. Mainly those aspects that evolved compared with the first flight are described. A tabular overview of the observations is given. In addition, an example time series of a part of the emerging active region NOAA AR 11768 observed relatively close to disk center is described and discussed in some detail. The observations cover the pores in the trailing polarity of the active region, as well as the polarity inversion line where flux emergence was ongoing and a small flare-like brightening occurred in the course of the time series. The pores are found to contain magnetic field strengths ranging up to 2500 G, and while large pores are clearly darker and cooler than the quiet Sun in all layers of the photosphere, the temperature and brightness of small pores approach or even exceed those of the quiet Sun in the upper photosphere.« less

Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality.

PubMed

Yang, William C; Lu, Jiuyi; Kwiatkowski, Chris; Yuan, Hang; Kshirsagar, Rashmi; Ryll, Thomas; Huang, Yao-Ming

2014-01-01

Volumetric productivity and product quality are two key performance indicators for any biopharmaceutical cell culture process. In this work, we showed proof-of-concept for improving both through the use of alternating tangential flow perfusion seed cultures coupled with high-seed fed-batch production cultures. First, we optimized the perfusion N-1 stage, the seed train bioreactor stage immediately prior to the production bioreactor stage, to minimize the consumption of perfusion media for one CHO cell line and then successfully applied the optimized perfusion process to a different CHO cell line. Exponential growth was observed throughout the N-1 duration, reaching >40 × 10(6) vc/mL at the end of the perfusion N-1 stage. The cultures were subsequently split into high-seed (10 × 10(6) vc/mL) fed-batch production cultures. This strategy significantly shortened the culture duration. The high-seed fed-batch production processes for cell lines A and B reached 5 g/L titer in 12 days, while their respective low-seed processes reached the same titer in 17 days. The shortened production culture duration potentially generates a 30% increase in manufacturing capacity while yielding comparable product quality. When perfusion N-1 and high-seed fed-batch production were applied to cell line C, higher levels of the active protein were obtained, compared to the low-seed process. This, combined with correspondingly lower levels of the inactive species, can enhance the overall process yield for the active species. Using three different CHO cell lines, we showed that perfusion seed cultures can optimize capacity utilization and improve process efficiency by increasing volumetric productivity while maintaining or improving product quality. © 2014 American Institute of Chemical Engineers.

An effective selection method for low-mass active black holes and first spectroscopic identification

NASA Astrophysics Data System (ADS)

Morokuma, Tomoki; Tominaga, Nozomu; Tanaka, Masaomi; Yasuda, Naoki; Furusawa, Hisanori; Taniguchi, Yuki; Kato, Takahiro; Jiang, Ji-an; Nagao, Tohru; Kuncarayakti, Hanindyo; Morokuma-Matsui, Kana; Ikeda, Hiroyuki; Blinnikov, Sergei; Nomoto, Ken'ichi; Kokubo, Mitsuru; Doi, Mamoru

2016-06-01

We present a new method for effectively selecting objects which may be low-mass active black holes (BHs) at galaxy centers using high-cadence optical imaging data, and our first spectroscopic identification of an active 2.7 × 106 M⊙ BH at z = 0.164. This active BH was originally selected due to its rapid optical variability, from a few hours to a day, based on Subaru Hyper Suprime-Cam g-band imaging data taken with a 1 hr cadence. Broad and narrow Hα lines and many other emission ones are detected in our optical spectra taken with Subaru FOCAS, and the BH mass is measured via the broad Hα emission line width (1880 km s-1) and luminosity (4.2 × 1040 erg s-1) after careful correction to the atmospheric absorption around 7580-7720 Å. We measure the Eddington ratio and find it to be as low as 0.05, considerably smaller than those in a previous SDSS sample with similar BH mass and redshift, which indicates one of the special potentials of our Subaru survey. The g - r color and morphology of the extended component indicate that the host galaxy is a star-forming galaxy. We also show the effectiveness of our variability selection for low-mass active BHs.

Double-peaked broad line emission from the LINER nucleus of NGC 1097

NASA Technical Reports Server (NTRS)

Storchi-Bergmann, Thaisa; Baldwin, Jack A.; Wilson, Andrew S.

1993-01-01

We report the recent appearance of a very broad component in the H-alpha and H-beta emission lines of the weakly active nucleus of the Sersic-Pastoriza galaxy NGC 1097. The FWZI of the broad component is about 21,000 km/s, and its profile is double-peaked; the presence of a blue, featureless continuum in the nucleus is also suggested. The broad component was first observed in H-alpha in November 2, 1991, and confirmed 11 months later. The H-alpha profile and flux did not change in this time interval. Comparison with previously published spectral data indicates that the broad lines have only recently appeared. Together with the relatively high X-ray luminosity and the compact nuclear radio source, our results characterize the presence of a Seyfert 1 nucleus in a galaxy which had previously shown only LINER characteristics. Obscuring material along our line of sight to the nucleus appears to have recently cleared, permitting a direct view of the active nucleus. We discuss two possible structures for the broad line region, biconical outflow and an accretion disk, that could give rise to the observed profile.

Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves.

PubMed

Malek, Sri Nurestri Abdul; Shin, Sim Kae; Wahab, Norhanom Abdul; Yaacob, Hashim

2009-05-06

Dihydroactinidiolide (1) and a mixture of sterols [campesterol (2), stigmasterol (3) and beta-sitosterol (4)], together with the previously isolated individual compounds beta-sitosterol (4), 2,4-di-tert-butylphenol (5), alpha-tocopherol (6), phytol (7) were isolated from the active ethyl acetate fraction of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Cytotoxic activities of the above mentioned compounds against five human carcinoma cell lines, namely the human nasopharyngeal epidermoid carcinoma cell line (KB), human cervical carcinoma cell line (CasKi), human colon carcinoma cell line (HCT 116), human hormone-dependent breast carcinoma cell line (MCF7) and human lung carcinoma cell line (A549); and non-cancer human fibroblast cell line (MRC-5) were investigated. Compound 5 possessed very remarkable cytotoxic activity against KB cells, with an IC(50 )value of 0.81microg/mL. This is the first report on the cytotoxic activities of the compounds isolated from Pereskia bleo.

The Palomar Testbed Interferometer

NASA Technical Reports Server (NTRS)

Colavita, M. M.; Wallace, J. K.; Hines, B. E.; Gursel, Y.; Malbet, F.; Palmer, D. L.; Pan, X. P.; Shao, M.; Yu, J. W.; Boden, A. F.

1999-01-01

The Palomar Testbed Interferometer (PTI) is a long-baseline infrared interferometer located at Palomar Observatory, California. It was built as a testbed for interferometric techniques applicable to the Keck Interferometer. First fringes were obtained in 1995 July. PTI implements a dual-star architecture, tracking two stars simultaneously for phase referencing and narrow-angle astrometry. The three fixed 40 cm apertures can be combined pairwise to provide baselines to 110 m. The interferometer actively tracks the white-light fringe using an array detector at 2.2 microns and active delay lines with a range of +/-38 m. Laser metrology of the delay lines allows for servo control, and laser metrology of the complete optical path enables narrow-angle astrometric measurements. The instrument is highly automated, using a multiprocessing computer system for instrument control and sequencing.

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

PubMed Central

Rizo, Walace Fraga; Ferreira, Luis Eduardo; Colnaghi, Vanessa; Martins, Juliana Simões; Franchi, Leonardo Pereira; Takahashi, Catarina Satie; Beleboni, Rene Oliveira; Marins, Mozart; Pereira, Paulo Sérgio; Fachin, Ana Lúcia

2013-01-01

Cancer has become a major public health problem worldwide and the number of deaths due to this disease is increasing almost exponentially. In the constant search for new treatments, natural products of plant origin have provided a variety of new compounds to be explored as antitumor agents. Tabernaemontana catharinensis is a medicinal plant that produces alkaloids with expressive antitumor activity, such as heyneanine, coronaridine and voacangine. The aim of present study was firstly to screen the cytotoxic activity of the indole alkaloids heyneanine, coronaridine and voacangine against HeLa (human cervix tumor), 3T3 (normal mouse embryo fibroblasts), Hep-2 (human laryngeal epithelial carcinoma) and B-16 (murine skin) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); and secondly to analyze the apoptotic activity, cell membrane damage and genotoxicity of the compound that showed the best cytotoxic activity against the tumor cell lines tested. Coronaridine was the one that exhibited greater cytotoxic activity in the laryngeal carcinoma cell line Hep-2 (IC50 = 54.47 μg/mL) than the other alkaloids tested (voacangine IC50 = 159.33 g/mL, and heyneanine IC50 = 689.45 μg/mL). Coronaridine induced apoptosis in cell lines 3T3 and Hep-2, even at high concentrations. The evaluation of genotoxicity by comet assay showed further that coronaridine caused minimal DNA damage in the Hep-2 tumor cell line, and the LDH test showed that it did not affect the plasma membrane. These results suggest that further investigation of coronaridine as an antitumor agent has merit. PMID:23569415

Socioeconomic position and survival after lung cancer: Influence of stage, treatment and comorbidity among Danish patients with lung cancer diagnosed in 2004-2010.

PubMed

Dalton, Susanne O; Steding-Jessen, Marianne; Jakobsen, Erik; Mellemgaard, Anders; Østerlind, Kell; Schüz, Joachim; Johansen, Christoffer

2015-05-01

To address social inequality in survival after lung cancer, it is important to consider how socioeconomic position (SEP) influences prognosis. We investigated whether SEP influenced receipt of first-line treatment and whether socioeconomic differences in survival could be explained by differences in stage, treatment and comorbidity. In the Danish Lung Cancer Register, we identified 13 045 patients with lung cancer diagnosed in 2004-2010, with information on stage, histology, performance status and first-line treatment. We obtained age, gender, vital status, comorbid conditions and socioeconomic information (education, income and cohabitation status) from nationwide population-based registers. Associations between SEP and receipt of first-line treatment were analysed in multivariate logistic regression models and those with overall mortality in Cox regression models with stepwise inclusion of possible mediators. For both low- and high-stage lung cancer, adjusted ORs for first-line treatment were reduced in patients with short education and low income, although the OR for education did not reach statistical significance in men with high-stage disease. Patients with high-stage disease who lived alone were less likely to receive first-line treatment. The socioeconomic difference in overall survival was partly explained by differences in stage, treatment and comorbidity, although some differences remained after adjustment. Among patients with high-stage disease, the hazard ratio (HR) for death of those with low income was 1.12 (95% CI 1.05-1.19) in comparison with those with high income. Among patients with low-stage disease, those who lived alone had a 14% higher risk for dying (95% CI 1.05-1.25) than those who lived with a partner. The differences in risk for death by SEP were greatest in the first six months after diagnosis. Socioeconomic differences in survival after lung cancer are partly explained by social inequality in stage, first-line treatment and comorbidity. Efforts should be made to improve early diagnosis and adherence to first-line treatment recommendations among disadvantaged lung cancer patients.

Preparing for Evaluation: Lessons from the Evaluability Assessment of the Teagle Foundation's College-Community Connections Initiative. Report

ERIC Educational Resources Information Center

Black, Kristin

2016-01-01

Funders, policymakers, and program leaders recognize the value of high-quality evidence. To make good use of a program evaluation, initiatives must contend with a set of fundamental questions first. Some of these are about the initiative itself: What outcomes does it seek to affect? Are daily activities in line with long-term goals? Others are…

Two-Dimensional Electronic Spectroscopy of Benzene, Phenol, and Their Dimer: An Efficient First-Principles Simulation Protocol.

PubMed

Nenov, Artur; Mukamel, Shaul; Garavelli, Marco; Rivalta, Ivan

2015-08-11

First-principles simulations of two-dimensional electronic spectroscopy in the ultraviolet region (2DUV) require computationally demanding multiconfigurational approaches that can resolve doubly excited and charge transfer states, the spectroscopic fingerprints of coupled UV-active chromophores. Here, we propose an efficient approach to reduce the computational cost of accurate simulations of 2DUV spectra of benzene, phenol, and their dimer (i.e., the minimal models for studying electronic coupling of UV-chromophores in proteins). We first establish the multiconfigurational recipe with the highest accuracy by comparison with experimental data, providing reference gas-phase transition energies and dipole moments that can be used to construct exciton Hamiltonians involving high-lying excited states. We show that by reducing the active spaces and the number of configuration state functions within restricted active space schemes, the computational cost can be significantly decreased without loss of accuracy in predicting 2DUV spectra. The proposed recipe has been successfully tested on a realistic model proteic system in water. Accounting for line broadening due to thermal and solvent-induced fluctuations allows for direct comparison with experiments.

Glaciation as a destructive and constructive control on mountain building.

PubMed

Thomson, Stuart N; Brandon, Mark T; Tomkin, Jonathan H; Reiners, Peter W; Vásquez, Cristián; Wilson, Nathaniel J

2010-09-16

Theoretical analysis predicts that enhanced erosion related to late Cenozoic global cooling can act as a first-order influence on the internal dynamics of mountain building, leading to a reduction in orogen width and height. The strongest response is predicted in orogens dominated by highly efficient alpine glacial erosion, producing a characteristic pattern of enhanced erosion on the windward flank of the orogen and maximum elevation controlled by glacier equilibrium line altitude, where long-term glacier mass gain equals mass loss. However, acquiring definitive field evidence of an active tectonic response to global climate cooling has been elusive. Here we present an extensive new low-temperature thermochronologic data set from the Patagonian Andes, a high-latitude active orogen with a well-documented late Cenozoic tectonic, climatic and glacial history. Data from 38° S to 49° S record a marked acceleration in erosion 7 to 5 Myr ago coeval with the onset of major Patagonian glaciation and retreat of deformation from the easternmost thrust front. The highest rates and magnitudes of erosion are restricted to the glacial equilibrium line altitude on the windward western flank of the orogen, as predicted in models of glaciated critical taper orogens where erosion rate is a function of ice sliding velocity. In contrast, towards higher latitudes (49° S to 56° S) a transition to older bedrock cooling ages signifies much reduced late Cenozoic erosion despite dominantly glacial conditions here since the latest Miocene. The increased height of the orogenic divide at these latitudes (well above the equilibrium line altitude) leads us to conclude that the southernmost Patagonian Andes represent the first recognized example of regional glacial protection of an active orogen from erosion, leading to constructive growth in orogen height and width.

[Antihistamines for the treatment of urticaria in Mexico].

PubMed

Larenas-Linnemann, Désirée; Sánchez-Borges, Mario; Del Río-Navarro, Blanca Estela; Alonzo-Romero Pareyón, María De Lourdes; Maldonado-García, César Alfonso; Mendoza-López, Enrique; Ortega-Martell, José Antonio; Sienra-Monge, Juan José Luis; Medina-Ávalos, Miguel Alejandro; Rojo-Gutiérrez, María Isabel; Beirana-Palencia, Angélica María; Vargas-Correa, Jorge Bernardo; Báez-Loyola, Carlos; Ramírez-Segura, Ruth Ivonne Mireya; Guzmán-Perea, María Graciela

2015-01-01

There are four types of histamine receptors. Allergic symptoms, especially those in rhinoconjunctivitis and urticaria, are mainly caused by activation of histamine receptor 1 (H1). Consequently, oral H1-antihistamines form and integral part of the treatment of these diseases. Antihistamines are inverse agonists that stabilize the non-active configuration of the histamine receptor. First generation H1-antihistamines cause a variety of adverse effects via several mechanisms: sedation (accumulation in the central nervous system), dry mouth, urinary retention, weight gain (low selectivity: stimulation of serotonin/muscarinic/alpha-adrenergic receptors) and drug interactions (substrate of CYP450-3A4). Generally second generation H1-antihistamines have a better safety profile. New guidelines on allergic rhinitis and urticaria recommend second generation H1-antihistamines as first line drugs, with -if necessary- four-times updosing to obtain control in urticaria. The enhanced efficacy of quadruple doses in urticaria, while maintaining a good safety profile, has been shown for bilastine, desloratadine and levocetirizine (rupatadine). For ebastine and fexofenadine only the safety of quadruple doses has been shown till now. Extreme precaution should be taken with astemizol and terfenadine that never should be up-dosed, as high serum concentrations can cause potentially fatal ventricular tachycardia. First generation antihistamines are not recommended as first line treatment and updosing is not safe.

Physically active rats lose more weight during calorie restriction.

PubMed

Smyers, Mark E; Bachir, Kailey Z; Britton, Steven L; Koch, Lauren G; Novak, Colleen M

2015-02-01

Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity. Copyright © 2014 Elsevier Inc. All rights reserved.

Physically Active Rats Lose More Weight during Calorie Restriction

PubMed Central

Smyers, Mark E.; Bachir, Kailey Z.; Britton, Steven L.; Koch, Lauren G.; Novak, Colleen M.

2014-01-01

Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity. PMID:25449411

Synthesis, characterization, cytotoxic and antitubercular activities of new gold(I) and gold(III) complexes containing ligands derived from carbohydrates.

PubMed

Chaves, Joana Darc Souza; Damasceno, Jaqueline Lopes; Paula, Marcela Cristina Ferreira; de Oliveira, Pollyanna Francielli; Azevedo, Gustavo Chevitarese; Matos, Renato Camargo; Lourenço, Maria Cristina S; Tavares, Denise Crispim; Silva, Heveline; Fontes, Ana Paula Soares; de Almeida, Mauro Vieira

2015-10-01

Novel gold(I) and gold(III) complexes containing derivatives of D-galactose, D-ribose and D-glucono-1,5-lactone as ligands were synthesized and characterized by IR, (1)H, and (13)C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in μg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.

High speed transient sampler

DOEpatents

McEwan, T.E.

1995-11-28

A high speed sampler comprises a meandered sample transmission line for transmitting an input signal, a straight strobe transmission line for transmitting a strobe signal, and a plurality of sampling gates along the transmission lines. The sampling gates comprise a four terminal diode bridge having a first strobe resistor connected from a first terminal of the bridge to the positive strobe line, a second strobe resistor coupled from the third terminal of the bridge to the negative strobe line, a tap connected to the second terminal of the bridge and to the sample transmission line, and a sample holding capacitor connected to the fourth terminal of the bridge. The resistance of the first and second strobe resistors is much higher than the signal transmission line impedance in the preferred system. This results in a sampling gate which applies a very small load on the sample transmission line and on the strobe generator. The sample holding capacitor is implemented using a smaller capacitor and a larger capacitor isolated from the smaller capacitor by resistance. The high speed sampler of the present invention is also characterized by other optimizations, including transmission line tap compensation, stepped impedance strobe line, a multi-layer physical layout, and unique strobe generator design. A plurality of banks of such samplers are controlled for concatenated or interleaved sample intervals to achieve long sample lengths or short sample spacing. 17 figs.

High speed transient sampler

DOEpatents

McEwan, Thomas E.

1995-01-01

A high speed sampler comprises a meandered sample transmission line for transmitting an input signal, a straight strobe transmission line for transmitting a strobe signal, and a plurality of sampling gates along the transmission lines. The sampling gates comprise a four terminal diode bridge having a first strobe resistor connected from a first terminal of the bridge to the positive strobe line, a second strobe resistor coupled from the third terminal of the bridge to the negative strobe line, a tap connected to the second terminal of the bridge and to the sample transmission line, and a sample holding capacitor connected to the fourth terminal of the bridge. The resistance of the first and second strobe resistors is much higher than the signal transmission line impedance in the preferred system. This results in a sampling gate which applies a very small load on the sample transmission line and on the strobe generator. The sample holding capacitor is implemented using a smaller capacitor and a larger capacitor isolated from the smaller capacitor by resistance. The high speed sampler of the present invention is also characterized by other optimizations, including transmission line tap compensation, stepped impedance strobe line, a multi-layer physical layout, and unique strobe generator design. A plurality of banks of such samplers are controlled for concatenated or interleaved sample intervals to achieve long sample lengths or short sample spacing.

Motorized Activity on Legacy Seismic Lines: A Predictive Modeling Approach to Prioritize Restoration Efforts.

PubMed

Hornseth, M L; Pigeon, K E; MacNearney, D; Larsen, T A; Stenhouse, G; Cranston, J; Finnegan, L

2018-05-11

Natural regeneration of seismic lines, cleared for hydrocarbon exploration, is slow and often hindered by vegetation damage, soil compaction, and motorized human activity. There is an extensive network of seismic lines in western Canada which is known to impact forest ecosystems, and seismic lines have been linked to declines in woodland caribou (Rangifer tarandus caribou). Seismic line restoration is costly, but necessary for caribou conservation to reduce cumulative disturbance. Understanding where motorized activity may be impeding regeneration of seismic lines will aid in prioritizing restoration. Our study area in west-central Alberta, encompassed five caribou ranges where restoration is required under federal species at risk recovery strategies, hence prioritizing seismic lines for restoration is of immediate conservation value. To understand patterns of motorized activity on seismic lines, we evaluated five a priori hypotheses using a predictive modeling framework and Geographic Information System variables across three landscapes in the foothills and northern boreal regions of Alberta. In the northern boreal landscape, motorized activity was most common in dry areas with a large industrial footprint. In highly disturbed areas of the foothills, motorized activity on seismic lines increased with low vegetation heights, relatively dry soils, and further from forest cutblocks, while in less disturbed areas of the foothills, motorized activity on seismic lines decreased proportional to seismic line density, slope steepness, and white-tailed deer abundance, and increased proportional with distance to roads. We generated predictive maps of high motorized activity, identifying 21,777 km of seismic lines where active restoration could expedite forest regeneration.

The emerging planetary nebula CRL 618 and its unsettled central star(s)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balick, B.; Riera, A.; Raga, A.

We report deep long-slit emission-line spectra, the line flux ratios, and Doppler profile shapes of various bright optical lines. The low-ionization lines (primarily [N I], [O I], [S II], and [N II]) originate in shocked knots, as reported by many previous observers. Dust-scattered lines of higher ionization are seen throughout the lobes but do not peak in the knots. Our analysis of these line profiles and the readily discernible stellar continuum shows that (1) the central star is an active symbiotic (whose spectrum resembles the central stars of highly bipolar and young planetary nebulae such as M2-9 and Hen2-437) whosemore » compact companion shows a WC8-type spectrum, (2) extended nebular lines of [O III] and He I originate in the heavily obscured nuclear H II region, and (3) the Balmer lines observed throughout the lobes are dominated by reflected Hα emission from the symbiotic star. Comparing our line ratios with those observed historically shows that (1) the [O III]/Hβ and He I/Hβ ratios have been steadily rising by large amounts throughout the nebula, (2) the Hα/Hβ ratio is steadily decreasing while Hγ/Hβ remains nearly constant, and (3) the low-ionization line ratios formed in the shocked knots have been in decline in different ways at various locations. We show that the first two of these results might be expected if the symbiotic central star has been active and if its bright Hα line has faded significantly in the past 20 years.« less

Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer.

PubMed

Rossi, Antonio; Muscarella, Lucia Anna; Di Micco, Concetta; Carbonelli, Cristiano; D'alessandro, Vito; Notarangelo, Stefano; Palomba, Giuseppe; Sanpaolo, Gerardo; Taurchini, Marco; Graziano, Paolo; Maiello, Evaristo

2017-12-01

First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9-13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice. Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken. Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.

Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine.

PubMed

Sandmaier, B M; Oparin, D V; Holmberg, L A; Reddish, M A; MacLean, G D; Longenecker, B M

1999-01-01

Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen.

Different responses of Drosophila subobscura isofemale lines to extremely low frequency magnetic field (50 Hz, 0.5 mT): fitness components and locomotor activity.

PubMed

Zmejkoski, Danica; Petković, Branka; Pavković-Lučić, Sofija; Prolić, Zlatko; Anđelković, Marko; Savić, Tatjana

2017-05-01

Extremely low frequency (ELF) magnetic fields as essential ecological factors may induce specific responses in genetically different lines. The object of this study was to investigate the impact of the ELF magnetic field on fitness components and locomotor activity of five Drosophila subobscura isofemale (IF) lines. Each D. subobscura IF line, arbitrarily named: B16/1, B24/4, B39/1, B57/2 and B69/5, was maintained in five full-sib inbreeding generations. Their genetic structures were defined based on the mitochondrial DNA variability. Egg-first instar larvae and 1-day-old flies were exposed to an ELF magnetic field (50 Hz, 0.5 mT, 48 h) and thereafter, fitness components and locomotor activity of males and females in an open field test were observed for each selected IF line, respectively. Exposure of egg-first instar larvae to an ELF magnetic field shortened developmental time, and did not affect the viability and sex ratio of D. subobscura IF lines. Exposure of 1-day-old males and females IF lines B16/1 and B24/4 to an ELF magnetic field significantly decreased their locomotor activity and this effect lasted longer in females than males. These results indicate various responses of D. subobscura IF lines to the applied ELF magnetic field depending on their genetic background.

An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab.

PubMed

Lombardi, Giuseppe; Farina, Patrizia; Della Puppa, Alessandro; Cecchin, Diego; Pambuku, Ardi; Bellu, Luisa; Zagonel, Vittorina

2014-01-01

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab

PubMed Central

Lombardi, Giuseppe; Farina, Patrizia; Della Puppa, Alessandro; Cecchin, Diego; Pambuku, Ardi; Bellu, Luisa; Zagonel, Vittorina

2014-01-01

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas. PMID:24800248

Solvent-resistant sol-gel polydimethyldiphenylsiloxane coating for on-line hyphenation of capillary microextraction with high-performance liquid chromatography.

PubMed

Segro, Scott S; Malik, Abdul

2008-09-26

A sol-gel polydimethyldiphenylsiloxane (PDMDPS) coating was developed for capillary microextraction on-line hyphenated with high-performance liquid chromatography (HPLC). This coating was created using methyltrimethoxysilane (MTMS) as the sol-gel precursor and di-hydroxy-terminated PDMDPS as the sol-gel active polymer. The methyl and phenyl groups on the sol-gel active polymer and the methyl groups on the sol-gel precursor ultimately turned into pendant groups providing the ability to extract non-polar analytes. A 40-cm segment of 0.25 mm I.D. fused silica capillary containing the sol-gel PDMDPS coating was installed as an external sampling loop in an HPLC injection port. Aqueous samples containing polycyclic aromatic hydrocarbons (PAHs), aromatic compounds, ketones, and aldehydes were passed through this capillary wherein the analytes were extracted by the sol-gel coating. The extracted analytes were then transferred to the HPLC column using isocratic or gradient elution with an acetonitrile/water mobile phase. This capillary demonstrated excellent extraction capability for non-polar (e.g., polycyclic aromatic hydrocarbons and aromatic compounds) as well as moderately polar compounds, such as aromatic amines, ketones, and aldehydes. The test results indicate that PDMDPS can be successfully immobilized into a sol-gel network and that the resulting solvent-resistant sol-gel organic-inorganic hybrid coating can be effectively used for on-line hyphenation of capillary microextraction with high-performance liquid chromatography. The test results also indicate that the sol-gel PDMDPS coated capillary is resistant to high-temperature solvents, making it suitable for applications in high-temperature HPLC. To the best of our knowledge, this is the first report on the creation of a silica-based sol-gel PDMDPS coating used in capillary microextraction on-line hyphenated to HPLC.

Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer

PubMed Central

Marmorino, Federica; Salvatore, Lisa; Barbara, Cecilia; Allegrini, Giacomo; Antonuzzo, Lorenzo; Masi, Gianluca; Loupakis, Fotios; Borelli, Beatrice; Chiara, Silvana; Banzi, Maria Chiara; Miraglio, Emanuela; Amoroso, Domenico; Dargenio, Francesco; Bonetti, Andrea; Martignetti, Angelo; Paris, Myriam; Tomcikova, Daniela; Boni, Luca; Falcone, Alfredo; Cremolini, Chiara

2017-01-01

Background: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. Methods: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. Results: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23–0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74–1.64)). Consistent results were reported in overall survival (OS; P=0.075). Conclusions: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted. PMID:28081548

Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy.

PubMed

Ishihara, Hiroki; Takagi, Toshio; Kondo, Tsunenori; Tachibana, Hidekazu; Yoshida, Kazuhiko; Omae, Kenji; Iizuka, Junpei; Kobayashi, Hirohito; Tanabe, Kazunari

2018-06-01

The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited. The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy. In addition, dose-limiting toxicities (DLTs) were evaluated. Twenty-two of 48 patients (45.8%) received third-line therapy, and TKI and mammalian target of rapamycin inhibitor were each administered in 11 patients (50%). Patients with third-line therapy had significantly longer median OS after first-line therapy (26.6 vs. 14.6 months, p = 0.0010) and second-line therapy (18.2 vs. 7.4 months, p < 0.0001) compared to those without third-line therapy. Multivariate analysis showed that the use of third-line therapy following second-line therapy was an independent prognosticator for longer OS (hazard ratio 0.29, 95% confidence interval 0.14-0.58, p = 0.0005). The median progression-free survival and OS after third-line therapy was 2.76 and 8.71 months, respectively. Although a high frequency of DLTs was observed (n = 10, 45.5%), the frequencies were similar among the sequential therapies. Third-line therapy has a beneficial therapeutic effect in patients with mRCC that is resistant to previous therapies. However, there is a need to evaluate in detail the high frequency of adverse events, including DLTs.

Hydrogen Masers. I. Theory and Prospects

NASA Astrophysics Data System (ADS)

Strelnitski, Vladimir S.; Ponomarev, Victor O.; Smith, Howard A.

1996-10-01

The discovery of the first high-gain hydrogen recombination line (HRL) maser in the millimeter/ submillimeter spectrum of the emission-line star MWC 349A requires an expansion of current paradigms about HRLs. In this paper we reexamine the problem of non-LTE populations in recombining hydrogen and specify the conditions necessary for high-gain masing and lasing in HRLs. To do so, we use the extensive new results on hydrogen level populations produced by Storey & Hummer and our calculations for the net (that is, line plus continuum) absorption coefficient for HRLs. We present results for the α- and β-lines whose principal quantum numbers n are between five and 100, for gas whose electron number density 3 ≤ log Ne(cm-3) ≤ 11, at two electron temperatures, Te = 5000 and 10,000 K. We show that the unsaturated maser gain in an HRL is a sharp function of Ne, and thus to achieve high-gain masing, each line requires a sufficiently extended region over which the density is rather closely specified. Saturation of masing recombination lines is a critical consideration. We derive a simple equation for estimating the degree of saturation from the observed flux density and the interferometric and/or model information about the amplification path length, avoiding the vague issue of the solid angle of masing. We also present a qualitative way to approach the effects of saturation on adjacent emission lines, although the detailed modeling is highly case-specific. We draw attention to another non-LTE phenomenon active in hydrogen: the overcooling of populations. This occurs for HRLs with n ≲ 20, in gas where Ne ≲ 105 cm-3. Observationally, the HRL over- cooling might manifest itself as an anomalously weak emission recombination line, or as a "dasar," that is, an anomalously strong absorption line. In the simplest case of a homogeneous H II region, the absorption can be observed on the proper free-free continuum of the region, if some conditions for the line or/and continuum optical depths are satisfied. We briefly discuss the prospects of detecting hydrogen masers, lasers, and dasars in several classes of Galactic and extragalactic objects, including compact H II regions, Be or Wolf-Rayet stars, starburst galaxies, and active galactic nuclei.

[Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].

PubMed

Bernard-Tessier, Alice; Bonnet, Clément; Lavaud, Pernelle; Gizzi, Marco; Loriot, Yohann; Massard, Christophe

2018-02-01

Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq ® ) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

In vitro anticancer activity of Betulinic acid and derivatives thereof on equine melanoma cell lines from grey horses and in vivo safety assessment of the compound NVX-207 in two horses.

PubMed

Liebscher, G; Vanchangiri, K; Mueller, Th; Feige, K; Cavalleri, J-M V; Paschke, R

2016-02-25

Betulinic acid, a pentacyclic triterpene, and its derivatives are promising compounds for cancer treatment in humans. Melanoma is not only a problem for humans but also for grey horses as they have a high potential of developing melanoma lesions coupled to the mutation causing their phenotype. Current chemotherapeutic treatment carries the risk of adverse health effects for the horse owner or the treating veterinarian by exposure to antineoplastic compounds. Most treatments have low prospects for systemic tumor regression. Thus, a new therapy is needed. In this in vitro study, Betulinic acid and its two derivatives B10 and NVX-207, both with an improved water solubility compared to Betulinic acid, were tested on two equine melanoma cell lines (MelDuWi and MellJess/HoMelZh) and human melanoma (A375) cell line. We could demonstrate that all three compounds especially NVX-207 show high cytotoxicity on both equine melanoma cell lines. The treatment with these compounds lead to externalization of phosphatidylserines on the cell membrane (AnnexinV-staining), DNA-fragmentation (cell cycle analysis) and activation of initiator and effector caspases (Caspase assays). Our results indicate that the apoptosis is induced in the equine melanoma cells by all three compounds. Furthermore, we succeed in encapsulating the most active compound NVX-207 in 2-Hydroxyprolyl-β-cyclodextrine without a loss of its activity. This formulation can be used as a promising antitumor agent for treating grey horse melanoma. In a first tolerability evaluation in vivo the formulation was administered every one week for 19 consecutive weeks and well tolerated in two adult melanoma affected horses. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prediction and Characterization of High-Activity Events in Social Media Triggered by Real-World News.

PubMed

Kalyanam, Janani; Quezada, Mauricio; Poblete, Barbara; Lanckriet, Gert

2016-01-01

On-line social networks publish information on a high volume of real-world events almost instantly, becoming a primary source for breaking news. Some of these real-world events can end up having a very strong impact on on-line social networks. The effect of such events can be analyzed from several perspectives, one of them being the intensity and characteristics of the collective activity that it produces in the social platform. We research 5,234 real-world news events encompassing 43 million messages discussed on the Twitter microblogging service for approximately 1 year. We show empirically that exogenous news events naturally create collective patterns of bursty behavior in combination with long periods of inactivity in the network. This type of behavior agrees with other patterns previously observed in other types of natural collective phenomena, as well as in individual human communications. In addition, we propose a methodology to classify news events according to the different levels of intensity in activity that they produce. In particular, we analyze the most highly active events and observe a consistent and strikingly different collective reaction from users when they are exposed to such events. This reaction is independent of an event's reach and scope. We further observe that extremely high-activity events have characteristics that are quite distinguishable at the beginning stages of their outbreak. This allows us to predict with high precision, the top 8% of events that will have the most impact in the social network by just using the first 5% of the information of an event's lifetime evolution. This strongly implies that high-activity events are naturally prioritized collectively by the social network, engaging users early on, way before they are brought to the mainstream audience.

Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells.

PubMed Central

Tosato, G; Tanner, J; Jones, K D; Revel, M; Pike, S E

1990-01-01

Autocrine growth factors are believed to be important for maintenance of an immortalized state by Epstein-Barr virus (EBV), because cell-free supernatants of EBV-immortalized cell lines promote the proliferation of autologous cells and permit their growth at low cell density. In this study, we provide evidence for the existence of two autocrine growth factor activities produced by EBV-immortalized lines distinguished by size and biological activities. Much of the autocrine growth factor activity in lymphoblastoid cell line supernatants resided in a low-molecular-weight (less than 5,000) fraction. However, up to 20 to 30% of the autocrine growth factor activity resided in the high-molecular-weight (greater than 5,000) fraction. While the nature of the low-molecular-weight growth factor activity remains undefined, the high-molecular-weight growth factor activity was identified as interleukin-6 (IL-6). Culture supernatants from six EBV-induced lymphoblastoid cell lines tested contained IL-6 activity, because they promoted proliferation in the IL-6-dependent hybridoma cell line B9. In addition, a rabbit antibody to human IL-6 neutralized the capacity of the high-molecular-weight (greater than 5,000) fraction of a lymphoblastoid cell line supernatant to promote growth both in autologous EBV-immortalized cells and in B9 cells. Similarly, this high-molecular-weight autocrine growth factor activity was neutralized by a monoclonal antibody to human IL-6. Furthermore, characteristic bands, attributable to IL-6, were visualized in supernatants of each of four EBV-induced lymphoblastoid cell lines after immunoprecipitation with a rabbit antiserum to human IL-6. Thus, in addition to its previously reported properties, IL-6 is an autocrine growth factor for EBV-immortalized B cells cultured under serum-free conditions. Images PMID:2159561

The first γ-ray detection of the narrow-line Seyfert 1 FBQS J1644+2619

DOE PAGES

D'Ammando, F.; Orienti, M.; Larsson, J.; ...

2015-07-06

Here, we report the discovery of γ-ray emission from the narrow-line Seyfert 1 (NLSy1) galaxy FBQS J1644+2619 by the Large Area Telescope on board the Fermi satellite. The Third Fermi LAT Source catalogue reports an unidentified γ-ray source, detected over the first four years of Fermi operation, 0.°23 from the radio position of the NLSy1. Analysing 76 months of γ-ray data (2008 August 4–2014 December 31) we are able to better constrain the localization of the γ-ray source. The new position of the γ- ray source is 0.°05 from FBQS J1644+2619, suggesting a spatial association with the NLSy1. This ismore » the sixth NLSy1 detected at high significance by Fermi-LAT so far. Notably, a significant increase of activity was observed in γ-rays from FBQS J1644+2619 during 2012 July–October, and an increase of activity in V -band was detected by the Catalina Real-Time Sky Survey in the same period.« less

The first γ-ray detection of the narrow-line Seyfert 1 FBQS J1644+2619

NASA Astrophysics Data System (ADS)

D'Ammando, F.; Orienti, M.; Larsson, J.; Giroletti, M.

2015-09-01

We report the discovery of γ-ray emission from the narrow-line Seyfert 1 (NLSy1) galaxy FBQS J1644+2619 by the Large Area Telescope on board the Fermi satellite. The Third Fermi LAT Source catalogue reports an unidentified γ-ray source, detected over the first four years of Fermi operation, 0.23° from the radio position of the NLSy1. Analysing 76 months of γ-ray data (2008 August 4-2014 December 31) we are able to better constrain the localization of the γ-ray source. The new position of the γ-ray source is 0.05° from FBQS J1644+2619, suggesting a spatial association with the NLSy1. This is the sixth NLSy1 detected at high significance by Fermi-LAT so far. Notably, a significant increase of activity was observed in γ-rays from FBQS J1644+2619 during 2012 July-October, and an increase of activity in the V band was detected by the Catalina Real-Time Sky Survey in the same period.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

NASA Astrophysics Data System (ADS)

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-03-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071-40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.

Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

PubMed Central

McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

2014-01-01

Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands. PMID:24670678

Knockdown of Ice-Binding Proteins in Brachypodium distachyon Demonstrates Their Role in Freeze Protection

PubMed Central

Bredow, Melissa; Vanderbeld, Barbara; Walker, Virginia K.

2016-01-01

Sub-zero temperatures pose a major threat to the survival of cold-climate perennials. Some of these freeze-tolerant plants produce ice-binding proteins (IBPs) that offer frost protection by restricting ice crystal growth and preventing expansion-induced lysis of the plasma membranes. Despite the extensive in vitro characterization of such proteins, the importance of IBPs in the freezing stress response has not been investigated. Using the freeze-tolerant grass and model crop, Brachypodium distachyon, we characterized putative IBPs (BdIRIs) and generated the first ‘IBP-knockdowns’. Seven IBP sequences were identified and expressed in Escherichia coli, with all of the recombinant proteins demonstrating moderate to high levels of ice-recrystallization inhibition (IRI) activity, low levels of thermal hysteresis (TH) activity (0.03−0.09°C at 1 mg/mL) and apparent adsorption to ice primary prism planes. Following plant cold acclimation, IBPs purified from wild-type B. distachyon cell lysates similarly showed high levels of IRI activity, hexagonal ice-shaping, and low levels of TH activity (0.15°C at 0.5 mg/mL total protein). The transfer of a microRNA construct to wild-type plants resulted in the attenuation of IBP activity. The resulting knockdown mutant plants had reduced ability to restrict ice-crystal growth and a 63% reduction in TH activity. Additionally, all transgenic lines were significantly more vulnerable to electrolyte leakage after freezing to −10°C, showing a 13−22% increase in released ions compared to wild-type. IBP-knockdown lines also demonstrated a significant decrease in viability following freezing to −8°C, with some lines showing only two-thirds the survival seen in control lines. These results underscore the vital role IBPs play in the development of a freeze-tolerant phenotype and suggests that expression of these proteins in frost-susceptible plants could be valuable for the production of more winter-hardy crops. PMID:27959937

Knockdown of Ice-Binding Proteins in Brachypodium distachyon Demonstrates Their Role in Freeze Protection.

PubMed

Bredow, Melissa; Vanderbeld, Barbara; Walker, Virginia K

2016-01-01

Sub-zero temperatures pose a major threat to the survival of cold-climate perennials. Some of these freeze-tolerant plants produce ice-binding proteins (IBPs) that offer frost protection by restricting ice crystal growth and preventing expansion-induced lysis of the plasma membranes. Despite the extensive in vitro characterization of such proteins, the importance of IBPs in the freezing stress response has not been investigated. Using the freeze-tolerant grass and model crop, Brachypodium distachyon, we characterized putative IBPs (BdIRIs) and generated the first 'IBP-knockdowns'. Seven IBP sequences were identified and expressed in Escherichia coli, with all of the recombinant proteins demonstrating moderate to high levels of ice-recrystallization inhibition (IRI) activity, low levels of thermal hysteresis (TH) activity (0.03-0.09°C at 1 mg/mL) and apparent adsorption to ice primary prism planes. Following plant cold acclimation, IBPs purified from wild-type B. distachyon cell lysates similarly showed high levels of IRI activity, hexagonal ice-shaping, and low levels of TH activity (0.15°C at 0.5 mg/mL total protein). The transfer of a microRNA construct to wild-type plants resulted in the attenuation of IBP activity. The resulting knockdown mutant plants had reduced ability to restrict ice-crystal growth and a 63% reduction in TH activity. Additionally, all transgenic lines were significantly more vulnerable to electrolyte leakage after freezing to -10°C, showing a 13-22% increase in released ions compared to wild-type. IBP-knockdown lines also demonstrated a significant decrease in viability following freezing to -8°C, with some lines showing only two-thirds the survival seen in control lines. These results underscore the vital role IBPs play in the development of a freeze-tolerant phenotype and suggests that expression of these proteins in frost-susceptible plants could be valuable for the production of more winter-hardy crops.

Direct current power delivery system and method

DOEpatents

Zhang, Di; Garces, Luis Jose; Dai, Jian; Lai, Rixin

2016-09-06

A power transmission system includes a first unit for carrying out the steps of receiving high voltage direct current (HVDC) power from an HVDC power line, generating an alternating current (AC) component indicative of a status of the first unit, and adding the AC component to the HVDC power line. Further, the power transmission system includes a second unit for carrying out the steps of generating a direct current (DC) voltage to transfer the HVDC power on the HVDC power line, wherein the HVDC power line is coupled between the first unit and the second unit, detecting a presence or an absence of the added AC component in the HVDC power line, and determining the status of the first unit based on the added AC component.

Monolithic microwave integrated circuit devices for active array antennas

NASA Technical Reports Server (NTRS)

Mittra, R.

1984-01-01

Two different aspects of active antenna array design were investigated. The transition between monolithic microwave integrated circuits and rectangular waveguides was studied along with crosstalk in multiconductor transmission lines. The boundary value problem associated with a discontinuity in a microstrip line is formulated. This entailed, as a first step, the derivation of the propagating as well as evanescent modes of a microstrip line. The solution is derived to a simple discontinuity problem: change in width of the center strip. As for the multiconductor transmission line problem. A computer algorithm was developed for computing the crosstalk noise from the signal to the sense lines. The computation is based on the assumption that these lines are terminated in passive loads.

Correlations of frontal lip-line canting with craniofacial morphology and muscular activity.

PubMed

Cho, Jin-Hyoung; Kim, Eun-Jung; Kim, Byeong-Chae; Cho, Ki-Hyun; Lee, Ki-Heon; Hwang, Hyeon-Shik

2007-09-01

The purpose of this study was to investigate factors affecting lip-line canting by using musculoskeletal analyses. Fifty-six adults with lip-line canting were selected as subjects. They were divided into 3 groups according to the changes of lip line during smiling: increasing (group I), decreasing (group D), and minimal (group M). Lip-line canting at rest was correlated to craniofacial morphology and muscular activity: Regarding craniofacial morphology, various craniofacial measurements in lateral and frontal cephalograms were used, including inclination of the tongue blade placed across both first molars. The zygomaticus major was the focus of the measurement of muscular activity affecting lip-line canting, and its activity during smiling was evaluated by using a needle electrode. In group I, lip-line canting at rest showed a significant correlation with the right-left (R/L) difference of muscular activity, but no significant correlation with the measurements of craniofacial morphology. In group D, lip-line canting showed a positive correlation with the measurements of craniofacial morphology, such as the inclination of the tongue blade, and a negative correlation with the R/L difference of muscular activity. In group M, lip-line canting showed no significant correlation with the R/L difference of muscular activity, but a significant correlation with inclination of the tongue blade. The results indicate that lip-line canting is caused by craniofacial morphology when the change of lip-line canting during smiling is minimal, whereas lip-line canting is affected by the R/L difference of muscular activity in addition to craniofacial morphology when the cant of lip line markedly changes during smiling. The findings suggest that the cause of lip-line canting can be identified easily by the change of canting during smiling, without complicated musculoskeletal analyses.

High rate of virological failure and low rate of switching to second-line treatment among adolescents and adults living with HIV on first-line ART in Myanmar, 2005-2015

PubMed Central

Harries, Anthony D.; Kumar, Ajay M. V.; Oo, Myo Minn; Kyaw, Khine Wut Yee; Win, Than; Aung, Thet Ko; Min, Aung Chan; Oo, Htun Nyunt

2017-01-01

Background The number of people living with HIV on antiretroviral treatment (ART) in Myanmar has been increasing rapidly in recent years. This study aimed to estimate rates of virological failure on first-line ART and switching to second-line ART due to treatment failure at the Integrated HIV Care program (IHC). Methods Routinely collected data of all adolescent and adult patients living with HIV who were initiated on first-line ART at IHC between 2005 and 2015 were retrospectively analyzed. The cumulative hazard of virological failure on first-line ART and switching to second-line ART were estimated. Crude and adjusted hazard ratios were calculated using the Cox regression model to identify risk factors associated with the two outcomes. Results Of 23,248 adults and adolescents, 7,888 (34%) were tested for HIV viral load. The incidence rate of virological failure among those tested was 3.2 per 100 person-years follow-up and the rate of switching to second-line ART among all patients was 1.4 per 100 person-years follow-up. Factors associated with virological failure included: being adolescent; being lost to follow-up at least once; having WHO stage 3 and 4 at ART initiation; and having taken first-line ART elsewhere before coming to IHC. Of the 1032 patients who met virological failure criteria, 762 (74%) switched to second-line ART. Conclusions We found high rates of virological failure among one third of patients in the cohort who were tested for viral load. Of those failing virologically on first-line ART, about one quarter were not switched to second-line ART. Routine viral load monitoring, especially for those identified as having a higher risk of treatment failure, should be considered in this setting to detect all patients failing on first-line ART. Strategies also need to be put in place to prevent treatment failure and to treat more of those patients who are actually failing. PMID:28182786

Prior Knowledge Activation: How Different Concept Mapping Tasks Lead to Substantial Differences in Cognitive Processes, Learning Outcomes, and Perceived Self-Efficacy

ERIC Educational Resources Information Center

Gurlitt, Johannes; Renkl, Alexander

2010-01-01

Two experiments investigated the effects of characteristic features of concept mapping used for prior knowledge activation. Characteristic demands of concept mapping include connecting lines representing the relationships between concepts and labeling these lines, specifying the type of the semantic relationships. In the first experiment,…

The hazard education model in the high school science-club activities above active huge fault

NASA Astrophysics Data System (ADS)

Nakamura, R.

2017-12-01

Along the west coast of pacific ocean, includes Japan, there are huge numerous volcanoes and earthquakes. The biggest cause is their location on the border of plates. The pressure among the plates cause strains and cracks. By the island arc lines, strains make long and enormous faults. More than huge 150 faults are reported (the head quarters for earthquake research promotion, Japan, 2017). Below my working school, it is laying one of the biggest faults Nagamachi-Rifu line which is also laying under 1 million population city Sendai. Before 2011 Tohoku earthquake, one of the hugest earthquake was predicted because of the fault activities. Investigating the fault activity with our school student who live in the closest area is one of the most important hazard education. Therefore, now we are constructing the science club activity with make attention for (1) seeking fault line(s) with topographic land maps and on foot search (2) investigate boling core sample soils that was brought in our school founded. (1) Estimate of displacement of the faults on foot observation In order to seek the unknown fault line in Rifu area, at first it was needed to estimate on the maps(1:25,000 Scale Topographic Maps and Active Faults in Urban Area of Map(Sendai), Geographical Survey Institute of Japan). After that estimation, walked over the region with club students to observe slopes which was occurred by the faults activation and recorded on the maps. By observant slope gaps, there has a possibilities to have 3 or 4 fault lines that are located parallel to the known activate faults. (2) Investigate of the boling core samples above the fault. We investigated 6 columnar-shaped boling core samples which were excavated when the school has been built. The maximum depth of the samples are over 20m, some are new filled sands over original ash tephra and pumice from old volcanoes located west direction. In the club activities, we described column diagram of sediments and discussed the sediment circumstances by the sediments grain observation, however, it was impossible to describe the sediments origin of exact volcano(es).

X-ray stars observed in LAMOST spectral survey

NASA Astrophysics Data System (ADS)

Lu, Hong-peng; Zhang, Li-yun; Han, Xianming L.; Shi, Jianrong

2018-05-01

X-ray stars have been studied since the beginning of X-ray astronomy. Investigating and studying the chromospheric activity from X-ray stellar optical spectra is highly significant in providing insights into stellar magnetic activity. The big data of LAMOST survey provides an opportunity for researching stellar optical spectroscopic properties of X-ray stars. We inferred the physical properties of X-ray stellar sources from the analysis of LAMOST spectra. First, we cross-matched the X-ray stellar catalogue (12254 X-ray stars) from ARXA with LAMOST data release 3 (DR3), and obtained 984 good spectra from 713 X-ray sources. We then visually inspected and assigned spectral type to each spectrum and calculated the equivalent width (EW) of Hα line using the Hammer spectral typing facility. Based on the EW of Hα line, we found 203 spectra of 145 X-ray sources with Hα emission above the continuum. For these spectra we also measured the EWs of Hβ, Hγ, Hδ and Ca ii IRT lines of these spectra. After removing novae, planetary nebulae and OB-type stars, we found there are 127 X-ray late-type stars with Hα line emission. By using our spectra and results from the literature, we found 53 X-ray stars showing Hα variability; these objects are Classical T Tauri stars (CTTs), cataclysmic variables (CVs) or chromospheric activity stars. We also found 18 X-ray stars showing obvious emissions in the Ca ii IRT lines. Of the 18 X-ray stars, 16 are CTTs and 2 are CVs. Finally, we discussed the relationships between the EW of Hα line and X-ray flux.

Advanced multiphoton methods for in vitro and in vivo functional imaging of mouse retinal neurons (Conference Presentation)

NASA Astrophysics Data System (ADS)

Cohen, Noam; Schejter, Adi; Farah, Nairouz; Shoham, Shy

2016-03-01

Studying the responses of retinal ganglion cell (RGC) populations has major significance in vision research. Multiphoton imaging of optogenetic probes has recently become the leading approach for visualizing neural populations and has specific advantages for imaging retinal activity during visual stimulation, because it leads to reduced direct photoreceptor excitation. However, multiphoton retinal activity imaging is not straightforward: point-by-point scanning leads to repeated neural excitation while optical access through the rodent eye in vivo has proven highly challenging. Here, we present two enabling optical designs for multiphoton imaging of responses to visual stimuli in mouse retinas expressing calcium indicators. First, we present an imaging solution based on Scanning Line Temporal Focusing (SLITE) for rapidly imaging neuronal activity in vitro. In this design, we scan a temporally focused line rather than a point, increasing the scan speed and reducing the impact of repeated excitation, while maintaining high optical sectioning. Second, we present the first in vivo demonstration of two-photon imaging of RGC activity in the mouse retina. To obtain these cellular resolution recordings we integrated an illumination path into a correction-free imaging system designed using an optical model of the mouse eye. This system can image at multiple depths using an electronically tunable lens integrated into its optical path. The new optical designs presented here overcome a number of outstanding obstacles, allowing the study of rapid calcium- and potentially even voltage-indicator signals both in vitro and in vivo, thereby bringing us a step closer toward distributed monitoring of action potentials.

Selective breeding for infant rat separation-induced ultrasonic vocalizations: developmental precursors of passive and active coping styles.

PubMed

Brunelli, Susan A; Hofer, Myron A

2007-09-04

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate "anxious"/"depressed" phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an "aggressive" phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting "coping styles" with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation.

Study of the Many Fluorescent Lines and the Absorption Variability in GX 301-2 with XMM-Newton

NASA Technical Reports Server (NTRS)

Fuerst, F.; Suchy, S.; Kreykenbohm, I.; Barragan, L.; Wilms, J.; Pottschmidt, K.; Caballero, I.; Kretschmar, P.; Ferrigno, C.; Rothschild, R. E.

2011-01-01

We present an in-depth study of the High Mass X-ray Binary (HMXB) GX 301-2 during its pre-periastron flare using data from the XMM-Newton satellite. The energy spectrum shows a power law continuum absorbed by a large equivalent hydrogen column on the order of 10(exp 24)/ sq cm and a prominent Fe K-alpha fluorescent emission line. Besides the Fe K-alpha line, evidence for Fe K-Beta, Ni K-alpha, Ni K-Beta, S K-alpha, Ar K-alpha, Ca K-alpha, and Cr K-alpha fluorescent lines is found. The observed line strengths are consistent with fluorescence in a cold absorber. This is the first time that Cr K-alpha is seen in emission in the X-ray spectrum of a HMXB. In addition to the modulation by the strong pulse period of approx 685 sec the source is highly variable and shows different states of activity. We perform time-resolved as well as pulse-to-pulse resolved spectroscopy to investigate differences between these states of activity. We find that fluorescent line fluxes are strongly variable and generally follow the overall flux. The N-H value is variable by a factor of 2, but not correlated to continuum normalization. We find an interval of low flux in the light curve in which the pulsations cease almost completely, without any indication of an increasing absorption column. We investigate this dip in detail and argue that it is most likely that during the dip the accretion ceased and the afterglow of the fluorescent iron accounted for the main portion of the X-ray flux. A similar dip was found earlier in RXTE data, and we compare our findings to these results.

Bilingual Cancer Information: Access Is the First Line of Defense

ERIC Educational Resources Information Center

Boudreault, Patrick; Palmer, Christina

2015-01-01

Information about cancer, the disease that kills more Americans than any other except heart disease, is essential. In some ways, information is our first line of defense. It allows us to identify individual risk factors, to note when a problem means we should see a professional, and to avoid activities that might put us at risk. However,…

TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials.

PubMed

Grimminger, P P; Shi, M; Barrett, C; Lebwohl, D; Danenberg, K D; Brabender, J; Vigen, C L P; Danenberg, P V; Winder, T; Lenz, H-J

2012-10-01

To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.

Exploring the characteristics of patients with mesothelioma who chose active symptom control over chemotherapy as first-line treatment: a prospective, observational, single centre study.

PubMed

Bibby, Anna C; De Fonseka, Duneesha; Morley, Anna J; Keenan, Emma; Addeo, Alfredo; Smith, Sarah; Edey, Anthony J; Maskell, Nick A

2017-12-08

Mesothelioma is an aggressive thoracic tumour with a poor prognosis. The only treatment that extends survival is chemotherapy. However, in the UK, up to 50% of patients who are suitable for chemotherapy choose not to receive it, opting for active symptom control instead. The aim of this prospective, single-centre observational study was to describe the characteristics of patients who chose active symptom control over chemotherapy and explore their reasons for doing so. Two hundred consecutive patients with mesothelioma from one UK centre were included. Eligibility for chemotherapy and choice of first-line treatment were recorded prospectively. Patient characteristics and outcomes were compared using descriptive statistics, regression analysis and survival analysis. Reasons for choosing active symptom control over chemotherapy were extracted, retrospectively. People who chose active symptom control were older, more likely to be female and had worse performance statuses than patients who received front-line chemotherapy. Concern over side effects, the modest survival benefit and previous adverse experiences with chemotherapy were reported as reasons for the decision. Median survival was 13.9 months in the chemotherapy group compared with 6.7 months in the active symptom control group. This is the first study to describe the characteristics of patients with mesothelioma who chose active symptom control over chemotherapy, in the front-line setting. Important differences were seen between this group and patients who received chemotherapy, although confounding is likely to have affected some outcomes. Future research could use qualitative methods to explore patients' reasons for choosing active symptom control, and to further elucidate the decision-making process.

ATLASGAL-selected massive clumps in the inner Galaxy. II. Characterisation of different evolutionary stages and their SiO emission

NASA Astrophysics Data System (ADS)

Csengeri, T.; Leurini, S.; Wyrowski, F.; Urquhart, J. S.; Menten, K. M.; Walmsley, M.; Bontemps, S.; Wienen, M.; Beuther, H.; Motte, F.; Nguyen-Luong, Q.; Schilke, P.; Schuller, F.; Zavagno, A.; Sanna, C.

2016-02-01

Context. The processes leading to the birth of high-mass stars are poorly understood. The key first step to reveal their formation processes is characterising the clumps and cores from which they form. Aims: We define a representative sample of massive clumps in different evolutionary stages selected from the APEX Telescope Large Area Survey of the Galaxy (ATLASGAL), from which we aim to establish a census of molecular tracers of their evolution. As a first step, we study the shock tracer, SiO, mainly associated with shocks from jets probing accretion processes. In low-mass young stellar objects (YSOs), outflow and jet activity decreases with time during the star formation processes. Recently, a similar scenario was suggested for massive clumps based on SiO observations. Here we analyse observations of the SiO (2-1) and (5-4) lines in a statistically significant sample to constrain the change of SiO abundance and the excitation conditions as a function of evolutionary stage of massive star-forming clumps. Methods: We performed an unbiased spectral line survey covering the 3-mm atmospheric window between 84-117 GHz with the IRAM 30 m telescope of a sample of 430 sources of the ATLASGAL survey, covering various evolutionary stages of massive clumps. A smaller sample of 128 clumps has been observed in the SiO (5-4) transition with the APEX telescope to complement the (2-1) line and probe the excitation conditions of the emitting gas. We derived detection rates to assess the star formation activity of the sample, and we estimated the column density and abundance using both an LTE approximation and non-LTE calculations for a smaller subsample, where both transitions have been observed. Results: We characterise the physical properties of the selected sources, which greatly supersedes the largest samples studied so far, and show that they are representative of different evolutionary stages. We report a high detection rate of >75% of the SiO (2-1) line and a >90% detection rate from the dedicated follow-ups in the (5-4) transition. Up to 25% of the infrared-quiet clumps exhibit high-velocity line wings, suggesting that molecular tracers are more efficient tools to determine the level of star formation activity than infrared colour criteria. We also find infrared-quiet clumps that exhibit only a low-velocity component (FWHM ~ 5-6 km s-1) SiO emission in the (2-1) line. In the current picture, where this is attributed to low-velocity shocks from cloud-cloud collisions, this can be used to pinpoint the youngest, thus, likely prestellar massive structures. Using the optically thin isotopologue (29SiO), we estimate that the (2-1) line is optically thin towards most of the sample. Furthermore, based on the line ratio of the (5-4) to the (2-1) line, our study reveals a trend of changing excitation conditions that lead to brighter emission in the (5-4) line towards more evolved sources. Our models show that a proper treatment of non-LTE effects and beam dilution is necessary to constrain trends in the SiO column density and abundance. Conclusions: We conclude that the SiO (2-1) line with broad line profiles and high detection rates is a powerful probe of star formation activity in the deeply embedded phase of the evolution of massive clumps. The ubiquitous detection of SiO in all evolutionary stages suggests a continuous star formation process in massive clumps. Our analysis delivers a more robust estimate of SiO column density and abundance than previous studies and questions the decrease of jet activity in massive clumps as a function of age. The observed increase of excitation conditions towards the more evolved clumps suggests a higher pressure in the shocked gas towards more evolved or more massive clumps in our sample. Full Tables 4, 6, 7 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/586/A149

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients.

PubMed

Passaro, A; Prelaj, A; Pochesci, A; Spitaleri, G; Rossi, G; Del Signore, E; Catania, C; de Marinis, F

2017-08-01

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Copyright 2017 Clarivate Analytics.

Pharmacoeconomic analysis of recombinant factor VIIa versus APCC in the treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors.

PubMed

Joshi, Ashish V; Stephens, Jennifer M; Munro, Vicki; Mathew, Prasad; Botteman, Marc F

2006-01-01

To compare the cost-effectiveness of three treatment regimens using recombinant activated Factor VII (rFVIIa), NovoSeven, and activated prothrombin-complex concentrate (APCC), FEIBA VH, for home treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors. A literature-based, decision-analytic model was developed to compare three treatment regimens. The regimens consisting of first-, second-, and third-line treatments were: rFVIIa-rFVIIa-rFVIIa; APCC-rFVIIa-rFVIIa; and APCC-APCC-rFVIIa. Patients not responding to first-line treatment were administered second-line treatment, and those failing second-line received third-line treatment. Using literature and expert opinion, the model structure and base-case inputs were adapted to the US from a previously published analysis. The percentage of evaluable bleeds controlled with rFVIIa and APCC were obtained from published literature. Drug costs (2005 US$) based on average wholesale price were included in the base-case model. Univariate and probabilistic sensitivity analyses (second-order Monte Carlo simulation) were conducted by varying the efficacy, re-bleeding rates, patient weight, and dosing to ascertain robustness of the model. In the base-case analysis, the average cost per resolved bleed using rFVIIa as first-, second-, and third-line treatment was $28 076. Using APCC as first-line and rFVIIa as second- and third-line treatment resulted in an average cost per resolved bleed of $30 883, whereas the regimen using APCC as first- and second-line, and rFVIIa as third-line treatment was the most expensive, with an average cost per resolved bleed of $32 150. Cost offsets occurred for the rFVIIa-only regimen through avoidance of second and third lines of treatment. In probabilistic sensitivity analyses, the rFVIIa-only strategy was the least expensive strategy more than 68% of the time. The management of minor-to-moderate bleeds extends beyond the initial line of treatment, and should include the economic impact of re-bleeding and failures over multiple lines of treatment. In the majority of cases, the rFVIIa-only regimen appears to be a less expensive treatment option in inhibitor patients with minor-to-moderate bleeds over three lines of treatment.

Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.

PubMed

Burlison, Joseph A; Avila, Christopher; Vielhauer, George; Lubbers, Donna J; Holzbeierlein, Jeffrey; Blagg, Brian S J

2008-03-21

Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.

THE COMPLEX CIRCUMNUCLEAR ENVIRONMENT OF THE BROAD-LINE RADIO GALAXY 3C 390.3 REVEALED BY CHANDRA HETG

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tombesi, F.; Kallman, T.; Leutenegger, M. A.

2016-10-20

We present the first high spectral resolution X-ray observation of the broad-line radio galaxy 3C 390.3 obtained with the high-energy transmission grating spectrometer on board the Chandra X-ray Observatory . The spectrum shows complex emission and absorption features in both the soft X-rays and Fe K band. We detect emission and absorption lines in the energy range E = 700–1000 eV associated with ionized Fe L transitions (Fe XVII–XX). An emission line at the energy of E ≃ 6.4 keV consistent with the Fe K α is also observed. Our best-fit model requires at least three different components: (i) amore » hot emission component likely associated with the hot interstellar medium in this elliptical galaxy with temperature kT = 0.5 ± 0.1 keV; (ii) a warm absorber with ionization parameter log ξ = 2.3 ± 0.5 erg s{sup −1} cm, column density log N {sub H} = 20.7 ± 0.1 cm{sup −2}, and outflow velocity v {sub out} < 150 km s{sup −1}; and (iii) a lowly ionized reflection component in the Fe K band likely associated with the optical broad-line region or the outer accretion disk. These evidences suggest the possibility that we are looking directly down the ionization cone of this active galaxy and that the central X-ray source only photoionizes along the unobscured cone. This is overall consistent with the angle-dependent unified picture of active galactic nuclei.« less

The Complex Circumnuclear Environment of the Broad-Line Radio Galaxy 3C 390.3 Revealed by Chandra HETG

NASA Technical Reports Server (NTRS)

Tombesi, F.; Reeves, J. N.; Kallman, Timothy R.; Reynolds, C. S.; Mushotzky, R. F.; Braito, V.; Behar, E.; Leutenegger, Maurice A.; Cappi, M.

2016-01-01

We present the first high spectral resolution X-ray observation of the broad-line radio galaxy 3C 390.3 obtained with the high-energy transmission grating spectrometer on board the Chandra X-ray Observatory. The spectrum shows complex emission and absorption features in both the soft X-rays and Fe K band. We detect emission and absorption lines in the energy range E = 700-1000 eV associated with ionized Fe L transitions (Fe XVIIXX). An emission line at the energy of E approximately equal to 6.4 keV consistent with the Fe K alpha is also observed. Our best-fit model requires at least three different components: (i) a hot emission component likely associated with the hot interstellar medium in this elliptical galaxy with temperature kT = 0.5 +/- 0.1 keV; (ii) a warm absorber with ionization parameter log Epislon = 2.3 +/- 0.5 erg s(exp 1) cm, column density logN(sub H) = 20.7 +/- 0.1 cm(exp -2), and outflow velocity v(sub out) less than 150 km s(exp -1); and (iii) a lowly ionized reflection component in the Fe K band likely associated with the optical broad-line region or the outer accretion disk. These evidences suggest the possibility that we are looking directly down the ionization cone of this active galaxy and that the central X-ray source only photoionizes along the unobscured cone. This is overall consistent with the angle-dependent unified picture of active galactic nuclei.

Discovery of a very Lyman-α-luminous quasar at z = 6.62.

PubMed

Koptelova, Ekaterina; Hwang, Chorng-Yuan; Yu, Po-Chieh; Chen, Wen-Ping; Guo, Jhen-Kuei

2017-02-02

Distant luminous quasars provide important information on the growth of the first supermassive black holes, their host galaxies and the epoch of reionization. The identification of quasars is usually performed through detection of their Lyman-α line redshifted to 0.9 microns at z > 6.5. Here, we report the discovery of a very Lyman-α luminous quasar, PSO J006.1240 + 39.2219 at redshift z = 6.618, selected based on its red colour and multi-epoch detection of the Lyman-α emission in a single near-infrared band. The Lyman-α line luminosity of PSO J006.1240 + 39.2219 is unusually high and estimated to be 0.8 × 10 12 Solar luminosities (about 3% of the total quasar luminosity). The Lyman-α emission of PSO J006.1240 + 39.2219 shows fast variability on timescales of days in the quasar rest frame, which has never been detected in any of the known high-redshift quasars. The high luminosity of the Lyman-α line, its narrow width and fast variability resemble properties of local Narrow-Line Seyfert 1 galaxies which suggests that the quasar is likely at the active phase of the black hole growth accreting close or even beyond the Eddington limit.

Discovery of a very Lyman-α-luminous quasar at z = 6.62

PubMed Central

Koptelova, Ekaterina; Hwang, Chorng-Yuan; Yu, Po-Chieh; Chen, Wen-Ping; Guo, Jhen-Kuei

2017-01-01

Distant luminous quasars provide important information on the growth of the first supermassive black holes, their host galaxies and the epoch of reionization. The identification of quasars is usually performed through detection of their Lyman-α line redshifted to 0.9 microns at z > 6.5. Here, we report the discovery of a very Lyman-α luminous quasar, PSO J006.1240 + 39.2219 at redshift z = 6.618, selected based on its red colour and multi-epoch detection of the Lyman-α emission in a single near-infrared band. The Lyman-α line luminosity of PSO J006.1240 + 39.2219 is unusually high and estimated to be 0.8 × 1012 Solar luminosities (about 3% of the total quasar luminosity). The Lyman-α emission of PSO J006.1240 + 39.2219 shows fast variability on timescales of days in the quasar rest frame, which has never been detected in any of the known high-redshift quasars. The high luminosity of the Lyman-α line, its narrow width and fast variability resemble properties of local Narrow-Line Seyfert 1 galaxies which suggests that the quasar is likely at the active phase of the black hole growth accreting close or even beyond the Eddington limit. PMID:28150701

The first gamma-ray outburst of a narrow-line Seyfert 1 galaxy: The case of PMN J0948+0022 in 2010 July

DOE PAGES

Foschini, Luigi; Ghisellini, G.; Kovalev, Y. Y.; ...

2011-05-11

We report on a multiwavelength campaign for the radio-loud narrow-line Seyfert 1 (NLS1) galaxy PMN J0948+0022 (z= 0.5846) performed in 2010 July–September and triggered by a high-energy γ-ray outburst observed by the Large Area Telescope onboard the Fermi Gamma-ray Space Telescope. The peak flux in the 0.1–100 GeV energy band exceeded, for the first time in this type of source, the value of ~10–6 photon cm–2 s–1, corresponding to an observed luminosity of ~1048 erg s–1. Although the source was too close to the Sun position to organize a densely sampled follow-up, it was possible to gather some multiwavelength datamore » that confirmed the state of high activity across the sampled electromagnetic spectrum. Furthermore, the comparison of the spectral energy distribution of the NLS1 PMN J0948+0022 with that of a typical blazar – such as 3C 273 – shows that the power emitted at γ-rays is extreme.« less

When Genomics Is Not Enough: Experimental Evidence for a Decrease in LINE-1 Activity During the Evolution of Australian Marsupials

PubMed Central

Gallus, Susanne; Lammers, Fritjof

2016-01-01

The autonomous transposable element LINE-1 is a highly abundant element that makes up between 15% and 20% of therian mammal genomes. Since their origin before the divergence of marsupials and placental mammals, LINE-1 elements have contributed actively to the genome landscape. A previous in silico screen of the Tasmanian devil genome revealed a lack of functional coding LINE-1 sequences. In this study we present the results of an in vitro analysis from a partial LINE-1 reverse transcriptase coding sequence in five marsupial species. Our experimental screen supports the in silico findings of the genome-wide degradation of LINE-1 sequences in the Tasmanian devil, and identifies a high frequency of degraded LINE-1 sequences in other Australian marsupials. The comparison between the experimentally obtained LINE-1 sequences and reference genome assemblies suggests that conclusions from in silico analyses of retrotransposition activity can be influenced by incomplete genome assemblies from short reads. PMID:27389686

Influence of observers and stream flow on northern two-lined salamander (Eurycea bislineata bislineata) relative abundance estimates in Acadia and Shenandoah National Parks, USA

USGS Publications Warehouse

Crocker, J.B.; Bank, M.S.; Loftin, C.S.; Jung Brown, R.E.

2007-01-01

We investigated effects of observers and stream flow on Northern Two-Lined Salamander (Eurycea bislineata bislineata) counts in streams in Acadia (ANP) and Shenandoah National Parks (SNP). We counted salamanders in 22 ANP streams during high flow (May to June 2002) and during low flow (July 2002). We also counted salamanders in SNP in nine streams during high flow (summer 2003) and 11 streams during low flow (summers 2001?02, 2004). In 2002, we used a modified cover-controlled active search method with a first and second observer. In succession, observers turned over 100 rocks along five 1-m belt transects across the streambed. The difference between observers in total salamander counts was not significant. We counted fewer E. b. bislineata during high flow conditions, confirming that detection of this species is reduced during high flow periods and that assessment of stream salamander relative abundance is likely more reliable during low or base flow conditions.

Radio stars observed in the LAMOST spectral survey

NASA Astrophysics Data System (ADS)

Zhang, Li-Yun; Yue, Qiang; Lu, Hong-Peng; Han, Xian-Ming L.; Zhang, Yong; Shi, Jian-Rong; Wang, Yue-Fei; Hou, Yong-Hui; Zi-Huang, Cao

2017-09-01

Radio stars have attracted astronomers’ attention for several decades. To better understand the physics behind stellar radio emissions, it is important to study their optical behaviors. The LAMOST survey provides a large database for researching stellar spectroscopic properties of radio stars. In this work, we concentrate on their spectroscopic properties and infer physical properties from their spectra, such as stellar activity and variability. We mined big data from the LAMOST spectral survey Data Release 2 (DR2), published on 2016 June 30, by cross-matching them with radio stars from FIRST and other surveys. We obtained 783 good stellar spectra with high signal to noise ratio for 659 stars. The criteria for selection were positional coincidence within 1.5‧‧ and LAMOST objects classified as stars. We calculated the equivalent widths (EWs) of the Ca ii H&K, Hδ, Hγ, Hβ, Hα and Ca ii IRT lines by integrating the line profiles. Using the EWs of the Hα line, we detected 147 active stellar spectra of 89 objects having emissions above the Hα continuum. There were also 36 objects with repeated spectra, 28 of which showed chromospheric activity variability. Furthermore, we found 14 radio stars emitting noticeably in the Ca ii IRT lines. The low value of the EW8542/EW8498 ratio for these 14 radio stars possibly alludes to chromospheric plage regions.

Functional endogenous LINE-1 retrotransposons are expressed and mobilized in rat chloroleukemia cells.

PubMed

Kirilyuk, Alexander; Tolstonog, Genrich V; Damert, Annette; Held, Ulrike; Hahn, Silvia; Löwer, Roswitha; Buschmann, Christian; Horn, Axel V; Traub, Peter; Schumann, Gerald G

2008-02-01

LINE-1 (L1) is a highly successful autonomous non-LTR retrotransposon and a major force shaping mammalian genomes. Although there are about 600 000 L1 copies covering 23% of the rat genome, full-length rat L1s (L1Rn) with intact open reading frames (ORFs) representing functional master copies for retrotransposition have not been identified yet. In conjunction with studies to elucidate the role of L1 retrotransposons in tumorigenesis, we isolated and characterized 10 different cDNAs from transcribed full-length L1Rn elements in rat chloroleukemia (RCL) cells, each encoding intact ORF1 proteins (ORF1p). We identified the first functional L1Rn retrotransposon from this pool of cDNAs, determined its activity in HeLa cells and in the RCL cell line the cDNAs originated from and demonstrate that it is mobilized in the tumor cell line in which it is expressed. Furthermore, we generated monoclonal antibodies directed against L1Rn ORF1 and ORF2-encoded recombinant proteins, analyzed the expression of L1-encoded proteins and found ORF1p predominantly in the nucleus. Our results support the hypothesis that the reported explosive amplification of genomic L1Rn sequences after their transcriptional activation in RCL cells is based on L1 retrotransposition. Therefore, L1 activity might be one cause for genomic instability observed during the progression of leukemia.

A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.

PubMed

Dalziel, Stuart R; Furyk, Jeremy; Bonisch, Megan; Oakley, Ed; Borland, Meredith; Neutze, Jocelyn; Donath, Susan; Sharpe, Cynthia; Harvey, Simon; Davidson, Andrew; Craig, Simon; Phillips, Natalie; George, Shane; Rao, Arjun; Cheng, Nicholas; Zhang, Michael; Sinn, Kam; Kochar, Amit; Brabyn, Christine; Babl, Franz E

2017-06-22

Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom benzodiazepines have failed. This study will provide the first high quality evidence for management of paediatric CSE post first-line benzodiazepines. Prospectively registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR): ACTRN12615000129583 (11/2/2015). UTN U1111-1144-5272. ConSEPT protocol version 4 (12/12/2014).

IK channel activation increases tumor growth and induces differential behavioral responses in two breast epithelial cell lines.

PubMed

Thurber, Amy E; Nelson, Michaela; Frost, Crystal L; Levin, Michael; Brackenbury, William J; Kaplan, David L

2017-06-27

Many potassium channel families are over-expressed in cancer, but their mechanistic role in disease progression is poorly understood. Potassium channels modulate membrane potential (Vmem) and thereby influence calcium ion dynamics and other voltage-sensitive signaling mechanisms, potentially acting as transcriptional regulators. This study investigated the differential response to over-expression and activation of a cancer-associated potassium channel, the intermediate conductance calcium-activated potassium channel (IK), on aggressive behaviors in mammary epithelial and breast cancer cell lines. IK was over-expressed in the highly metastatic breast cancer cell line MDA-MB-231 and the spontaneously immortalized breast epithelial cell line MCF-10A, and the effect on cancer-associated behaviors was assessed. IK over-expression increased primary tumor growth and metastasis of MDA-MB-231 in orthotopic xenografts, demonstrating for the first time in any cancer type that increased IK is sufficient to promote cancer aggression. The primary tumors had similar vascularization as determined by CD31 staining and similar histological characteristics. Interestingly, despite the increased in vivo growth and metastasis, neither IK over-expression nor activation with agonist had a significant effect on MDA-MB-231 proliferation, invasion, or migration in vitro. In contrast, IK decreased MCF-10A proliferation and invasion through Matrigel but had no effect on migration in a scratch-wound assay. We conclude that IK activity is sufficient to promote cell aggression in vivo. Our data provide novel evidence supporting IK and downstream signaling networks as potential targets for cancer therapies.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection.

PubMed

Derache, Anne; Wallis, Carole L; Vardhanabhuti, Saran; Bartlett, John; Kumarasamy, Nagalingeswaran; Katzenstein, David

2016-01-15

Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure. AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations. Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI. Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Accretion, winds and jets: High-energy emission from young stellar objects

NASA Astrophysics Data System (ADS)

Günther, Hans Moritz

2009-03-01

Stars form by gravitational collapse from giant molecular clouds. Due to the conservation of angular momentum this collapse does not happen radially, but the matter forms circumstellar disk first and is consequently accreted from the disk onto the star. This thesis deals with the high-energy emission from young stellar objects, which are on the one hand still actively accreting from their disk, and on the other hand are no longer deeply obscured by their natal cloud. Stars of spectral type B and A are called Herbig Ae/Be (HAeBe) stars in this stage, all stars of later spectral type are termed classical T Tauri stars (CTTS); strictly speaking both types are defined by spectroscopic signatures, which are equivalent to the evolutionary stage described above. In this thesis CTTS and HAeBes are studied through high-resolution X-ray and UV spectroscopy and through detailed physical simulations. Spectroscopic X-ray data is reduced and presented for two targets: The CTTS V4046 Sgr was observed with Chandra for 100 ks, using a high-resolution grating spectrometer. The lightcurve contains one flare and the He-like triplets of SiXIII, NeIX and OVII indicate high densities in the X-ray emitting regions. The second target is the HAeBe HD 163296, which was observed with XMM-Newton for 130 ks. The lightcurve shows only moderate variability, the elemental abundance follows a pattern, that is usual for active stars. The He-like triplet of OVII exhibits line ratios similar to coronal sources, indicating that neither a high density nor a strong UV-field is present in the region of the X-ray emission. Using these and similar observations, it can be concluded that at least three mechanisms contribute to the observed high-energy emission from CTTS: First, those stars have active coronae similar to main-sequence stars, second, the accreted material passes through a strong accretion shock at the stellar surface, which heats it to a few MK, and, third, some CTTS drive powerful outflows. Shocks within these jets can heat the matter to X-ray emitting temperatures. The first is already well characterised; for the latter two scenarios models are presented in this thesis. The accretion shock is treated in a stationary 1D model, taking non-equilibrium ionisations explicitly into account. The magnetic field is strong enough to suppress motion perpendicular to the field lines, so the use of a 1D geometry is justified. The radiative loss is calculated as optically thin emission with the CHIANTI database. A combination of simulated post-shock cooling zone spectra and coronal gas is fitted to the observations of the CTTS TW Hya and V4046 Sgr. Both stars require only small mass accretion rates to power the X-ray emission (2×10-10 Msun/yr and 3×10-11 Msun/yr, respectively). The CTTS DG Tau is heavily absorbed and the observed soft X-ray emission originates spatially offset from the star. In this thesis a physical model is presented which explains the emission by a shock front travelling along the ejected jet. Shock velocities between 400 and 500 km/s are required to explain the observed spectrum. For a electron density >105 cm-3 all shock dimensions are so small that they remain undetectable in optical observations as observed. The spectral resolution in X-rays is not sufficient to analyse the line profiles, so UV data is used for this purpose. Line profiles extend up to 500 km/s in sample of CTTS observed with FUSE. Likely contribution from both, infalling and outflowing gas, contributes to the observed emission. The current models do not explain the observed line profiles in detail, especially the line width causes problems. HAeBe stars have hot plasma, which can only be explained as an active corona, similar to the CTTS. Accretion does not contribute significantly to the X-ray emission, instead the line ratios in the He-like triplets point to an origin in the outflows, similar to the CTTS jets. A model comparable to DG Tau reproduces the observed emission.

A Best-Fit Line Using the Method of Averages.

ERIC Educational Resources Information Center

Hoppe, Jack

2002-01-01

Describes a method for calculating lines of best fit that is easy to understand and apply. Presents an example using the Arrhenius plot of a first-order reaction from which the energy of activation is calculated. (MM)

High prevalence of HIV-1 drug resistance among patients on first-line antiretroviral treatment in Lomé, Togo.

PubMed

Dagnra, Anoumou Y; Vidal, Nicole; Mensah, Akovi; Patassi, Akouda; Aho, Komi; Salou, Mounerou; Monleau, Marjorie; Prince-David, Mireille; Singo, Assétina; Pitche, Palokinam; Delaporte, Eric; Peeters, Martine

2011-06-10

With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. Our objective is to evaluate the virological failure and genotypic drug-resistance mutations in patients receiving first-line highly active antiretroviral therapy (HAART) in routine clinics that use the World Health Organization public health approach to monitor antiretroviral treatment (ART) in Togo. Patients on HAART for one year (10-14 months) were enrolled between April and October 2008 at three sites in Lomé, the capital city of Togo. Plasma viral load was measured with the NucliSENS EasyQ HIV-1 assay (Biomérieux, Lyon, France) and/or a Generic viral load assay (Biocentric, Bandol, France). Genotypic drug-resistance testing was performed with an inhouse assay on plasma samples from patients with viral loads of more than 1000 copies/ml. CD4 cell counts and demographic data were also obtained from medical records. A total of 188 patients receiving first-line antiretroviral treatment were enrolled, and 58 (30.8%) of them experienced virologic failure. Drug-resistance mutations were present in 46 patients, corresponding to 24.5% of all patients enrolled in the study. All 46 patients were resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTIs): of these, 12 were resistant only to NNRTIs, 25 to NNRTIs and lamivudine/emtricitabine, and eight to all three drugs of their ARV regimes. Importantly, eight patients were already predicted to be resistant to etravirine, the new NNRTI, and three patients harboured the K65R mutation, inducing major resistance to tenofovir. In Togo, efforts to provide access to ARV therapy for infected persons have increased since 2003, and scaling up of ART started in 2007. The high number of resistant strains observed in Togo shows clearly that the emergence of HIV drug resistance is of increasing concern in countries where ART is now widely used, and can compromise the long-term success of first- and second-line ART.

The multi-line slope method for measuring the effective magnetic field of cool stars: an application to the solar-like cycle of ɛ Eri

NASA Astrophysics Data System (ADS)

Scalia, C.; Leone, F.; Gangi, M.; Giarrusso, M.; Stift, M. J.

2017-12-01

One method for the determination of integrated longitudinal stellar fields from low-resolution spectra is the so-called slope method, which is based on the regression of the Stokes V signal against the first derivative of Stokes I. Here we investigate the possibility of extending this technique to measure the magnetic fields of cool stars from high-resolution spectra. For this purpose we developed a multi-line modification to the slope method, called the multi-line slope method. We tested this technique by analysing synthetic spectra computed with the COSSAM code and real observations obtained with the high-resolution spectropolarimeters Narval, HARPSpol and the Catania Astrophysical Observatory Spectropolarimeter (CAOS). We show that the multi-line slope method is a fast alternative to the least squares deconvolution technique for the measurement of the effective magnetic fields of cool stars. Using a Fourier transform on the effective magnetic field variations of the star ε Eri, we find that the long-term periodicity of the field corresponds to the 2.95-yr period of the stellar dynamo, revealed by the variation of the activity index.

Saving Now and Saving Later: How High School Reform Can Reduce the Nation's Wasted Remediation Dollars. Issue Brief

ERIC Educational Resources Information Center

Alliance for Excellent Education, 2011

2011-01-01

For young people entering the twenty-first-century job market, high school graduation is no longer the finish line, but the starting line. While one-third of students will fail to graduate from high school, too many students who do graduate and make it to the postsecondary starting line find that they are underprepared for postsecondary work. A…

Virtual screening, SAR, and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor.

PubMed

Ziedan, Noha I; Hamdy, Rania; Cavaliere, Alessandra; Kourti, Malamati; Prencipe, Filippo; Brancale, Andrea; Jones, Arwyn T; Westwell, Andrew D

2017-07-01

A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small-molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with submicromolar IC 50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme-linked immunosorbent assay (IC 50  = 4.27 μm). Compound 16j has a great potential to develop into highly active anticancer agent. © 2017 John Wiley & Sons A/S.

Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Husmann, Knut, E-mail: khusmann@research.balgrist.ch; Ducommun, Pascal; Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich

2015-09-04

The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS andmore » 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.« less

The Peculiar Radio-loud Narrow Line Seyfert 1 Galaxy 1H 0323+342

NASA Astrophysics Data System (ADS)

Paliya, Vaidehi S.; Sahayanathan, S.; Parker, M. L.; Fabian, A. C.; Stalin, C. S.; Anjum, Ayesha; Pandey, S. B.

2014-07-01

We present a multiwavelength study of the radio-loud narrow-line Seyfert 1 galaxy (NLSy1) 1H 0323+342, detected by the Fermi Gamma-Ray Space Telescope. Multiband light curves show many orphan X-ray and optical flares having no corresponding γ-ray counterparts. Such anomalous variability behavior can be due to different locations of the emission region from the central source. During a large flare, a γ-ray flux doubling timescale as small as ~3 hr is noticed. We built spectral energy distributions (SEDs) during different activity states and modeled them using a one-zone leptonic model. The shape of the optical/UV component of the SEDs is dominated by accretion disk emission in all the activity states. In the X-ray band, significant thermal emission from the hot corona is inferred during quiescent and first flaring states; however, during subsequent flares, the nonthermal jet component dominates. The γ-ray emission in all the states can be well explained by inverse-Compton scattering of accretion disk photons reprocessed by the broad-line region. The source showed violent intra-night optical variability, coinciding with one of the high γ-ray activity states. An analysis of the overall X-ray spectrum fitted with an absorbed power-law plus relativistic reflection component hints at the presence of an Fe Kα line and returns a high black hole spin value of a = 0.96 ± 0.14. We argue that 1H 0323+342 possesses dual characteristics, akin to both flat-spectrum radio quasars (FSRQs) and radio-quiet NLSy1 galaxies, though at a low jet power regime compared to powerful FSRQs.

Low current performance of the Bern medical cyclotron down to the pA range

NASA Astrophysics Data System (ADS)

Auger, M.; Braccini, S.; Ereditato, A.; Nesteruk, K. P.; Scampoli, P.

2015-09-01

A medical cyclotron accelerating H- ions to 18 MeV is in operation at the Bern University Hospital (Inselspital). It is the commercial IBA 18/18 cyclotron equipped with a specifically conceived 6 m long external beam line ending in a separate bunker. This feature is unique for a hospital-based facility and makes it possible to conduct routine radioisotope production for PET diagnostics in parallel with multidisciplinary research activities, among which are novel particle detectors, radiation biophysics, radioprotection, radiochemistry and radiopharmacy developments. Several of these activities, such as radiobiology experiments for example, require low current beams down to the pA range, while medical cyclotrons are designed for high current operation above 10 μA. In this paper, we present the first results on the low current performance of a PET medical cyclotron obtained by ion source, radio-frequency and main coil tuning. With this method, stable beam currents down to (1.5+/- 0.5 ) pA were obtained and measured with a high-sensitivity Faraday cup located at the end of the beam transport line.

First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial.

PubMed

Kaufmann, M; Maass, N; Costa, S D; Schneeweiss, A; Loibl, S; Sütterlin, M W; Schrader, I; Gerber, B; Bauer, W; Wiest, W; Tomé, O; Distelrath, A; Hagen, V; Kleine-Tebbe, A; Ruckhaeberle, E; Mehta, K; von Minckwitz, G

2010-12-01

To determine activity and safety of capecitabine at a moderate dose of 2000 mg/m(2) as first-line therapy for metastatic breast cancer. In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000 mg/m(2) on days 1-14 every 3 weeks. The primary aim was to exclude a time to progression (TTP) <6 months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life. Median age of the 161 included patients was 65 years. Median TTP and OS were 7.3 months [95% (confidence interval) CI: 6.2-8.4] and 17.1 months (95% CI: 14.0-20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I-III hand-foot syndrome had a significantly longer TTP and OS and patients >65 years also achieved a significantly longer TTP. Haematological grade I-IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1-10. Capecitabine at a dose of 2000 mg/m(2) is active and safe as first-line treatment of patients with metastatic breast cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

PubMed

Tang, Michele W; Rhee, Soo-Yon; Bertagnolio, Silvia; Ford, Nathan; Holmes, Susan; Sigaloff, Kim C; Hamers, Raph L; de Wit, Tobias F Rinke; Fleury, Herve J; Kanki, Phyllis J; Ruxrungtham, Kiat; Hawkins, Claudia A; Wallis, Carole L; Stevens, Wendy; van Zyl, Gert U; Manosuthi, Weerawat; Hosseinipour, Mina C; Ngo-Giang-Huong, Nicole; Belec, Laurent; Peeters, Martine; Aghokeng, Avelin; Bunupuradah, Torsak; Burda, Sherri; Cane, Patricia; Cappelli, Giulia; Charpentier, Charlotte; Dagnra, Anoumou Y; Deshpande, Alaka K; El-Katib, Ziad; Eshleman, Susan H; Fokam, Joseph; Gody, Jean-Chrysostome; Katzenstein, David; Koyalta, Donato D; Kumwenda, Johnstone J; Lallemant, Marc; Lynen, Lutgarde; Marconi, Vincent C; Margot, Nicolas A; Moussa, Sandrine; Ndung'u, Thumbi; Nyambi, Phillipe N; Orrell, Catherine; Schapiro, Jonathan M; Schuurman, Rob; Sirivichayakul, Sunee; Smith, Davey; Zolfo, Maria; Jordan, Michael R; Shafer, Robert W

2013-06-15

The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Rabeprazole, Minocycline, Amoxicillin, and Bismuth as First-Line and Second-Line Regimens for Helicobacter pylori Eradication.

PubMed

Song, Zhiqiang; Suo, Baojun; Zhang, Lingyun; Zhou, Liya

2016-12-01

Because of general unavailability of tetracycline, common adverse effects, and complicated administration, the clinical application of bismuth quadruple therapy often faces difficulties. Whether the combination of minocycline and amoxicillin can replace tetracycline and metronidazole for Helicobacter pylori eradication remains unclear. This study was to determine the efficacy, compliance, and safety of rabeprazole, minocycline, amoxicillin, and bismuth (RMAB) therapy as first-line and second-line regimens. Between July 2013 and December 2015, a total of 160 patients in first-line and 70 patients in second-line therapies received rabeprazole 10 mg, minocycline 100 mg, amoxicillin 1000 mg, and bismuth potassium citrate 220 mg twice daily for 14 days. Eradication status was assessed 6-12 weeks after treatment. RMAB therapy achieved the eradication rates of 87.5% (95% confidence interval, 81.9-92.5%, intention-to-treat analysis), 90.9% (85.7-95.5%, modified intention-to-treat analysis), and 92.6% (88.5-96.6%, per-protocol analysis) in first-line therapy in a setting with high antibiotic resistance rates (amoxicillin 3.4%, clarithromycin 39.7%, metronidazole 60.3%, levofloxacin 36.2%, tetracycline 3.4%, and minocycline 6.9%). As for second-line therapy, the eradication rates were 82.9% (74.3-91.4%, intention-to-treat analysis), 86.6% (77.6-94.0%, modified intention-to-treat analysis), and 89.1% (81.3-95.3%, per-protocol analysis). Totally, 24.0% patients had adverse effects, 2.2% discontinued medications, and good compliance was achieved in 94.7%. Poor compliance and minocycline resistance were identified as the risk factors for treatment failure. Significant differences in efficacy existed among the groups of both sensitive (48/51 and 18/20), isolated amoxicillin resistance (1/1 and 0/0), isolated minocycline resistance (2/3 and 1/1), and dual resistance (0/1 and 0/1) in both first-line (p = .004) and second-line (p = .035) therapies. The eradication efficacies of RMAB therapy as first-line and second-line regimens were satisfactory with good compliance and safety in a region with high antibiotic resistance. © 2016 John Wiley & Sons Ltd.

TALEN-mediated targeted mutagenesis of fatty acid desaturase 2 (FAD2) in peanut (Arachis hypogaea L.) promotes the accumulation of oleic acid.

PubMed

Wen, Shijie; Liu, Hao; Li, Xingyu; Chen, Xiaoping; Hong, Yanbin; Li, Haifen; Lu, Qing; Liang, Xuanqiang

2018-05-01

A first creation of high oleic acid peanut varieties by using transcription activator-like effecter nucleases (TALENs) mediated targeted mutagenesis of Fatty Acid Desaturase 2 (FAD2). Transcription activator like effector nucleases (TALENs), which allow the precise editing of DNA, have already been developed and applied for genome engineering in diverse organisms. However, they are scarcely used in higher plant study and crop improvement, especially in allopolyploid plants. In the present study, we aimed to create targeted mutagenesis by TALENs in peanut. Targeted mutations in the conserved coding sequence of Arachis hypogaea fatty acid desaturase 2 (AhFAD2) were created by TALENs. Genetic stability of AhFAD2 mutations was identified by DNA sequencing in up to 9.52 and 4.11% of the regeneration plants at two different targeted sites, respectively. Mutation frequencies among AhFAD2 mutant lines were significantly correlated to oleic acid accumulation. Genetically, stable individuals of positive mutant lines displayed a 0.5-2 fold increase in the oleic acid content compared with non-transgenic controls. This finding suggested that TALEN-mediated targeted mutagenesis could increase the oleic acid content in edible peanut oil. Furthermore, this was the first report on peanut genome editing event, and the obtained high oleic mutants could serve for peanut breeding project.

T-DM1, a novel antibody–drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo

PubMed Central

English, Diana P; Bellone, Stefania; Schwab, Carlton L; Bortolomai, Ileana; Bonazzoli, Elena; Cocco, Emiliano; Buza, Natalia; Hui, Pei; Lopez, Salvatore; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Santin, Alessandro D

2014-01-01

Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy. PMID:24890382

T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo.

PubMed

English, Diana P; Bellone, Stefania; Schwab, Carlton L; Bortolomai, Ileana; Bonazzoli, Elena; Cocco, Emiliano; Buza, Natalia; Hui, Pei; Lopez, Salvatore; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Santin, Alessandro D

2014-10-01

Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The Evolution of Stellar Chromospheres

NASA Astrophysics Data System (ADS)

Simon, Theodore

1984-07-01

59 Vir (GO V) and 31 Com (GO III) are among the youngest G stars for which high dispersion spectra can be obtained with the short-wavelength camera of IUE. Their ages are estimated to be 0.2 Gyr (31 Com is a member of the Coma cluster). 59 Vir was observed at low resolution in a study of the relation between ultraviolet chromospheric activity and age in solar dwarf stars. 31 Com was observed as an example of a young yellow giant making its first crossing of the Hertzsprung Gap. Their spectra show bright chromospheric and transition region emission lines. We request observing time in this proposal to secure doubleshift (up to 16 hours) high dispersion exposures of each star with the SWP camera. These observations will allow us to resolve the profiles of individual chromospheric and transition region emission lines. From radiative transfer calculations, emission measure analyses, and line flux ratios, we will derive temperature, density, and velocity field models in the chromosphere and transition region. We will investigate the energy balance of these atmospheres in order to compare their non-thermal energy requirements with results derived for older solar-type dwarfs and more highly evolved yellow and red giants. With precautions to ensure the fidelity of the wavelength scale, we will also look far differential velocity shifts between TR and chromospheric lines, which may arise from global atmospheric circulation patterns. We have shown in previous work that redshifted TR lines are most clearly seen in giant stars and that the downflows causing the line shifts may affect the energy balance of giant atmospheres. As one of the very few normal G giants whose spectrum can be studied at high dispersion, 31 Com is important to such studies.

A Chandra Observation of the Ultraluminous Infrared Galaxy IRAS 19254-7245 (THE SUPERANTENNAE): X-Ray Emission From the Compton-Thick Active Galactic Nucleus and the Diffuse Starburst

NASA Technical Reports Server (NTRS)

Jia, Jianjun; Ptak, Andrew Francis; Heckman, Timothy M.; Braito, Valantina; Reeves, James

2012-01-01

We present a Chandra observation of IRAS 19254-7245, a nearby ultraluminous infrared galaxy also known as the Superantennae. The high spatial resolution of Chandra allows us to disentangle for the first time the diffuse starburst (SB) emission from the embedded Compton-thick active galactic nucleus (AGN) in the southern nucleus. No AGN activity is detected in the northern nucleus. The 2-10 keV spectrum of the AGN emission is fitted by a flat power law (G = 1.3) and an He-like Fe Ka line with equivalent width 1.5 keV, consistent with previous observations. The Fe Ka line profile could be resolved as a blend of a neutral 6.4 keV line and an ionized 6.7 keV (He-like) or 6.9 keV (H-like) line. Variability of the neutral line is detected compared with the previous XMM-Newton and Suzaku observations, demonstrating the compact size of the iron line emission. The spectrum of the galaxy-scale extended emission excluding the AGN and other bright point sources is fitted with a thermal component with a best-fit kT of 0.8 keV. The 2-10 keV luminosity of the extended emission is about one order of magnitude lower than that of the AGN. The basic physical and structural properties of the extended emission are fully consistent with a galactic wind being driven by the SB. A candidate ultraluminous X-ray source is detected 8 south of the southern nucleus. The 0.3-10 keV luminosity of this off-nuclear point source is 6 × 1040 erg s-1 if the emission is isotropic and the source is associated with the Superantennae.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fausnaugh, M. M.; Grier, C. J.; Bentz, M. C.

We present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a “changing look” AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He II λ4686 lags for all objects except 3C 382. The He II λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. Themore » relative responsivities of these lines are also in qualitative agreement with photoionization models. Finally, these spectra have extremely high signal-to-noise ratios (100–300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.« less

MARVEL analysis of the measured high-resolution spectra of 14NH3

NASA Astrophysics Data System (ADS)

Al Derzi, Afaf R.; Furtenbacher, Tibor; Tennyson, Jonathan; Yurchenko, Sergei N.; Császár, Attila G.

2015-08-01

Accurate, experimental rotational-vibrational energy levels and line positions, with associated labels and uncertainties, are reported for the ground electronic state of the symmetric-top 14NH3 molecule. All levels and lines are based on critically reviewed and validated high-resolution experimental spectra taken from 56 literature sources. The transition data are in the 0.7-17 000 cm-1 region, with a large gap between 7000 and 15 000 cm-1. The MARVEL (Measured Active Rotational-Vibrational Energy Levels) algorithm is used to determine the energy levels. Out of the 29 450 measured transitions 10 041 and 18 947 belong to ortho- and para-14NH3, respectively. A careful analysis of the related experimental spectroscopic network (SN) allows 28 530 of the measured transitions to be validated, 18 178 of these are unique, while 462 transitions belong to floating components. Despite the large number of spectroscopic measurements published over the last 80 years, the transitions determine only 30 vibrational band origins of 14NH3, 8 for ortho- and 22 for para-14NH3. The highest J value, where J stands for the rotational quantum number, for which an energy level is validated is 31. The number of experimental-quality ortho- and para-14NH3 rovibrational energy levels is 1724 and 3237, respectively. The MARVEL energy levels are checked against ones in the BYTe first-principles database, determined previously. The lists of validated lines and levels for 14NH3 are deposited in the Supporting Information to this paper. Combination of the MARVEL energy levels with first-principles absorption intensities yields a huge number of experimental-quality rovibrational lines, which should prove to be useful for the understanding of future complex high-resolution spectroscopy on 14NH3; these lines are also deposited in the Supporting Information to this paper.

High School Open On-Line Courses (HOOC): A Case Study from Italy

ERIC Educational Resources Information Center

Canessa, Enrique; Pisani, Armando

2013-01-01

The first implementation of complete high school, open on-line courses (HOOC) aiming to support the training and basic scientific knowledge of young students from the Liceo Ginnasio Dante Alighieri in Gorizia, Italy, is discussed. Using the open source and automated recording system openEyA, HOOC give a student the opportunity to watch on-line, at…

Study on induced radioactivity of China Spallation Neutron Source

NASA Astrophysics Data System (ADS)

Wu, Qing-Biao; Wang, Qing-Bin; Wu, Jing-Min; Ma, Zhong-Jian

2011-06-01

China Spallation Neutron Source (CSNS) is the first High Energy Intense Proton Accelerator planned to be constructed in China during the State Eleventh Five-Year Plan period, whose induced radioactivity is very important for occupational disease hazard assessment and environmental impact assessment. Adopting the FLUKA code, the authors have constructed a cylinder-tunnel geometric model and a line-source sampling physical model, deduced proper formulas to calculate air activation, and analyzed various issues with regard to the activation of different tunnel parts. The results show that the environmental impact resulting from induced activation is negligible, whereas the residual radiation in the tunnels has a great influence on maintenance personnel, so strict measures should be adopted.

NtLTP4, a lipid transfer protein that enhances salt and drought stresses tolerance in Nicotiana tabacum.

PubMed

Xu, Yang; Zheng, Xinxin; Song, Yunzhi; Zhu, Lifei; Yu, Zipeng; Gan, Liming; Zhou, Shumei; Liu, Hongmei; Wen, Fujiang; Zhu, Changxiang

2018-06-11

Lipid transfer proteins (LTPs), a class of small, ubiquitous proteins, play critical roles in various environmental stresses. However, their precise biological functions remain unknown. Here we isolated an extracellular matrix-localised LTP, NtLTP4, from Nicotiana tabacum. The overexpression of NtLTP4 in N. tabacum enhanced resistance to salt and drought stresses. Upon exposure to high salinity, NtLTP4-overexpressing lines (OE lines) accumulated low Na + levels. Salt-responsive genes, including Na + /H + exchangers (NHX1) and high-affinity K + transporter1 (HKT1), were dramatically higher in OE lines than in wild-type lines. NtLTP4 might regulate transcription levels of NHX1 and HKT1 to alleviate the toxicity of Na + . Interestingly, OE lines enhanced the tolerance of N. tabacum to drought stress by reducing the transpiration rate. Moreover, NtLTP4 could increase reactive oxygen species (ROS)-scavenging enzyme activity and expression levels to scavenge excess ROS under drought and high salinity conditions. We used a two-hybrid yeast system and screened seven putative proteins that interact with NtLTP4 in tobacco. An MAPK member, wound-induced protein kinase, was confirmed to interact with NtLTP4 via co-immunoprecipitation and a firefly luciferase complementation imaging assay. Taken together, this is the first functional analysis of NtLTP4, and proves that NtLTP4 positively regulates salt and drought stresses in N. tabacum.

Mice from lines selectively bred for high voluntary wheel running exhibit lower blood pressure during withdrawal from wheel access.

PubMed

Kolb, Erik M; Kelly, Scott A; Garland, Theodore

2013-03-15

Exercise is known to be rewarding and have positive effects on mental and physical health. Excessive exercise, however, can be the result of an underlying behavioral/physiological addiction. Both humans who exercise regularly and rodent models of exercise addiction sometimes display behavioral withdrawal symptoms, including depression and anxiety, when exercise is denied. However, few studies have examined the physiological state that occurs during this withdrawal period. Alterations in blood pressure (BP) are common physiological indicators of withdrawal in a variety of addictions. In this study, we examined exercise withdrawal in four replicate lines of mice selectively bred for high voluntary wheel running (HR lines). Mice from the HR lines run almost 3-fold greater distances on wheels than those from non-selected control lines, and have altered brain activity as well as increased behavioral despair when wheel access is removed. We tested the hypothesis that male HR mice have an altered cardiovascular response (heart rate, systolic, diastolic, and mean arterial pressure [MAP]) during exercise withdrawal. Measurements using an occlusion tail-cuff system were taken during 8 days of baseline, 6 days of wheel access, and 2 days of withdrawal (wheel access blocked). During withdrawal, HR mice had significantly lower systolic BP, diastolic BP, and MAP than controls, potentially indicating a differential dependence on voluntary wheel running in HR mice. This is the first characterization of a cardiovascular withdrawal response in an animal model of high voluntary exercise. Copyright © 2013. Published by Elsevier Inc.

Antiproliferative activity of flavonoids on several cancer cell lines.

PubMed

Kawaii, S; Tomono, Y; Katase, E; Ogawa, K; Yano, M

1999-05-01

Twenty-seven Citrus flavonoids were examined for their antiproliferative activities against several tumor and normal human cell lines. As a result, 7 flavonoids were judged to be active against the tumor cell lines, while they had weak antiproliferative activity against the normal human cell lines. The rank order of potency was luteolin, natsudaidain, quercetin, tangeretin, eriodictyol, nobiletin, and 3,3',4',5,6,7,8-heptamethoxyflavone. The structure-activity relationship established from comparison among these flavones and flavanones showed that the ortho-catechol moiety in ring B and a C2-C3 double bond were important for the antiproliferative activity. As to polymethoxylated flavones, C-3 hydroxyl and C-8 methoxyl groups were essential for high activity.

Observational Requirements for High-Fidelity Reverberation Mapping

NASA Technical Reports Server (NTRS)

Horne, Keith; Peterson, Bradley M.; Collier, Stefan J.; Netzer, Hagai

2004-01-01

We present a series of simulations to demonstrate that high-fidelity velocity-delay maps of the emission-line regions in active galactic nuclei can be obtained from time-resolved spectrophotometric data sets like those that will arise from the proposed Kronos satellite. While previous reverberation-mapping experiments have established the size scale R of the broad emission-line regions from the mean time delay tau = R/c between the line and continuum variations and have provided strong evidence for supermassive black holes, the detailed structure and kinematics of the broad-line region remain ambiguous and poorly constrained. Here we outline the technical improvements that will be required to successfully map broad-line regions by reverberation techniques. For typical AGN continuum light curves, characterized by power-law power spectra P (f) is proportional to f(exp -alpha) with a = -1.5 +/- 0.5, our simulations show that a small UV/optical spectrometer like Kronos will clearly distinguish between currently viable alternative kinematic models. From spectra sampled at time intervals Delta t and sustained for a total duration T(sub dur), we can reconstruct high-fidelity velocity-delay maps with velocity resolution comparable to that of the spectra, and delay resolution Delta tau approx. 2 Delta t, provided T(sub dur) exceeds the broad-line region light crossing time by at least a factor of three. Even very complicated kinematical models, such as a Keplerian flow with superimposed spiral wave pattern, are resolved in maps from our simulated Kronos datasets. Reverberation mapping with Kronos data is therefore likely deliver the first clear maps of the geometry and kinematics in the broad emission-line regions 1-100 microarcseconds from supermassive black holes.

Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models.

PubMed

Della Corte, Carminia Maria; Ciaramella, Vincenza; Cardone, Claudia; La Monica, Silvia; Alfieri, Roberta; Petronini, Pier Giorgio; Malapelle, Umberto; Vigliar, Elena; Pepe, Francesco; Troncone, Giancarlo; Castellone, Maria Domenica; Troiani, Teresa; Martinelli, Erika; Ciardiello, Fortunato; Morgillo, Floriana

2018-03-08

Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models. We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments. The addition of selumetinib or cetuximab to osimertinib in second-line therapy reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50% to 80%, and a median progression-free survival (mPFS) of first- plus second-line of therapy of 28 weeks. The early use of combinations in first-line therapy increased the RR to 90%, with an mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0.005) as compared to osimertinib, achieving in first-line therapy an mPFS time of 17 to 18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found Hedgehog pathway activation and we showed that therapy with an SMO inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells. We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Magnetic Oscillations Mark Sites of Magnetic Transients in an Acoustically Active Flare

NASA Astrophysics Data System (ADS)

Lindsey, Charles A.; Donea, A.; Hudson, H. S.; Martinez Oliveros, J.; Hanson, C.

2011-05-01

The flare of 2011 February 15, in NOAA AR11158, was the first acoustically active flare of solar cycle 24, and the first observed by the Solar Dynamics Observatory (SDO). It was exceptional in a number of respects (Kosovichev 2011a,b). Sharp ribbon-like transient Doppler, and magnetic signatures swept over parts of the active region during the impulsive phase of the flare. We apply seismic holography to a 2-hr time series of HMI observations encompassing the flare. The acoustic source distribution appears to have been strongly concentrated in a single highly compact penumbral region in which the continuum-intensity signature was unusually weak. The line-of-sight magnetic transient was strong in parts of the active region, but relatively weak in the seismic-source region. On the other hand, the neighbourhoods of the regions visited by the strongest magnetic transients maintained conspicuous 5-minutes-period variations in the line of sight magnetic signature for the full 2-hr duration of the time series, before the flare as well as after. We apply standard helioseismic control diagnostics for clues as to the physics underlying 5-minute magnetic oscillations in regions conducive to magnetic transients during a flare and consider the prospective development of this property as an indicator of flare potentiality on some time scale. We make use of high-resolution data from AIA, using diffracted images where necessary to obtain good photometry where the image is otherwise saturated. This is relevant to seismic emission driven by thick-target heating in the absence of back-warming. We also use RHESSI imaging spectroscopy to compare the source distributions of HXR and seismic emission.

Multi-event study of high-latitude thermospheric wind variations at substorm onset with a Fabry-Perot interferometer at Tromsoe, Norway

NASA Astrophysics Data System (ADS)

Xu, H.; Shiokawa, K.; Oyama, S. I.; Otsuka, Y.

2017-12-01

We studied the high-latitude thermospheric wind variations near the onset time of isolated substorms. Substorm-related energy input from the magnetosphere to the polar ionosphere modifies the high-latitude ionosphere and thermosphere. For the first time, this study showed the characteristics of high-latitude thermospheric wind variations at the substorm onset. We also investigated the possibility of these wind variations as a potential trigger of substorm onset by modifying the ionospheric current system (Kan, 1993). A Fabry-Perot interferometer (FPI) at Tromsoe, Norway provided wind measurements estimated from Doppler shift of both red-line (630.0 nm for the F region) and green-line (557.7 nm for the E region) emissions of aurora and airglow. We used seven-year data sets obtained from 2009 to 2015 with a time resolution of 13 min. We first identified the onset times of local isolated substorms using ground-based magnetometer data obtained at the Tromsoe and Bear Island stations, which belongs to the IMAGE magnetometer chain. We obtained 4 red-line events and 5 green-line events taken place at different local times. For all these events, the peak locations of westward ionospheric currents identified by the ground-based magnetometer chain were located at the poleward side of Tromsoe. Then, we calculated two weighted averages of wind velocities for 30 min around the onset time and 30 min after the onset time of substorms. We evaluated differences between these two weighted averages to estimate the strength of wind changes. The observed wind changes at these substorm onsets were less than 49 m/s (26 m/s) for red-line (green-line) events, which are much smaller than the typical plasma convection speed. This indicates that the plasma motion caused by substorm-induced thermospheric winds through ion-neutral collisions is a minor effect as the driver of high-latitude plasma convection, as well as the triggering of substorm onset. We discuss possible causes of these observed wind changes at the onset of substorms based on the mechanisms of thermospheric diurnal tides, arc-induced electric field and Joule heating caused by the auroral activities that were identified by the cross sections of all-sky images, as well as the IMF-associated plasma convection model.

Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma.

PubMed

Popov, Sergey W; Moldenhauer, Gerhard; Wotschke, Beate; Brüderlein, Silke; Barth, Thomas F; Dorsch, Karola; Ritz, Olga; Möller, Peter; Leithäuser, Frank

2007-07-15

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL.

The variability of the Seyfert galaxy NGC 2992: the case for a revived AGN

NASA Astrophysics Data System (ADS)

Gilli, R.; Maiolino, R.; Marconi, A.; Risaliti, G.; Dadina, M.; Weaver, K. A.; Colbert, E. J. M.

2000-03-01

We report the transition to an active state of the nucleus in the Seyfert 1.9 galaxy NGC 2992, discovered by means of new hard X-ray data. While the 2-10 keV flux declined by a factor of ~ 20 from 1978 to 1994, two recent BeppoSAX observations in 1997 and in 1998 caught the nuclear emission raising back to the same level of activity observed in 1978. In both BeppoSAX observations the X-ray spectrum of the source is well represented by a power law with spectral index Gamma =~ 1.7, absorbed by a column density of N_H =~ 1022 cm-2 and characterized by a prominent iron Kalpha line. While in the second BeppoSAX data set the line properties appear to be consistent with those expected from accretion disc models, in the first BeppoSAX data set the iron feature is rather peculiar. The broadening is not significant and the line energy is E_Kalpha =6.62+/-0.07 keV, indicating emission from highly ionized iron. The line has too high equivalent width ( ~ 700 eV) to be produced by a hot scattering medium. By comparing these data with data previously in the literature, we interpret the spectral and flux changes in terms of different phases of rebuilding an accretion disc. The timescale for the disc rebuilding is estimated to range between 1 and 5 years. The X-ray data are complemented with optical and near-infrared followup spectra taken 1.5 months after the discovery of the X-ray burst. The spectra are characterized by prominent broad emission lines. There is also evidence for hot dust emission in the H and K bands that, however, is probably still in the process of increasing.

First-generation science cases for ground-based terahertz telescopes

NASA Astrophysics Data System (ADS)

Hirashita, Hiroyuki; Koch, Patrick M.; Matsushita, Satoki; Takakuwa, Shigehisa; Nakamura, Masanori; Asada, Keiichi; Liu, Hauyu Baobab; Urata, Yuji; Wang, Ming-Jye; Wang, Wei-Hao; Takahashi, Satoko; Tang, Ya-Wen; Chang, Hsian-Hong; Huang, Kuiyun; Morata, Oscar; Otsuka, Masaaki; Lin, Kai-Yang; Tsai, An-Li; Lin, Yen-Ting; Srinivasan, Sundar; Martin-Cocher, Pierre; Pu, Hung-Yi; Kemper, Francisca; Patel, Nimesh; Grimes, Paul; Huang, Yau-De; Han, Chih-Chiang; Huang, Yen-Ru; Nishioka, Hiroaki; Lin, Lupin Chun-Che; Zhang, Qizhou; Keto, Eric; Burgos, Roberto; Chen, Ming-Tang; Inoue, Makoto; Ho, Paul T. P.

2016-02-01

Ground-based observations at terahertz (THz) frequencies are a newly explorable area of astronomy in the coming decades. We discuss science cases for a first-generation 10-m class THz telescope, focusing on the Greenland Telescope as an example of such a facility. We propose science cases and provide quantitative estimates for each case. The largest advantage of ground-based THz telescopes is their higher angular resolution (˜ 4″ for a 10-m dish), as compared to space or airborne THz telescopes. Thus, high-resolution mapping is an important scientific argument. In particular, we can isolate zones of interest for Galactic and extragalactic star-forming regions. The THz windows are suitable for observations of high-excitation CO lines and [N II] 205-μm lines, which are scientifically relevant tracers of star formation and stellar feedback. Those lines are the brightest lines in the THz windows, so they are suitable for the initiation of ground-based THz observations. THz polarization of star-forming regions can also be explored since it traces the dust population contributing to the THz spectral peak. For survey-type observations, we focus on "sub-THz" extragalactic surveys, the uniqueness of which is detecting galaxies at redshifts z ˜ 1-2, where the dust emission per comoving volume is the largest in the history of the Universe. Finally we explore possibilities of flexible time scheduling, which enables us to monitor active galactic nuclei, and to target gamma-ray burst afterglows. For these objects, THz and submillimeter wavelength ranges have not yet been explored.

Injector for use in high voltage isolators for liquid feed lines

NASA Technical Reports Server (NTRS)

Snyder, J. A. (Inventor)

1973-01-01

An improved injector is described for use in introducing fluid substances into feed lines employed in delivering flowing bodies of liquids. The injector includes a porous plug, concentrically related to a feed line, including an internally tapered surface of a truncated conical configuration with an inlet orifice of a first diameter substantially smaller than the first diameter and an external surface circumscribed by an annular chamber containing a body of insulating gas.

Identification of chalcone-based antileishmanial agents targeting trypanothione reductase.

PubMed

Ortalli, Margherita; Ilari, Andrea; Colotti, Gianni; De Ionna, Ilenia; Battista, Theo; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Di Martino, Rita M C; Gentilomi, Giovanna A; Varani, Stefania; Belluti, Federica

2018-05-02

All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Furthermore, some drugs are associated with the emergence of drug resistance. Thus, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The present work highlights the use of natural derived products, i.e. chalcones, as potential source of antileishmanial agents. Thirty-one novel chalcone compounds have been synthesized and their activity has been evaluated against promastigotes of Leishmania donovani; 16 compounds resulted active against L. donovani in a range from 3.0 to 21.5 μM, showing low toxicity against mammalian cells. Among these molecules, 6 and 16 showed good inhibitory activity on both promastigotes and intracellular amastigotes, coupled with an high selectivity index. Furthermore, compounds 6 and 16 inhibited the promastigote growth of other leishmanial species, including L. tropica, L. major and L. infantum. Finally, 6 and 16 interacted with high affinity with trypanothione reductase (TR), an essential enzyme for the leishmanial parasite and compound 6 inhibited TR with sub-micromolar potency. Thus, the effective inhibitory activity against Leishmania, the lack of toxicity on mammalian cells and the ability to block a crucial parasite's enzyme, highlight the potential for compound 6 to be optimized as novel drug candidate against leishmaniasis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao

Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression ofmore » Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.« less

Profiling of anthocyanins in transgenic purple-fleshed sweet potatoes by HPLC-MS/MS.

PubMed

Ge, Jingqiu; Hu, Yijie; Wang, Hongxia; Huang, Yuanshe; Zhang, Peng; Liao, Zhihua; Chen, Min

2017-11-01

Anthocyanins in purple-fleshed sweet potato (PSP) are beneficial to human health. The leaf color (Lc) gene is a transcription factor involved in regulating anthocyanin biosynthesis. The anthocyanin profiles of wild-type PSP of Ayamurasaki and its three Lc-transgenic lines were investigated by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). In vitro antioxidant activities of wild-type and Lc-transgenic lines, including reducing power activity, DPPH radical scavenging activity, hydroxyl radical scavenging activity, linoleic acid autoxidation inhibition activity, ABTS free radical scavenging activity and oxygen radical absorbance capacity activity, were measured. The results showed that the total anthocyanin contents increased 1.5-1.9 times in three transgenic lines compared with that in wild-type PSP. Seventeen anthocyanins were found in wild-type PSP, while 19 in Lc-transgenic lines including cyanidin-based, peonidin-based and pelargonidin-based anthocyanins. Three pelargonidin-based anthocyanins were detected in three Lc-transgenic lines. Among them, the relative contents of cyanidin-based and pelargonidin-based anthocyanins increased 1.9-2.0 and 3.4-4.5 times respectively, while peonidin-based anthocyanins decreased 1.8-1.9 times in Lc-transgenic lines, compared with wild-type PSP. PSP from wild-type Ayamurasaki and three Lc-transgenic lines exhibited potent antioxidant activities, whereas there was no distinct difference among them. The transgene Lc significantly increased the content of total anthocyanins and remarkably changed the anthocyanin profiles in Ayamurasaki. Such novel and high content of anthocyanins obtained in the Lc-transgenic lines with potent antioxidant activities may provide unique functional products with potential helpful for human health. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Resources and Costs Associated with the Treatment of Advanced and Metastatic Gastric Cancer in the Mexican Public Sector: A Patient Chart Review.

PubMed

Quintana, Miguel; Toriz, José A; Novick, Diego; Jones, Kyla; Botello, Brenda S; Silva, Juan Alejandro

2018-06-01

Little evidence is available on the management and cost of treating patients with advanced or metastatic gastric cancer (GC). This study evaluates patient characteristics, treatment patterns, and resource utilization for these patients in Mexico. Data were collected from three centers of investigation (tertiary level). Patients were ≥18 years of age, diagnosed between 1 January 2009 and 1 January 2015, had advanced or metastatic GC, received first-line fluoropyrimidine/platinum, and had ≥3 months follow-up after discontinuing first-line treatment. Data were summarized using descriptive statistics. The study sample totaled 180. Patients' mean age was 57.2 years (±12.4) and 57.0% were male; 151 (83.9%) patients received second-line chemotherapy. A total of 16 and 19 regimens were identified in first- and second-line therapy. Of the sample, 51 (28.3%) received third-line therapy, and <10% received more than three lines of active chemotherapy. Supportive care received in first- and second-line chemotherapy, included pain interventions (12.2 and 7.9%), nutritional support (3.3 and 1.3%), radiotherapy (6.1 and 16.6%), and transfusions (13.3 and 10.6%), respectively. Using Mexican Institute of Social Security (IMSS) tariffs, the average total cost per patient-month in first- and second-line therapy was US$1230 [95% confidence interval (CI) 1034-1425] and US$1192 (95% CI 913-1471), respectively. Administration and acquisition of chemotherapy comprised the majority of costs. This study shows considerable variation in first- and second-line chemotherapy regimens of patients with advanced or metastatic GC. Understanding GC treatment patterns in Mexico will help address unmet needs.

First laboratory detection of an absorption line of the first overtone electric quadrupolar band of N2 by CRDS near 2.2 μm

NASA Astrophysics Data System (ADS)

Čermák, P.; Vasilchenko, S.; Mondelain, D.; Kassi, S.; Campargue, A.

2017-01-01

The extremely weak 2-0 O(14) electric quadrupole transition of N2 has been detected by very high sensitivity Cavity Ring Down spectroscopy near 4518 cm-1. It is the first N2 absorption line in the first overtone band reported so far from laboratory experiments. By combining a feedback narrowed Distributed Feedback laser diode with a passive cell tracking technique, a limit of detection of αmin ∼ 1.2 × 10-11 cm-1 was achieved after one day of spectra averaging. The N2 2-0 O(14) line position and line intensity (about 1.5 × 10-30 cm/molecule) agree with calculated values provided in the HITRAN2012 database.

Quality work in long-term care: the role of first-line leaders.

PubMed

Kjøs, Bente Ødegård; Botten, Grete; Gjevjon, Edith Roth; Romøren, Tor Inge

2010-10-01

To explore the first-line leaders' role in quality work in long-term care in Norway, in order to determine how that work is related to such success characteristics as leadership, staff, patients, performance, information and information technology. Cross-sectional telephone survey. The text was analysed using content analysis. Thirty-two Norwegian municipalities stratified according to region and population size. Sixty-four first-line leaders in nursing homes and home-based care. Main outcome measure The clinical microsystem approach is used as a framework by defining and designing measureable variables. Thirty-six leaders described how they initiated and motivated employees to be active in quality work; the remaining leaders indicated that they played a passive role. The first-line leaders played a key role in implementing national quality policies and regulations. The quantity of other success characteristics was low. The municipalities delegated the responsibility of implanting national policies to the first-line leaders. Missing were key quality success criteria such as macro- and meso-perspectives for the municipality as a whole and co-operation with other leaders in the organization and fostering of relevant learning. Quality work was fragmented rather than comprehensive and systematic.

Measurement of O(6)-alkylguanine-DNA alkyltransferase activity in tumour cells using stable isotope dilution HPLC-ESI-MS/MS.

PubMed

Sun, Guohui; Zhao, Lijiao; Fan, Tengjiao; Ren, Ting; Zhong, Rugang

2016-10-15

The repair of DNA mediated by O(6)-alkylguanine-DNA alkyltransferase (AGT) provides protection against DNA damage from endogenous or exogenous alkylation of the O(6) position of guanine. However, this repair acts as a double-edged sword in cancer treatment, as it not only protects normal cells from chemotherapy-associated toxicities, but also results in cancer cell resistance to guanine O(6)-alkylating antitumour agents. Thus, AGT plays an important role in predicting the individual susceptibility to guanine O(6)-alkylating carcinogens and chemotherapies. Accordingly, it is necessary to establish a quantitative method for determining AGT activity with high accuracy, sensitivity and practicality. Here, we describe a novel nonradioactive method for measuring AGT activity using stable isotope dilution high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). This method is based on the irreversibility of the removal of the O(6)-alkyl group from guanine by AGT and on the high affinity of O(6)-benzylguanine (O(6)-BG) as an AGT substrate. HPLC-ESI-MS/MS was used to measure the AGT activities in cell protein extracts from eight tumour lines, demonstrating that AGT activity was quite variable among different cell lines, ranging from nondetectable to 1021 fmol/mg protein. The experiments performed in intact tumour cells yielded similar results but exhibited slightly higher activities than those observed in cell protein extracts. The accuracy of this method was confirmed by an examination of AGT expression levels using western blotting analysis. To our knowledge, this method is the first mass spectrometry-based AGT activity assay, and will likely provide assistance in the screening of cancer risk or the application of chemotherapies. Copyright © 2016 Elsevier B.V. All rights reserved.

A Census of Broad-line Active Galactic Nuclei in Nearby Galaxies: Coeval Star Formation and Rapid Black Hole Growth

NASA Astrophysics Data System (ADS)

Trump, Jonathan R.; Hsu, Alexander D.; Fang, Jerome J.; Faber, S. M.; Koo, David C.; Kocevski, Dale D.

2013-02-01

We present the first quantified, statistical map of broad-line active galactic nucleus (AGN) frequency with host galaxy color and stellar mass in nearby (0.01 < z < 0.11) galaxies. Aperture photometry and z-band concentration measurements from the Sloan Digital Sky Survey are used to disentangle AGN and galaxy emission, resulting in estimates of uncontaminated galaxy rest-frame color, luminosity, and stellar mass. Broad-line AGNs are distributed throughout the blue cloud and green valley at a given stellar mass, and are much rarer in quiescent (red sequence) galaxies. This is in contrast to the published host galaxy properties of weaker narrow-line AGNs, indicating that broad-line AGNs occur during a different phase in galaxy evolution. More luminous broad-line AGNs have bluer host galaxies, even at fixed mass, suggesting that the same processes that fuel nuclear activity also efficiently form stars. The data favor processes that simultaneously fuel both star formation activity and rapid supermassive black hole accretion. If AGNs cause feedback on their host galaxies in the nearby universe, the evidence of galaxy-wide quenching must be delayed until after the broad-line AGN phase.

In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process.

PubMed

Nagy, Brigitta; Farkas, Attila; Gyürkés, Martin; Komaromy-Hiller, Szofia; Démuth, Balázs; Szabó, Bence; Nusser, Dávid; Borbás, Enikő; Marosi, György; Nagy, Zsombor Kristóf

2017-09-15

The integration of Process Analytical Technology (PAT) initiative into the continuous production of pharmaceuticals is indispensable for reliable production. The present paper reports the implementation of in-line Raman spectroscopy in a continuous blending and tableting process of a three-component model pharmaceutical system, containing caffeine as model active pharmaceutical ingredient (API), glucose as model excipient and magnesium stearate as lubricant. The real-time analysis of API content, blend homogeneity, and tablet content uniformity was performed using a Partial Least Squares (PLS) quantitative method. The in-line Raman spectroscopic monitoring showed that the continuous blender was capable of producing blends with high homogeneity, and technological malfunctions can be detected by the proposed PAT method. The Raman spectroscopy-based feedback control of the API feeder was also established, creating a 'Process Analytically Controlled Technology' (PACT), which guarantees the required API content in the produced blend. This is, to the best of the authors' knowledge, the first ever application of Raman-spectroscopy in continuous blending and the first Raman-based feedback control in the formulation technology of solid pharmaceuticals. Copyright © 2017 Elsevier B.V. All rights reserved.

LeMMINGs - I. The eMERLIN legacy survey of nearby galaxies. 1.5-GHz parsec-scale radio structures and cores

NASA Astrophysics Data System (ADS)

Baldi, R. D.; Williams, D. R. A.; McHardy, I. M.; Beswick, R. J.; Argo, M. K.; Dullo, B. T.; Knapen, J. H.; Brinks, E.; Muxlow, T. W. B.; Aalto, S.; Alberdi, A.; Bendo, G. J.; Corbel, S.; Evans, R.; Fenech, D. M.; Green, D. A.; Klöckner, H.-R.; Körding, E.; Kharb, P.; Maccarone, T. J.; Martí-Vidal, I.; Mundell, C. G.; Panessa, F.; Peck, A. B.; Pérez-Torres, M. A.; Saikia, D. J.; Saikia, P.; Shankar, F.; Spencer, R. E.; Stevens, I. R.; Uttley, P.; Westcott, J.

2018-05-01

We present the first data release of high-resolution (≤0.2 arcsec) 1.5-GHz radio images of 103 nearby galaxies from the Palomar sample, observed with the eMERLIN array, as part of the LeMMINGs survey. This sample includes galaxies which are active (low-ionization nuclear emission-line regions [LINER] and Seyfert) and quiescent (H II galaxies and absorption line galaxies, ALGs), which are reclassified based upon revised emission-line diagrams. We detect radio emission ≳0.2 mJy for 47/103 galaxies (22/34 for LINERS, 4/4 for Seyferts, 16/51 for H II galaxies, and 5/14 for ALGs) with radio sizes typically of ≲100 pc. We identify the radio core position within the radio structures for 41 sources. Half of the sample shows jetted morphologies. The remaining half shows single radio cores or complex morphologies. LINERs show radio structures more core-brightened than Seyferts. Radio luminosities of the sample range from 1032 to 1040 erg s-1: LINERs and H II galaxies show the highest and lowest radio powers, respectively, while ALGs and Seyferts have intermediate luminosities. We find that radio core luminosities correlate with black hole (BH) mass down to ˜107 M⊙, but a break emerges at lower masses. Using [O III] line luminosity as a proxy for the accretion luminosity, active nuclei and jetted H II galaxies follow an optical Fundamental Plane of BH activity, suggesting a common disc-jet relationship. In conclusion, LINER nuclei are the scaled-down version of FR I radio galaxies; Seyferts show less collimated jets; H II galaxies may host weak active BHs and/or nuclear star-forming cores; and recurrent BH activity may account for ALG properties.

Optical identification of radio-loud active galactic nuclei in the ROSAT-Green-Bank sample with SDSS spectroscopy

NASA Astrophysics Data System (ADS)

Wang, De-Liang; Wang, Jian-Guo; Dong, Xiao-Bo

2009-10-01

Results of extended and refined optical identification of 181 radio/X-ray sources in the RASS-Green Bank (RGB) catalog are presented (Brinkmann et al. 1997) which have been spectroscopically observed in the Sloan Digital Sky Survey (SDSS) DR5. The SDSS spectra of the optical counterparts are modeled in a careful and self-consistent way by incorporating the host galaxy's starlight. Optical emission line parameters are presented, which are derived accurately and reliably, along with the radio 1.4-5 GHz spectral indices estimated using (non-simultaneous) archival data. For 72 sources, the identifications are presented for the first time. It is confirmed that the majority of strong radio/X-ray emitters are radio-loud active galactic nuclei (AGNs), particularly blazars. Taking advantage of the high spectral quality and resolution and our refined spectral modeling, we are able to disentangle narrow line radio galaxies (NLRGs), as vaguely termed in most previous identification work, into Seyfert II galaxies and LINERs (low-ionization nuclear emission regions), based on the standard emission line diagnostics. The NLRGs in the RGB sample, mostly belonging to 'weak line radio galaxies', are found to have optical spectra consistent predominantly with LINERs, and only a small fraction with Seyfert II galaxies. A small number of LINERs have radio power as high as 1023 - 1026 W Hz-1 at 5 GHz, being among the strongest radio emitting LINERs known so far. Two sources are identified with radio-loud narrow line Seyfert 1 galaxies (NLS1s), a class of rare objects. The presence is also confirmed of flat-spectrum radio quasars whose radio-optical-X-ray effective spectral indices are similar to those of High-energy peaked BL Lacs (HBLs), as suggested by Padovani et al., although it is still a debate as to whether this is the case for their actual spectral energy distributions.

Real-world Outcomes in Advanced Urothelial Cancer and the Role of Neutrophil to Lymphocyte Ratio.

PubMed

Yip, Steven M; Kaiser, Jeenan; Li, Haocheng; North, Scott; Heng, Daniel Y C; Alimohamed, Nimira S

2018-06-01

In the first- and second-line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real-world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR). A retrospective analysis was performed on patients with mUC treated with systemic therapy. Overall response rates (ORRs), median time to treatment failure (mTTF), and median overall survival (mOS) were calculated. The association between baseline NLR (using a literature-derived cut-off of 3, as well as the best cut-off NLR value of 5.45 as identified by X-Tile software from this dataset) and mTTF and mOS were evaluated using Cox regression analysis. We evaluated 233 patients. In the first-line, the ORR was 25%. mTTF and mOS were 6.9 months and 9.0 months, respectively. Low baseline NLR was significantly associated with improved 8.3-month mTTF, in contrast to 5.8 months for patients with high NLR (P = .046). Low NLR was significantly correlated with a longer mOS of 13.1 months, compared with high NLR (8.2 months; P = .007). In the second-line, an ORR of 22%, an mTTF of 4.1 months, and an mOS of 8 months were observed. Low NLR in the second-line was significantly associated with improved mTTF at 7.9 months versus high NLR patients (3.3 months; P = .023). Second-line low NLR was significantly associated with a longer mOS of 12.2 months, in comparison to 6.8 months with high NLR (P = .003). In this real-world analysis of patients with mUC, first-line outcomes were lower than expected. Low NLR in the first- and second-line is associated with improved mTTF and mOS. Copyright © 2017 Elsevier Inc. All rights reserved.

Ultra-high density diffraction grating

DOEpatents

Padmore, Howard A.; Voronov, Dmytro L.; Cambie, Rossana; Yashchuk, Valeriy V.; Gullikson, Eric M.

2012-12-11

A diffraction grating structure having ultra-high density of grooves comprises an echellette substrate having periodically repeating recessed features, and a multi-layer stack of materials disposed on the echellette substrate. The surface of the diffraction grating is planarized, such that layers of the multi-layer stack form a plurality of lines disposed on the planarized surface of the structure in a periodical fashion, wherein lines having a first property alternate with lines having a dissimilar property on the surface of the substrate. For example, in one embodiment, lines comprising high-Z and low-Z materials alternate on the planarized surface providing a structure that is suitable as a diffraction grating for EUV and soft X-rays. In some embodiments, line density of between about 10,000 lines/mm to about 100,000 lines/mm is provided.

First-line drugs for hypertension.

PubMed

Wright, James M; Musini, Vijaya M; Gill, Rupam

2018-04-18

This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question. To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment. The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure. The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI. The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed. First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.

The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy

PubMed Central

Hosseinipour, Mina C.; van Oosterhout, Joep J.G.; Weigel, Ralf; Phiri, Sam; Kamwendo, Debbie; Parkin, Neil; Fiscus, Susan A.; Nelson, Julie A.E.; Eron, Joseph J.; Kumwenda, Johnstone

2010-01-01

Background Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi. Methods Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed. Results Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine. Conclusion When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART. PMID:19417582

Electrical power inverter having a phase modulated, twin-inverter, high frequency link and an energy storage module

DOEpatents

Pitel, Ira J.

1987-02-03

The present invention provides an electrical power inverter method and apparatus, which includes a high frequency link, for converting DC power into AC power. Generally stated, the apparatus includes a first high frequency module which produces an AC voltage at a first output frequency, and a second high frequency inverter module which produces an AC voltage at a second output frequency that is substantially the same as the first output frequency. The second AC voltage is out of phase with the first AC voltage by a selected angular phase displacement. A mixer mixes the first and second output voltages to produce a high frequency carrier which has a selected base frequency impressed on the sidebands thereof. A rectifier rectifies the carrier, and a filter filters the rectified carrier. An output inverter inverts the filtered carrier to produce an AC line voltage at the selected base frequency. A phase modulator adjusts the relative angular phase displacement between the outputs of the first and second high frequency modules to control the base frequency and magnitude of the AC line voltage.

Electrical power inverter having a phase modulated, twin-inverter, high frequency link and an energy storage module

DOEpatents

Pitel, I.J.

1987-02-03

The present invention provides an electrical power inverter method and apparatus, which includes a high frequency link, for converting DC power into AC power. Generally stated, the apparatus includes a first high frequency module which produces an AC voltage at a first output frequency, and a second high frequency inverter module which produces an AC voltage at a second output frequency that is substantially the same as the first output frequency. The second AC voltage is out of phase with the first AC voltage by a selected angular phase displacement. A mixer mixes the first and second output voltages to produce a high frequency carrier which has a selected base frequency impressed on the sidebands thereof. A rectifier rectifies the carrier, and a filter filters the rectified carrier. An output inverter inverts the filtered carrier to produce an AC line voltage at the selected base frequency. A phase modulator adjusts the relative angular phase displacement between the outputs of the first and second high frequency modules to control the base frequency and magnitude of the AC line voltage. 19 figs.

Cytotoxicity of lapachol metabolites produced by probiotics.

PubMed

Oliveira Silva, E; Cruz de Carvalho, T; Parshikov, I A; Alves dos Santos, R; Silva Emery, F; Jacometti Cardoso Furtado, N A

2014-07-01

Probiotics are currently added to a variety of functional foods to provide health benefits to the host and are commonly used by patients with gastrointestinal complaints or diseases. The therapeutic effects of lapachol continue to inspire studies to obtain derivatives with improved bioactivity and lower unwanted effects. Therefore, the general goal of this study was to show that probiotics are able to convert lapachol and are important to assess the effects of bacterial metabolism on drug performance and toxicity. The microbial transformations of lapachol were carried out by Bifidobacterium sp. and Lactobacillus acidophilus and different metabolites were produced in mixed and isolated cultures. The cytotoxic activities against breast cancer and normal fibroblast cell lines of the isolated metabolites (4α-hydroxy-2,2-dimethyl-5-oxo-2,3,4,4α,5,9β-hexahydroindeno[1,2-β]pyran-9β-carboxilic acid, a new metabolite produced by mixed culture and dehydro-α-lapachone produced by isolated cultures) were assessed and compared with those of lapachol. The new metabolite displayed a lower activity against a breast cancer cell line (IC50 = 532.7 μmol l(-1) ) than lapachol (IC50 = 72.3 μmol l(-1) ), while dehydro-α-lapachone (IC50 = 10.4 μmol l(-1) ) displayed a higher activity than lapachol. The present study is the first to demonstrate that probiotics are capable of converting lapachol into the most effective cytotoxic compound against a breast cancer cell line. Probiotics have been used in dairy products to promote human health and have the ability to metabolize drugs and other xenobiotics. Naphthoquinones, such as lapachol, are considered privileged scaffolds due to their high propensity to interact with biological targets. The present study is the first to demonstrate that probiotics are capable of converting lapachol into the most effective cytotoxic compound against a breast cancer cell line. The developed approach highlights the importance of probiotics to assess the effects of bacterial metabolism on drug performance and toxicity. © 2014 The Society for Applied Microbiology.

Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients

PubMed Central

Neogi, Ujjwal; Gisslen, Magnus; Hejdeman, Bo; Flamholc, Leo; Sönnerborg, Anders

2017-01-01

Background Switch from first line antiretroviral therapy (ART) to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART. Material and methods Data from 869 patients with 14601 clinical visits between 1999–2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL) levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF). Results Most patients (n = 495; 57.0%) switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2%) or without drug resistance mutations (DRM) (n = 250; 28.8%) experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90–3.96) and 3.20 (95% 2.65–3.75), respectively) compared with those who switched without VF (4.53 years). Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART. Conclusions In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch. PMID:28727795

Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients.

PubMed

Häggblom, Amanda; Santacatterina, Michele; Neogi, Ujjwal; Gisslen, Magnus; Hejdeman, Bo; Flamholc, Leo; Sönnerborg, Anders

2017-01-01

Switch from first line antiretroviral therapy (ART) to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART. Data from 869 patients with 14601 clinical visits between 1999-2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL) levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF). Most patients (n = 495; 57.0%) switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2%) or without drug resistance mutations (DRM) (n = 250; 28.8%) experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90-3.96) and 3.20 (95% 2.65-3.75), respectively) compared with those who switched without VF (4.53 years). Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART. In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch.

FIP bias in a sigmoidal active region

NASA Astrophysics Data System (ADS)

Baker, D.; Brooks, D. H.; Démoulin, P.; van Driel-Gesztelyi, Lidia; Green, L. M.; Steed, K.; Carlyle, J.

2014-01-01

We investigate first ionization potential (FIP) bias levels in an anemone active region (AR) - coronal hole (CH) complex using an abundance map derived from Hinode/EIS spectra. The detailed, spatially resolved abundance map has a large field of view covering 359'' × 485''. Plasma with high FIP bias, or coronal abundances, is concentrated at the footpoints of the AR loops whereas the surrounding CH has a low FIP bias, ~1, i.e. photospheric abundances. A channel of low FIP bias is located along the AR's main polarity inversion line containing a filament where ongoing flux cancellation is observed, indicating a bald patch magnetic topology characteristic of a sigmoid/flux rope configuration.

Long-term complete remission with belinostat in a patient with chemotherapy refractory peripheral T-cell lymphoma.

PubMed

Reimer, Peter; Chawla, Shanta

2013-09-10

Peripheral T/NK-cell lymphomas (PTCL) are rare malignancies with a poor prognosis. Due to the lack of randomised studies, standard therapy has not been established. First-line treatment with anthracycline-based polychemotherapy followed by consolidation with high-dose therapy and autologous stem cell transplant in responding patients has demonstrated good feasibility with low toxicity in prospective studies and is widely used in eligible patients. In relapsed and refractory patients, who are not candidates for transplant approaches, therapeutic options are limited and are usually palliative. Several new agents are currently under investigation to improve the outcome of PTCL in the first line and salvage settings. Belinostat, a histone deacetylase (HDAC) inhibitor, has demonstrated broad antineoplastic activity in preclinical studies, and promising results in advanced relapsed/refractory lymphomas.Here, we report the case of a 73 year old patient with heavily pre-treated refractory PTCL in complete remission with belinostat for 39 months.

Rest-frame Optical Spectra and Black Hole Masses of 3 < z < 6 Quasars

NASA Astrophysics Data System (ADS)

Jun, Hyunsung David; Im, Myungshin; Lee, Hyung Mok; Ohyama, Youichi; Woo, Jong-Hak; Fan, Xiaohui; Goto, Tomotsugu; Kim, Dohyeong; Kim, Ji Hoon; Kim, Minjin; Lee, Myung Gyoon; Nakagawa, Takao; Pearson, Chris; Serjeant, Stephen

2015-06-01

We present the rest-frame optical spectral properties of 155 luminous quasars at 3.3 < z < 6.4 taken with the AKARI space telescope, including the first detection of the Hα emission line as far out as z ∼ 6. We extend the scaling relation between the rest-frame optical continuum and the line luminosity of active galactic nuclei (AGNs) to the high-luminosity, high-redshift regime that has rarely been probed before. Remarkably, we find that a single log-linear relation can be applied to the 5100 Å and Hα AGN luminosities over a wide range of luminosity (1042 < L5100 < 1047 ergs s-1) or redshift (0 < z < 6), suggesting that the physical mechanism governing this relation is unchanged from z = 0 to 6, over five decades in luminosity. Similar scaling relations are found between the optical and the UV continuum luminosities or line widths. Applying the scaling relations to the Hβ black hole (BH) mass (MBH) estimator of local AGNs, we derive the MBH estimators based on the Hα, Mg ii, and C iv lines, finding that the UV-line-based masses are overall consistent with the Balmer-line-based, but with a large intrinsic scatter of 0.40 dex for the C iv estimates. Our 43 MBH estimates from Hα confirm the existence of BHs as massive as ∼ 1010 M⊙ out to z ∼ 5 and provide a secure footing for previous results from Mg ii-line-based studies that a rapid MBH growth has occurred in the early universe.

Plasminogen Activator Production Accompanies Loss of Anchorage Regulation in Transformation of Primary Rat Embryo Cells by Simian Virus 40

PubMed Central

Pollack, R.; Risser, R.; Conlon, S.; Rifkin, D.

1974-01-01

We have isolated several lines of rat embryo cells transformed by simian virus 40. All these lines are fully transformed with regard to saturation density and serum sensitivity, but they differ greatly in their anchorage dependence, as assayed by efficiency of plating in methyl cellulose suspension. This set of lines reveals a consistent relation of plasminogen activator production to plating efficiency in methyl cellulose. T-antigen-positive transformed lines that synthesize activator grow in methyl cellulose suspension, while T-antigen-positive transformed lines that do not synthesize activator fail to form colonies in suspension. Normal rat embryo cells produce very little plasminogen activator and do not grow in methyl cellulose. Sera that permit high levels of plasmin formation and activity support growth in semi-solid medium better than sera whose plasminogen is activated poorly and/or sera that contain inhibitors to plasmin. PMID:4373730

A Required Rotation in Clinical Laboratory Management for Pathology Residents

PubMed Central

Hoda, Syed T.; Crawford, James M.

2016-01-01

Leadership and management training during pathology residency have been identified repeatedly by employers as insufficient. A 1-month rotation in clinical laboratory management (CLM) was created for third-year pathology residents. We report on our experience and assess the value of this rotation. The rotation was one-half observational and one-half active. The observational component involved being a member of department and laboratory service line leadership, both at the departmental and institutional level. Observational participation enabled learning of both the content and principles of leadership and management activities. The active half of the rotation was performance of a project intended to advance the strategic trajectory of the department and laboratory service line. In our program that matriculates 4 residents per year, 20 residents participated from April 2010 through December 2015. Their projects either activated a new priority area or helped propel an existing strategic priority forward. Of the 16 resident graduates who had obtained their first employment or a fellowship position, 9 responded to an assessment survey. The majority of respondents (5/9) felt that the rotation significantly contributed to their ability to compete for a fellowship or their first employment position. The top reported benefits of the rotation included people management; communication with staff, departmental, and institutional leadership; and involvement in department and institutional meetings and task groups. Our 5-year experience demonstrates both the successful principles by which the CLM rotation can be established and the high value of this rotation to residency graduates. PMID:28725766

A Stable Bacterial Peroxidase with Novel Halogenating Activity and an Autocatalytically Linked Heme Prosthetic Group*

PubMed Central

Auer, Markus; Gruber, Clemens; Bellei, Marzia; Pirker, Katharina F.; Zamocky, Marcel; Kroiss, Daniela; Teufer, Stefan A.; Hofbauer, Stefan; Soudi, Monika; Battistuzzi, Gianantonio; Furtmüller, Paul G.; Obinger, Christian

2013-01-01

Reconstructing the phylogenetic relationships of the main evolutionary lines of the mammalian peroxidases lactoperoxidase and myeloperoxidase revealed the presence of novel bacterial heme peroxidase subfamilies. Here, for the first time, an ancestral bacterial heme peroxidase is shown to possess a very high bromide oxidation activity (besides conventional peroxidase activity). The recombinant protein allowed monitoring of the autocatalytic peroxide-driven formation of covalent heme to protein bonds. Thereby, the high spin ferric rhombic heme spectrum became similar to lactoperoxidase, the standard reduction potential of the Fe(III)/Fe(II) couple shifted to more positive values (−145 ± 10 mV at pH 7), and the conformational and thermal stability of the protein increased significantly. We discuss structure-function relationships of this new peroxidase in relation to its mammalian counterparts and ask for its putative physiological role. PMID:23918925

A desirability-based multi objective approach for the virtual screening discovery of broad-spectrum anti-gastric cancer agents

PubMed Central

Sánchez-Rodríguez, Aminael; Tejera, Eduardo; Cruz-Monteagudo, Maykel; Borges, Fernanda; Cordeiro, M. Natália D. S.; Le-Thi-Thu, Huong; Pham-The, Hai

2018-01-01

Gastric cancer is the third leading cause of cancer-related mortality worldwide and despite advances in prevention, diagnosis and therapy, it is still regarded as a global health concern. The efficacy of the therapies for gastric cancer is limited by a poor response to currently available therapeutic regimens. One of the reasons that may explain these poor clinical outcomes is the highly heterogeneous nature of this disease. In this sense, it is essential to discover new molecular agents capable of targeting various gastric cancer subtypes simultaneously. Here, we present a multi-objective approach for the ligand-based virtual screening discovery of chemical compounds simultaneously active against the gastric cancer cell lines AGS, NCI-N87 and SNU-1. The proposed approach relays in a novel methodology based on the development of ensemble models for the bioactivity prediction against each individual gastric cancer cell line. The methodology includes the aggregation of one ensemble per cell line using a desirability-based algorithm into virtual screening protocols. Our research leads to the proposal of a multi-targeted virtual screening protocol able to achieve high enrichment of known chemicals with anti-gastric cancer activity. Specifically, our results indicate that, using the proposed protocol, it is possible to retrieve almost 20 more times multi-targeted compounds in the first 1% of the ranked list than what is expected from a uniform distribution of the active ones in the virtual screening database. More importantly, the proposed protocol attains an outstanding initial enrichment of known multi-targeted anti-gastric cancer agents. PMID:29420638

Comparing Ultraviolet Spectra Against Calculations: First Results

NASA Technical Reports Server (NTRS)

Peterson, Ruth C.

2003-01-01

The five-year goal of this effort is to calculate high fidelity mid-UV spectra for individual stars and stellar systems for a wide range of ages, abundances, and abundance ratios. In this first year, the emphasis was placed on revising the list of atomic line parameters used to calculate mid-UV spectra. First, new identifications of atomic lines and measurements of their transition probabilities were obtained for lines of the first and second ionization stages of iron-peak elements. Second, observed mid-UV and optical spectra for standard stars were re-analyzed and compared to new calculations, to refine the determination of transition probabilities and to estimate the identity of lines still missing from the laboratory lists. As evidenced by the figures, a dramatic improvement has resulted in the reproduction of the spectra of standard stars by the calculations.

Balmer Absorption Lines in FeLoBALs

NASA Astrophysics Data System (ADS)

Aoki, K.; Iwata, I.; Ohta, K.; Tamura, N.; Ando, M.; Akiyama, M.; Kiuchi, G.; Nakanishi, K.

2007-10-01

We discovered non-stellar Balmer absorption lines in two many-narrow-trough FeLoBALs (mntBALs) by the near-infrared spectroscopy with Subaru/CISCO. Presence of the non-stellar Balmer absorption lines is known to date only in the Seyfert galaxy NGC 4151; thus our discovery is the first cases for quasars. Since all known active galactic nuclei with Balmer absorption lines share similar characteristics, it is suggested that there is a population of BAL quasars which have unique structures at their nuclei or unique evolutionary phase.

The Effects of Different On-Line Searching Activities on High School Students' Cognitive Structures and Informal Reasoning regarding a Socio-Scientific Issue

ERIC Educational Resources Information Center

Wu, Ying-Tien; Tsai, Chin-Chung

2011-01-01

Learners' ability in dealing with socio-scientific issues has been highlighted in contemporary science education. This study explored the effects of different on-line searching activities on high school students' cognitive structure outcomes and informal reasoning outcomes. By using a quasi-experimental research approach, thirty-three students…

Sensitivity of grounding line dynamics to basal conditions

NASA Astrophysics Data System (ADS)

Gagliardini, O.; Brondex, J.; Chauveau, G.; Gillet-chaulet, F.; Durand, G.

2017-12-01

In the context of a warming climate, the dynamical contribution of Antarctica to future sea level rise is still tainted by high uncertainties. Among the processes entering these uncertainties is the link between basal hydrology, friction and grounding line dynamics. Recent works have shown how sensitive is the response of the grounding line retreat to the choice of the form of the friction law. Indeed, starting from the same initial state, grounding line retreat rates can range over almost two orders of magnitude depending on the friction law formulation.Here, we use a phenomenological law that depends on the water pressure and allows a continuous transition from a Weertman-type friction at low water pressure to a Coulomb-type friction at high water pressure. This friction law depends on two main parameters that control the Weertman and Coulomb regimes. The range of values for these two parameters is only weakly physically constrained, and it can be shown that, for a given basal shear stress, different couples of parameters can conduct to the same sliding velocity. In addition, we show that close to the grounding line where basal water pressure is high, determining these two parameters might conduct to an ill-posed inverse problem with no solution.The aim of this presentation is to discuss a methodology to guide the choice of the two friction parameters and explore the sensitivity of the grounding line dynamics to this initial choice. We present results obtained both on a synthetic configuration used by the Marine Ice Sheet Model Intercomparison exercise and for the Amundsen sea sector using the experiments proposed by InitMIP-Antarctica, the first exercise in a series of ISMIP6 ice-sheet model intercomparison activities.

Overexpression of Nitrate Reductase in Tobacco Delays Drought-Induced Decreases in Nitrate Reductase Activity and mRNA1

PubMed Central

Ferrario-Méry, Sylvie; Valadier, Marie-Hélène; Foyer, Christine H.

1998-01-01

Transformed (cauliflower mosaic virus 35S promoter [35S]) tobacco (Nicotiana plumbaginifolia L.) plants constitutively expressing nitrate reductase (NR) and untransformed controls were subjected to drought for 5 d. Drought-induced changes in biomass accumulation and photosynthesis were comparable in both lines of plants. After 4 d of water deprivation, a large increase in the ratio of shoot dry weight to fresh weight was observed, together with a decrease in the rate of photosynthetic CO2 assimilation. Foliar sucrose increased in both lines during water stress, but hexoses increased only in leaves from untransformed controls. Foliar NO3− decreased rapidly in both lines and was halved within 2 d of the onset of water deprivation. Total foliar amino acids decreased in leaves of both lines following water deprivation. After 4 d of water deprivation no NR activity could be detected in leaves of untransformed plants, whereas about 50% of the original activity remained in the leaves of the 35S-NR transformants. NR mRNA was much more stable than NR activity. NR mRNA abundance increased in the leaves of the 35S-NR plants and remained constant in controls for the first 3 d of drought. On the 4th d, however, NR mRNA suddenly decreased in both lines. Rehydration at d 3 caused rapid recovery (within 24 h) of 35S-NR transcripts, but no recovery was observed in the controls. The phosphorylation state of the protein was unchanged by long-term drought. There was a strong correlation between maximal extractable NR activity and ambient photosynthesis in both lines. We conclude that drought first causes increased NR protein turnover and then accelerates NR mRNA turnover. Constitutive NR expression temporarily delayed drought-induced losses in NR activity. 35S-NR expression may therefore allow more rapid recovery of N assimilation following short-term water deficit. PMID:9576799

Selective Breeding for Infant Rat Separation-Induced Ultrasonic Vocalizations: Developmental Precursors of Passive and Active Coping Styles

PubMed Central

Brunelli, Susan A.; Hofer, Myron A.

2009-01-01

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate “anxious”/“depressed” phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an “aggressive” phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting “coping styles” with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation. PMID:17543397

Liver metabolism traits in two rabbit lines divergently selected for intramuscular fat.

PubMed

Martínez-Álvaro, M; Paucar, Y; Satué, K; Blasco, A; Hernández, P

2018-06-01

Intramuscular fat (IMF) has a large effect in the sensory properties of meat because it affects tenderness, juiciness and flavour. A divergent selection experiment for IMF in longissimus dorsi (LD) muscle was performed in rabbits. Since liver is the major site of lipogenesis in rabbits, the objective of this work is to study the liver metabolism in the lines of the divergent selection experiment. Intramuscular fat content, perirenal fat weight, liver weight, liver lipogenic activities and plasma metabolites related to liver metabolism were measured in the eighth generation of selection. Direct response on IMF was 0.34 g/100 g of LD, which represented 2.7 SD of the trait, and selection showed a positive correlated response in the perirenal fat weight. High-IMF line showed greater liver size and greater liver lipogenic activities of enzymes glucose-6-phosphate dehydrogenase and malic enzyme. We did not find differences between lines for fatty acid synthase lipogenic activity. With regard to plasma metabolites, low-IMF line showed greater plasma concentration of triglycerides, cholesterol, bilirubin and alkaline phosphatase than high-IMF line, whereas high-IMF line showed greater albumin and alanine transaminase concentrations than low-IMF line. We did not observe differences between lines for glucose, total protein and plasma concentrations. Phenotypic correlations between fat (IMF and perirenal fat weight) and liver traits showed that liver lipogenesis affects fat deposition in both, muscle and carcass. However, the mechanisms whereby liver lipogenesis affected IMF content remain to be clarified.

Agreement between factor XIII activity and antigen assays in measurement of factor XIII: A French multicenter study of 147 human plasma samples.

PubMed

Caron, C; Meley, R; Le Cam Duchez, V; Aillaud, M F; Lavenu-Bombled, C; Dutrillaux, F; Flaujac, C; Ryman, A; Ternisien, C; Lasne, D; Galinat, H; Pouplard, C

2017-06-01

Factor XIII (FXIII) deficiency is a rare hemorrhagic disorder whose early diagnosis is crucial for appropriate treatment and prophylactic supplementation in cases of severe deficiency. International guidelines recommend a quantitative FXIII activity assay as first-line screening test. FXIII antigen measurement may be performed to establish the subtype of FXIII deficiency (FXIIID) when activity is decreased. The aim of this multicenter study was to evaluate the analytical and diagnostic levels of performance of a new latex immunoassay, K-Assay ® FXIII reagent from Stago, for first-line measurement of FXIII antigen. Results were compared to those obtained with the Berichrom ® FXIII chromogenic assay for measurement of FXIII activity. Of the 147 patient plasma samples, 138 were selected for analysis. The accuracy was very good, with intercenter reproducibility close to 7%. Five groups were defined on FXIII activity level (<5% (n = 5), 5%-30% (n = 23), 30%-60% (n = 17), 60%-120% (n = 69), above 120% (n = 24)), without statistical differences between activity and antigen levels (P value >0.05). Correlation of the K-Assay ® with the Berichrom ® FXIII activity results was excellent (r = 0.919). Good agreement was established by the Bland and Altman method, with a bias of +9.4% on all samples, and of -1.4% for FXIII levels lower than 30%. One patient with afibrinogenemia showed low levels of Berichrom ® FXIII activity but normal antigen level and clot solubility as expected. The measurement of FXIII antigen using the K-Assay ® is a reliable first-line tool for detection of FXIII deficiency when an activity assay is not available. © 2017 John Wiley & Sons Ltd.

High invertase activity in tomato reproductive organs correlates with enhanced sucrose import into, and heat tolerance of, young fruit

PubMed Central

Li, Zhimiao; Palmer, William M.; Martin, Antony P.; Wang, Rongqing; Rainsford, Frederick; Jin, Ye; Patrick, John W.; Yang, Yuejian; Ruan, Yong-Ling

2012-01-01

Heat stress can cause severe crop yield losses by impairing reproductive development. However, the underlying mechanisms are poorly understood. We examined patterns of carbon allocation and activities of sucrose cleavage enzymes in heat-tolerant (HT) and -sensitive (HS) tomato (Solanum lycopersicum L.) lines subjected to normal (control) and heat stress temperatures. At the control temperature of 25/20 °C (day/night) the HT line exhibited higher cell wall invertase (CWIN) activity in flowers and young fruits and partitioned more sucrose to fruits but less to vegetative tissues as compared to the HS line, independent of leaf photosynthetic capacity. Upon 2-, 4-, or 24-h exposure to day or night temperatures of 5 °C or more above 25/20 °C, cell wall (CWIN) and vacuolar invertases (VIN), but not sucrose synthase (SuSy), activities in young fruit of the HT line were significantly higher than those of the HS line. The HT line had a higher level of transcript of a CWIN gene, Lin7, in 5-day fruit than the HS line under control and heat stress temperatures. Interestingly, heat induced transcription of an invertase inhibitor gene, INVINH1, but reduced its protein abundance. Transcript levels of LePLDa1, encoding phospholipase D, which degrades cell membranes, was less in the HT line than in the HS line after exposure to heat stress. The data indicate that high invertase activity of, and increased sucrose import into, young tomato fruit could contribute to their heat tolerance through increasing sink strength and sugar signalling activities, possibly regulating a programmed cell death pathway. PMID:22105847

High invertase activity in tomato reproductive organs correlates with enhanced sucrose import into, and heat tolerance of, young fruit.

PubMed

Li, Zhimiao; Palmer, William M; Martin, Antony P; Wang, Rongqing; Rainsford, Frederick; Jin, Ye; Patrick, John W; Yang, Yuejian; Ruan, Yong-Ling

2012-02-01

Heat stress can cause severe crop yield losses by impairing reproductive development. However, the underlying mechanisms are poorly understood. We examined patterns of carbon allocation and activities of sucrose cleavage enzymes in heat-tolerant (HT) and -sensitive (HS) tomato (Solanum lycopersicum L.) lines subjected to normal (control) and heat stress temperatures. At the control temperature of 25/20 °C (day/night) the HT line exhibited higher cell wall invertase (CWIN) activity in flowers and young fruits and partitioned more sucrose to fruits but less to vegetative tissues as compared to the HS line, independent of leaf photosynthetic capacity. Upon 2-, 4-, or 24-h exposure to day or night temperatures of 5 °C or more above 25/20 °C, cell wall (CWIN) and vacuolar invertases (VIN), but not sucrose synthase (SuSy), activities in young fruit of the HT line were significantly higher than those of the HS line. The HT line had a higher level of transcript of a CWIN gene, Lin7, in 5-day fruit than the HS line under control and heat stress temperatures. Interestingly, heat induced transcription of an invertase inhibitor gene, INVINH1, but reduced its protein abundance. Transcript levels of LePLDa1, encoding phospholipase D, which degrades cell membranes, was less in the HT line than in the HS line after exposure to heat stress. The data indicate that high invertase activity of, and increased sucrose import into, young tomato fruit could contribute to their heat tolerance through increasing sink strength and sugar signalling activities, possibly regulating a programmed cell death pathway.

Promises and pitfalls of a Pannexin1 transgenic mouse line.

PubMed

Hanstein, Regina; Negoro, Hiromitsu; Patel, Naman K; Charollais, Anne; Meda, Paolo; Spray, David C; Suadicani, Sylvia O; Scemes, Eliana

2013-01-01

Gene targeting strategies have become a powerful technology for elucidating mammalian gene function. The recently generated knockout (KO)-first strategy produces a KO at the RNA processing level and also allows for the generation of conditional KO alleles by combining FLP/FRT and Cre/loxP systems, thereby providing high flexibility in gene manipulation. However, this multipurpose KO-first cassette might produce hypomorphic rather than complete KOs if the RNA processing module is bypassed. Moreover, the generation of a conditional phenotype is also dependent on specific activity of Cre recombinase. Here, we report the use of an efficient molecular biological approach to test pannexin1 (Panx1) mRNA expression in global and conditional Panx1 KO mice derived from the KO-first mouse line, Panx1(tm1a(KOMP)Wtsi). Using qRT-PCR, we demonstrate that tissues from wild-type (WT) mice show a range of Panx1 mRNA expression levels, with highest expression in trigeminal ganglia, bladder and spleen. Unexpectedly, we found that in mice homozygous for the KO-first allele, Panx1 mRNA expression is not abolished but reduced by 70% compared to that of WT tissues. Thus, Panx1 KO-first mice present a hypomorphic phenotype. Crosses of Panx1 KO-first with FLP deleter mice generated Panx1(f/f) mice. Further crosses of the latter mice with mGFAP-Cre or NFH-Cre mice were used to generate astrocyte- and neuron-specific Panx1 deletions, respectively. A high incidence of ectopic Cre expression was found in offspring of both types of conditional Panx1 KO mice. Our study demonstrates that Panx1 expression levels in the global and conditional Panx1 KO mice derived from KO-first mouse lines must be carefully characterized to ensure modulation of Panx1 gene expression. The precise quantitation of Panx1 expression and its relation to function is expected to provide a foundation for future efforts aimed at deciphering the role of Panx1 under physiological and pathological conditions.

Cabazitaxel overcomes cisplatin resistance in germ cell tumour cells.

PubMed

Gerwing, Mirjam; Jacobsen, Christine; Dyshlovoy, Sergey; Hauschild, Jessica; Rohlfing, Tina; Oing, Christoph; Venz, Simone; Oldenburg, Jan; Oechsle, Karin; Bokemeyer, Carsten; von Amsberg, Gunhild; Honecker, Friedemann

2016-09-01

Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10-30 % of patients develop resistance to cisplatin, requiring salvage therapy. We investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines. In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array. Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT. Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.

Helium liquefaction plant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toscano, W.M.

1981-05-19

In a helium liquefaction plant, a compressor includes first, second and third stages and a precooling section includes first, second and third turboexpanders in series between high and low pressure lines of a heat exchanger. A portion of the medium pressure gas at the output of the second turboexpander is directed back through the heat exchanger and mixed with the output of the first compressor stage. The third turboexpander is positioned between the medium and low pressure lines.

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

PubMed

Mignani, Serge; El Brahmi, Nabil; Eloy, Laure; Poupon, Joel; Nicolas, Valérie; Steinmetz, Anke; El Kazzouli, Said; Bousmina, Mosto M; Blanchard-Desce, Mireille; Caminade, Anne-Marie; Majoral, Jean-Pierre; Cresteil, Thierry

2017-05-26

A multivalent phosphorus dendrimer 1G 3 and its corresponding Cu-complex, 1G 3 -Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G 3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators.

PubMed

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2016-01-01

The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the high basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR.

The polarization and ultraviolet spectrum of Markarian 231

NASA Technical Reports Server (NTRS)

Smith, Paul S.; Schmidt, Gary D.; Allen, Richard G.; Angel, J. R. P.

1995-01-01

Ultraviolet spectropolarimetry acquired with the Hubble Space Telescope (HST) of the peculiar Seyfert galaxy Mrk 231 is combined with new high-quality ground-based measurements to provide the first, nearly complete, record of its linear polarization from 1575 to 7900 A. The accompanying ultraviolet spectrum portrays the heavily extinguished emission-line spectrum of the active nucleus plus the emergence of a blue continuum shortward of approximately 2400 A. In addition, absorption features due to He I lambda 3188, Mg I lambda 2853, Mg II lambda 2798, and especially several resonance multiplets of Fe II are identified with a well-known optical absorption system blueshifted approximately 4600 km/s with respect to emission lines. The continuum is attributed to approximately 10(exp 5) hot, young stars surrounding the nucleus. This component dilutes the polarized nuclear light, implying that the intrinsic polarization of the active galactic nucleus (AGN) spectrum approaches 20% at 2800 A. The rapid decline in degree of polarization toward longer wavelengths is best explained by the strongly frequency-dependent scattering cross section of dust grains coupled with modest starlight dilution. Peculiar S-shaped inflections in both the degree and position angle of polarization through H alpha and other major emission lines are interpreted as effects of scattering from two regions offset in velocity by several hundred km/s. A third source of (weakly) polarized flux is required to explain a nearly 40 deg rotation in position angle between 3200 and 1800 A. The displaced absorption features, polarimetry, and optical/infrared properties of Mrk 231 all point to its classification as a low-ionization, or Mg II broad absorption line quasar, in which most, if not all, lines of sight to the active nucleus are heavily obscured by dust and low-ionization gas clouds.

Study of phytochemical, anti-microbial, anti-oxidant, and anti-cancer properties of Allium wallichii.

PubMed

Bhandari, Jaya; Muhammad, BushraTaj; Thapa, Pratiksha; Shrestha, Bhupal Govinda

2017-02-08

There is growing interest in the use of plants for the treatment and prevention of cancer. Medicinal plants are currently being evaluated as source of promising anticancer agents. In this paper, we have investigated the anticancer potential of plant Allium wallichii, a plant native to Nepal and growing at elevations of 2300-4800 m. This is the first study of its kind for the plant mentioned. The dried plant was extracted in aqueous ethanol. Phytochemical screening, anti-microbial assay, anti-oxidant assay, cytotoxicity assay and the flow-cytometric analysis were done for analyzing different phytochemicals present, anti-microbial activity, anti-oxidant activity and anti-cancer properties of Allium wallichii. We observed the presence of steroids, terpenoids, flavonoids, reducing sugars and glycosides in the plant extract and the plant showed moderate anti-microbial and anti-oxidant activity. The IC 50 values of Allium wallichii in different cancer cell lines are 69.69 μg/ml for Prostate cancer (PC3) cell line, 55.29 μg/ml for Breast Cancer (MCF-7) cell line and 46.51 μg/ml for cervical cancer (HeLa) cell line as compared to Doxorubicin (0.85 μg/ml). The cell viability assay using FACS showed that the IC 50 value of Allium wallichii for Burkitt's lymphoma (B-Lymphoma) cell line was 3.817 ± 1.99 mg/ml. Allium wallichii can be an important candidate to be used as an anticancer agent. Separation of pure compounds with bioassay guided extraction, spectrometric analysis and subsequent cytotoxicity assay of the pure bioactive compounds from Allium wallichii is highly recommended as the crude extract itself showed promising cytotoxicity.

A DEEP X-RAY VIEW OF THE BARE AGN ARK 120. I. REVEALING THE SOFT X-RAY LINE EMISSION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reeves, J. N.; Braito, V.; Porquet, D.

2016-09-10

The Seyfert 1 galaxy Ark 120 is a prototype example of the so-called class of bare nucleus active galactic nuclei (AGNs), whereby there is no known evidence for the presence of ionized gas along the direct line of sight. Here deep (>400 ks exposure), high-resolution X-ray spectroscopy of Ark 120 is presented from XMM-Newton observations that were carried out in 2014 March, together with simultaneous Chandra /High Energy Transmission Grating exposures. The high-resolution spectra confirmed the lack of intrinsic absorbing gas associated with Ark 120, with the only X-ray absorption present originating from the interstellar medium (ISM) of our ownmore » Galaxy, with a possible slight enhancement of the oxygen abundance required with respect to the expected ISM values in the solar neighborhood. However, the presence of several soft X-ray emission lines are revealed for the first time in the XMM-Newton RGS spectrum, associated with the AGN and arising from the He- and H-like ions of N, O, Ne, and Mg. The He-like line profiles of N, O, and Ne appear velocity broadened, with typical FWHMs of ∼5000 km s{sup −1}, whereas the H-like profiles are unresolved. From the clean measurement of the He-like triplets, we deduce that the broad lines arise from a gas of density n {sub e} ∼ 10{sup 11} cm{sup −3}, while the photoionization calculations infer that the emitting gas covers at least 10% of 4 π steradian. Thus the broad soft X-ray profiles appear coincident with an X-ray component of the optical–UV broad-line region on sub-parsec scales, whereas the narrow profiles originate on larger parsec scales, perhaps coincident with the AGN narrow-line region. The observations show that Ark 120 is not intrinsically bare and substantial X-ray-emitting gas exists out of our direct line of sight toward this AGN.« less

PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonen, Nitzan; Bram, Eran E.; Assaraf, Yehuda G.

2008-11-28

The proton-coupled folate transporter (PCFT/SLC46A1) displays optimal and prominent folate and antifolate transport activity at acidic pH in human carcinoma cells but poor activity in leukemia cells. Consistently herein, human leukemia cell lines expressed poor PCFT transcript levels, whereas various carcinoma cell lines showed substantial PCFT gene expression. We identified a CpG island with high density at nucleotides -200 through +100 and explored its role in PCFT promoter silencing. Leukemia cells with barely detectable PCFT transcripts consistently harbored 85-100% methylation of this CpG island, whereas no methylation was found in carcinoma cells. Treatment with 5-Aza-2'-deoxycytidine which induced demethylation but notmore » with the histone deacetylase inhibitor trichostatin A, restored 50-fold PCFT expression only in leukemia cells. These findings constitute the first demonstration of the dominant epigenetic silencing of the PCFT gene in leukemia cells. The potential translational implications of the restoration of PCFT expression in chemotherapy of leukemia are discussed.« less

Melting properties of Pt and its transport coefficients in liquid states under high pressures

NASA Astrophysics Data System (ADS)

Wang, Pan-Pan; Shao, Ju-Xiang; Cao, Qi-Long

2016-11-01

Molecular dynamics (MD) simulations of the melting and transport properties in liquid states of platinum for the pressure range (50-200 GPa) are reported. The melting curve of platinum is consistent with previous ab initio MD simulation results and the first-principles melting curve. Calculated results for the pressure dependence of fusion entropy and fusion volume show that the fusion entropy and the fusion volume decrease with increasing pressure, and the ratio of the fusion volume to fusion entropy roughly reproduces the melting slope, which has a moderate decrease along the melting line. The Arrhenius law well describes the temperature dependence of self-diffusion coefficients and viscosity under high pressure, and the diffusion activation energy decreases with increasing pressure, while the viscosity activation energy increases with increasing pressure. In addition, the entropy-scaling law, proposed by Rosenfeld under ambient pressure, still holds well for liquid Pt under high pressure conditions.

Chromospheres of late-type active and quiescent dwarfs. III - Variability of CA II H emission profiles

NASA Astrophysics Data System (ADS)

Garcia Lopez, R. J.; Crivellari, L.; Beckman, J. E.; Rebolo, R.

1992-08-01

We have used high-resolution spectra of the Ca II H resonance line in late-type dwarfs, obtained with high S:N ratios, over a period of four years to widen our understanding of the dynamical behavior of the Ca II emission cores. All of the stars dealt with in this article, which are chromospherically active, show variability both in core emission flux and line width. They also show significant wavelength shifts with time of order hundreds of meters per second in the mean core wavelength, and with lower amplitude in the H3 self-absorption, compared to the photospheric rest wavelength of Ca II H. Comparing the emission core shifts with those observed in the H3 features, we find, for the first time, direct prima facie evidence for vertical chromospheric velocity fields, which show stability in sense over periods of years in a given star, with notable modulation in gradient, and which differ in gradient from star to star. We present evidence to show that the observed effects are almost certainly not due to projected rotational modulation, and offer new prospects, given spectral measurements closely sampled in time, for investigating the vertical velocity structures of chromospheres.

The year's new drugs & biologics, 2014: Part I.

PubMed

Graul, A I; Cruces, E; Stringer, M

2015-01-01

A year-end wrap-up of new drug approvals and launches reveals that activity in the pharmaceutical industry continues at a high level, with 55 new drugs and biologics introduced on their first markets in 2014 (as of December 23, 2014). Additionally, 29 important new line extensions (new formulations, new combinations or new indications for previously marketed products) also reached their first markets during the year. The most active therapeutic group in terms of new launches was anti-infective therapies, with 11 new drugs and biologics launched, most for the treatment of multidrug-resistant bacterial infections or hepatitis C. The most active market for new launches was again the U.S., site of more than half of all new launches in 2014. However new launch activity increased considerably last year in Japan, which actually pulled ahead of the E.U. for the first time in many years. In another important new development, 15 of the new drugs and biologics launched last year had orphan drug status, 5 had breakthrough therapy designation and 3 had Qualified Infectious Disease Product (QIDP) status. Another 19 products were approved for the first time during the year but not yet launched by close of this article; most are slated for launch in the first months of the new year. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII produced in a human cell-line.

PubMed

Winge, Stefan; Yderland, Louise; Kannicht, Christoph; Hermans, Pim; Adema, Simon; Schmidt, Torben; Gilljam, Gustav; Linhult, Martin; Tiemeyer, Maya; Belyanskaya, Larisa; Walter, Olaf

2015-11-01

Human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII (rFVIII), is the first rFVIII produced in a human cell-line approved by the European Medicines Agency. To describe the development, upscaling and process validation for industrial-scale human-cl rhFVIII purification. The purification process involves one centrifugation, two filtration, five chromatography columns and two dedicated pathogen clearance steps (solvent/detergent treatment and 20 nm nanofiltration). The key purification step uses an affinity resin (VIIISelect) with high specificity for FVIII, removing essentially all host-cell proteins with >80% product recovery. The production-scale multi-step purification process efficiently removes process- and product-related impurities and results in a high-purity rhFVIII product, with an overall yield of ∼50%. Specific activity of the final product was >9000 IU/mg, and the ratio between active FVIII and total FVIII protein present was >0.9. The entire production process is free of animal-derived products. Leaching of potential harmful compounds from chromatography resins and all pathogens tested were below the limit of quantification in the final product. Human-cl rhFVIII can be produced at 500 L bioreactor scale, maintaining high purity and recoveries. The innovative purification process ensures a high-purity and high-quality human-cl rhFVIII product with a high pathogen safety margin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

[Blonanserin in the treatment of schizophrenia].

PubMed

Tenjin, Tomomi; Miyamoto, Seiya

2013-04-01

Blonanserin was developed in Japan in 2008 as an antipsychotic drug. It has high affinity for dopamine D2/3 and serotonin 5-HT2A receptors, but shows low affinity for adrenergic alpha1, histamine H1, and muscarinic M1 receptors. Several short-term double-blind trials demonstrated that blonanserin was well tolerated and had equal efficacy to haloperidol and risperidone in terms of positive symptoms and depressive symptoms in patients with chronic schizophrenia. It was also superior to haloperidol in improving negative symptoms. We have recently reported that blonanserin may improve some types of cognitive function associated with the frontal lobe activity in patients with first-episode schizophrenia. Taken together, blonanserin may be a promising candidate for a first-line antipsychotic for patients with first-episode and chronic schizophrenia.

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias.

PubMed

Muriel, Carolina; Esteban, Emilio; Corral, Norberto; Fonseca, Paula J; Luque, María; Berros, José Pablo; Fernández, Yolanda; Blay, Pilar; Fra, Joaquín; Villanueva, Noemí; Sanmamed, Miguel; Pardo, Pablo; Izquierdo, Marta; Vieitez, José María; Estrada, Enrique; Lacave, Ángel J

2010-08-01

For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second-line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.

SEMI-EMPIRICAL MODELING OF THE PHOTOSPHERE, CHROMOPSHERE, TRANSITION REGION, AND CORONA OF THE M-DWARF HOST STAR GJ 832

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fontenla, J. M.; Linsky, Jeffrey L.; Witbrod, Jesse

Stellar radiation from X-rays to the visible provides the energy that controls the photochemistry and mass loss from exoplanet atmospheres. The important extreme ultraviolet (EUV) region (10–91.2 nm) is inaccessible and should be computed from a reliable stellar model. It is essential to understand the formation regions and physical processes responsible for the various stellar emission features to predict how the spectral energy distribution varies with age and activity levels. We compute a state-of-the-art semi-empirical atmospheric model and the emergent high-resolution synthetic spectrum of the moderately active M2 V star GJ 832 as the first of a series of modelsmore » for stars with different activity levels. We construct a one-dimensional simple model for the physical structure of the star’s chromosphere, chromosphere-corona transition region, and corona using non-LTE radiative transfer techniques and many molecular lines. The synthesized spectrum for this model fits the continuum and lines across the UV-to-optical spectrum. Particular emphasis is given to the emission lines at wavelengths that are shorter than 300 nm observed with the Hubble Space Telescope , which have important effects on the photochemistry of the exoplanet atmospheres. The FUV line ratios indicate that the transition region of GJ 832 is more biased to hotter material than that of the quiet Sun. The excellent agreement of our computed EUV luminosity with that obtained by two other techniques indicates that our model predicts reliable EUV emission from GJ 832. We find that the unobserved EUV flux of GJ 832, which heats the outer atmospheres of exoplanets and drives their mass loss, is comparable to the active Sun.« less

Feasibility of line-ratio spectroscopy on helium and neon as edge diagnostic tool for Wendelstein 7-X

DOE PAGES

Barbui, T.; Krychowiak, M.; König, R.; ...

2016-09-27

A beam emission spectroscopy system on thermal helium (He) and neon (Ne) has been set up at Wendelstein 7-X to measure edge electron temperature and density profiles utilizing the line-ratio technique or its extension by the analysis of absolutely calibrated line emissions. The setup for a first systematic test of these techniques of quantitative atomic spectroscopy in the limiter startup phase (OP1.1) is reported together with first measured profiles. Lastly, this setup and the first results are an important test for developing the technique for the upcoming high density, low temperature island divertor regime.

Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002).

PubMed

Miyauchi, Eisaku; Inoue, Akira; Kobayashi, Kunihiko; Maemondo, Makoto; Sugawara, Shunichi; Oizumi, Satoshi; Isobe, Hiroshi; Gemma, Akihiko; Saijo, Yasuo; Yoshizawa, Hirohisa; Hagiwara, Koichi; Nukiwa, Toshihiro

2015-07-01

Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptor mutations (the NEJ002 study). Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0). Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first- and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant. The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence the efficacy of second-line platinum-based chemotherapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Antioxidant potential, cytotoxic activity and total phenolic content of Alpinia pahangensis rhizomes.

PubMed

Phang, Chung-Weng; Malek, Sri Nurestri Abd; Ibrahim, Halijah

2013-10-01

Alpinia pahangensis, a wild ginger distributed in the lowlands of Pahang, Malaysia, is used by the locals to treat flatulence. In this study, the antioxidant and cytotoxic activities of the crude aqueous methanol and fractionated extracts of Alpinia pahangensis against five different cancer and one normal cell lines were investigated. The total phenolic content of each extract and its fractions were also quantified. This is the first report on the antioxidant and cytotoxic activities of Alpinia pahangensis extract. In the current study, the crude methanol and fractionated extract of the rhizomes of Alpinia pahangensis were investigated for their antioxidant activity using four different assays namely, the DPPH scavenging activity, superoxide anion scavenging, β-carotene bleaching and reducing power assays whilst their phenolic contents were measured by the Folin-Ciocalteu's method.In vitro neutral red cytotoxicity assay was employed to evaluate the cytotoxic activity against five different cancer cell lines, colon cancer (HCT 116 and HT-29), cervical cancer (Ca Ski), breast cancer (MCF7) and lung cancer (A549) cell lines, and one normal cell line (MRC-5). The extract that showed high cytotoxic activity was further investigated for its chemical constituents by GC-MS (gas chromatography-mass spectrometry) analysis. The ethyl acetate fraction showed the strongest DPPH radical scavenging (0.35 ± 0.094 mg/ml) and SOD activities (51.77 ± 4.9%) whilst the methanol extract showed the highest reducing power and also the strongest antioxidant activity in the β-carotene bleaching assays in comparison to other fractions. The highest phenolic content was found in the ethyl acetate fraction, followed by the crude methanol extract, hexane and water fractions. The results showed a positive correlation between total phenolic content with DPPH radical scavenging capacities and SOD activities. The hexane fraction showed potent cytotoxic effect against KB, Ca Ski and HCT 116 cell lines with IC₅₀ of 5.8 ± 0.1 and 9.1 ± 2.0 ug/ml, respectively. The major components of hexane fraction analysed by GC-MS analysis were mostly methyl esters. The current study suggests that the methanol extract and ethyl acetate fraction of A. pahangensis is a potential source of natural antioxidant for protective as well as prevention of life-threatening diseases. The hexane fraction of A. pahangensis may have the potential to be developed into therapeutic option for treating cancer.

Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities

NASA Astrophysics Data System (ADS)

Zhan, Guanqun; Qu, Xiaolan; Liu, Junjun; Tong, Qingyi; Zhou, Junfei; Sun, Bin; Yao, Guangmin

2016-09-01

Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 μM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary.

Antioxidant enzymes activity and phenolic compounds content in red cabbage seedlings exposed to copper stress.

PubMed

Posmyk, M M; Kontek, R; Janas, K M

2009-02-01

The phenolics: anthocyanin (ATH), sinapoyl esters and activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POX), ascorbate peroxidase (APX), glutathione peroxidase (GPX) and glutathione reductase (GR), in red cabbage seedlings subjected to Cu2+ stress were investigated. Cu2+ at low doses (0.5 mM), increased the levels of ATH and sinapoyl derivatives in red cabbage. High Cu2+ concentration (2.5 mM) provoked oxidative stress and enhanced thiobarbituric acid reactive substances (TBARS) content in tissues. A lower level of TBARS was correlated with high ATH content. It seems that synthesis of these isoflavonoids is an effective strategy against reactive oxygen species (ROS). The analysis of the antioxidant enzymes activity suggested that peroxidases were the most active enzymes in red cabbage seedlings exposed to Cu2+ stress. It could results from the fact that phenolic compounds (PhC), which could be also substrates for different peroxidases, were the first line of defence against metal stress.

The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity.

PubMed

Chen, Peng-Hsu; Shen, Wan-Lin; Shih, Chwen-Ming; Ho, Kuo-Hao; Cheng, Chia-Hsiung; Lin, Cheng-Wei; Lee, Chin-Cheng; Liu, Ann-Jeng; Chen, Ku-Chung

2017-04-01

Glioblastoma multiforme (GBM) is the high-grade primary glioma in adults. Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug for clinical therapy. However, the expense of TMZ therapy and increasing drug resistance to TMZ decreases its therapeutic effects. Therefore, our aim was to investigate the detailed molecular mechanisms of TMZ-mediated cytotoxicity to enhance the efficacy of TMZ in clinical GBM therapy. First, TMZ-mediated gene expression profiles and networks in U87-MG cells were identified by transcriptome microarray and bioinformatic analyses. Cation transport regulator-like protein 1 (CHAC1) was the most highly TMZ-upregulated gene. Overexpression and knockdown of CHAC1 expression significantly influenced TMZ-mediated cell viability, apoptosis, caspase-3 activation, and poly(ADP ribose) polymerase (PARP) degradation. The c-Jun N-terminal kinase (JNK)1/c-JUN pathway was identified to participate in TMZ-upregulated CHAC1 expression via transcriptional control. Furthermore, CHAC1 levels were significantly decreased in GBM cell lines, TCGA array data, and tumor tissues. Overexpression of CHAC1 enhanced glioma apoptotic death via caspase-3/9 activation, PARP degradation, autophagy formation, reactive oxygen species generation, increased intracellular calcium, and loss of the mitochondria membrane potential. Finally, we also identified that TMZ significantly reduced Notch3 levels, which are upregulated in gliomas. TMZ also induced CHAC1 to bind to the Notch3 protein and inhibit Notch3 activation, resulting in attenuation of Notch3-mediated downstream signaling pathways. These results emphasize that CHAC1-inhibited Notch3 signaling can influence TMZ-mediated cytotoxicity. Our findings may provide novel therapeutic strategies for future glioblastoma therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Polyphenol oxidase activity and differential accumulation of polyphenolics in seed coats of pinto bean (Phaseolus vulgaris L.) characterize postharvest color changes.

PubMed

Marles, M A Susan; Vandenberg, Albert; Bett, Kirstin E

2008-08-27

Postharvest darkening of pinto bean (Phaseolus vulgaris L.) was evaluated in a population of recombinant inbred lines derived from a cross between CDC Pintium (a regular-darkening line) and 1533-15 (a slow-darkening line). Flavonoid metabolite concentrations, polyphenol oxidase activity, lignin concentration, and seed coat anatomy characteristics were assessed for cosegregation with the darkening phenotype. Significantly lower kaempferol concentrations (p = 0.00001) together with differences in polyphenol oxidase activity (p = 0.0045) were two of the key findings associated with these recombinant inbred lines. In addition, two different assays (thioglycolic acid and Klason lignin) to quantify lignin together with an assessment of extractable condensed tannin were used to estimate the contribution of these polymers to changes in the seed coat tissue. This is the first report of precise biochemical characterization of polyphenolics that associate with postharvest darkening in legumes.

Icotinib is an active treatment of non-small-cell lung cancer: a retrospective study.

PubMed

Chen, Xiaofeng; Zhu, Quan; Liu, Yiqian; Liu, Ping; Yin, Yongmei; Guo, Renhua; Lu, Kaihua; Gu, Yanhong; Liu, Lianke; Wang, Jinghua; Wang, Zhaoxia; Røe, Oluf Dimitri; Shu, Yongqian; Zhu, Lingjun

2014-01-01

Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC). 82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method. Median PFS was 4.0 months (95% CI 2.311-5.689). Median OS was 11.0 months (95% CI 8.537-13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151-11.8) and 3.0 months (95% CI 1.042-4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305-15.695) and 10.0 months (95% CI 7.295-12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18-0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02-0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%). Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile.

Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents.

PubMed

Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, M Natália D S

2012-08-01

The discovery of new and more potent anti-cancer agents constitutes one of the most active fields of research in chemotherapy. Colorectal cancer (CRC) is one of the most studied cancers because of its high prevalence and number of deaths. In the current pharmaceutical design of more efficient anti-CRC drugs, the use of methodologies based on Chemoinformatics has played a decisive role, including Quantitative-Structure-Activity Relationship (QSAR) techniques. However, until now, there is no methodology able to predict anti-CRC activity of compounds against more than one CRC cell line, which should constitute the principal goal. In an attempt to overcome this problem we develop here the first multi-target (mt) approach for the virtual screening and rational in silico discovery of anti-CRC agents against ten cell lines. Here, two mt-QSAR classification models were constructed using a large and heterogeneous database of compounds. The first model was based on linear discriminant analysis (mt-QSAR-LDA) employing fragment-based descriptors while the second model was obtained using artificial neural networks (mt-QSAR-ANN) with global 2D descriptors. Both models correctly classified more than 90% of active and inactive compounds in training and prediction sets. Some fragments were extracted from the molecules and their contributions to anti-CRC activity were calculated using mt-QSAR-LDA model. Several fragments were identified as potential substructural features responsible for the anti-CRC activity and new molecules designed from those fragments with positive contributions were suggested and correctly predicted by the two models as possible potent and versatile anti-CRC agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

Observations and NLTE modeling of Ellerman bombs

NASA Astrophysics Data System (ADS)

Berlicki, A.; Heinzel, P.

2014-07-01

Context. Ellerman bombs (EBs) are short-lived, compact, and spatially well localized emission structures that are observed well in the wings of the hydrogen Hα line. EBs are also observed in the chromospheric CaII lines and in UV continua as bright points located within active regions. Hα line profiles of EBs show a deep absorption at the line center and enhanced emission in the line wings with maxima around ±1 Å from the line center. Similar shapes of the line profiles are observed for the CaII IR line at 8542 Å. In CaII H and K lines the emission peaks are much stronger, and EBs emission is also enhanced in the line center. Aims: It is generally accepted that EBs may be considered as compact microflares located in lower solar atmosphere that contribute to the heating of these low-lying regions, close to the temperature minimum of the atmosphere. However, it is still not clear where exactly the emission of EBs is formed in the solar atmosphere. High-resolution spectrophotometric observations of EBs were used for determining of their physical parameters and construction of semi-empirical models. Obtained models allow us to determine the position of EBs in the solar atmosphere, as well as the vertical structure of the activated EB atmosphere Methods: In our analysis we used observations of EBs obtained in the Hα and CaII H lines with the Dutch Open Telescope (DOT). These one-hour long simultaneous sequences obtained with high temporal and spatial resolution were used to determine the line emissions. To analyze them, we used NLTE numerical codes for the construction of grids of 243 semi-empirical models simulating EBs structures. In this way, the observed emission could be compared with the synthetic line spectra calculated for all such models. Results: For a specific model we found reasonable agreement between the observed and theoretical emission and thus we consider such model as a good approximation to EBs atmospheres. This model is characterized by an enhanced temperature in the lower chromosphere and can be considered as a compact structure (hot spot), which is responsible for the emission observed in the wings of chromospheric lines, in particular in the Hα and CaII H lines. Conclusions: For the first time the set of two lines Hα and CaII H was used to construct semi-empirical models of EBs. Our analysis shows that EBs can be described by a "hot spot" model, with the temperature and/or density increase through a few hundred km atmospheric structure. We confirmed that EBs are located close to the temperature minimum or in the lower chromosphere. Two spectral features (lines in our case), observed simultaneously, significantly strengthen the constraints on a realistic model.

In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis.

PubMed Central

Rastogi, N; Goh, K S; Bryskier, A; Devallois, A

1996-01-01

By using the radiometric BACTEC 460-TB methodology, the inhibitory and bactericidal activity of the optically active L-isomer of ofloxacin (levofloxacin) was compared with those of the D-isomer and the commercially available mixture containing equal amounts of DL-isomers (ofloxacin) against the Mycobacterium tuberculosis complex (type strain H37Rv, a panel of drug-susceptible and -resistant clinical isolates including multidrug-resistant isolates of M. tuberculosis, as well as M. africanum, M. bovis, and M. bovis BCG). Levofloxacin MICs (range 0.50 to 0.75 microgram/ml) were about 1 dilution lower than those of ofloxacin (MIC range, 0.75 to 1.00 microgram/ml) and 5 to 6 dilutions lower than those of the D-isomer (MIC range, 32 to 60 micrograms/ml). The MICs of levofloxacin, ofloxacin, and D-ofloxacin at which 90% of the strains are inhibited were 0.50, 1.00, and 64 micrograms/ml, respectively. The multidrug-resistant M. tuberculosis strains resistant to first-line drugs were as susceptible to quinolones as the wild-type drug-susceptible isolates. Levofloxacin at 0.5 microgram/ml showed bactericidal activity comparable to the activities of 1.0 microgram of ofloxacin per ml and 64 micrograms of D-ofloxacin per ml, with MBCs within the range of 0.5 to 2.0 micrograms/ml, compared with MBCs of 0.75 to 4.0 micrograms of ofloxacin per ml for M. tuberculosis, M. africanum, M. bovis BCG. Combination testing of sub-MICs of levolofoxacin with other first-line (isoniazid, rifampin, and ethambutol) and second-line (amikacin and clofazimine) antituberculous drugs was evaluated with various two-, three-, and four-drug combinations; enhanced drug activity was observed in 8 of 25, 12 of 20, and 8 of 15 tests, respectively, indicating that levofloxacin acts in synergy with other antituberculous drugs. PMID:8807049

Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy.

PubMed

Oluwasanmi, Adeolu; Al-Shakarchi, Wejdan; Manzur, Ayesha; Aldebasi, Mohammed H; Elsini, Rayan S; Albusair, Malek K; Haxton, Katherine J; Curtis, Anthony D M; Hoskins, Clare

2017-11-28

Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4.3 times less cytotoxic than gemcitabine, but exhibited 11-fold improvement in cellular uptake. Heat activation of the formulation led to a 56% rise in cytotoxicity causing it to outperform gemcitabine by 26%. In vivo the formulation outperformed free gemcitabine with a 62% reduction in tumor weight in pancreatic xenografts. This HNP formulation is the first of its kind and has displayed superior anti-cancer activity as compared to the current first line drug gemcitabine after heat mediated controlled release. Copyright © 2017 Elsevier B.V. All rights reserved.

Shock wave trauma leads to inflammatory response and morphological activation in macrophage cell lines, but does not induce iNOS or NO synthesis.

PubMed

Günther, Mattias; Plantman, Stefan; Gahm, Caroline; Sondén, Anders; Risling, Mårten; Mathiesen, Tiit

2014-12-01

Experimental CNS trauma results in post-traumatic inflammation for which microglia and macrophages are vital. Experimental brain contusion entails iNOS synthesis and formation of free radicals, NO and peroxynitrite. Shock wave trauma can be used as a model of high-energy trauma in cell culture. It is known that shock wave trauma causes sub-lytic injury and inflammatory activation in endothelial cells. Mechanical disruption of red blood cells can induce iNOS synthesis in experimental systems. However, it is not known whether trauma can induce activation and iNOS synthesis in inflammatory cell lines with microglial or macrophage lineage. We studied the response and activation in two macrophage cell lines and the consequence for iNOS and NO formation after shock wave trauma. Two macrophage cell lines from rat (NR8383) and mouse (RAW264.7) were exposed to shock wave trauma by the Flyer Plate method. The cellular response was investigated by Affymetrix gene arrays. Cell survival and morphological activation was monitored for 24 h in a Cell-IQ live cell imaging system. iNOS induction and NO synthesis were analyzed by Western blot, in cell Western IR-immunofluorescence, and Griess nitrite assay. Morphological signs of activation were detected in both macrophage cell lines. The activation of RAW264.7 was statistically significant (p < 0.05), but activation of NR8383 did not pass the threshold of statistical significance alpha (p > 0.05). The growth rate of idle cells was unaffected and growth arrest was not seen. Trauma did not result in iNOS synthesis or NO induction. Gene array analyses showed high enrichment for inflammatory response, G-protein coupled signaling, detection of stimulus and chemotaxis. Shock wave trauma combined with low LPS stimulation instead led to high enrichment in apoptosis, IL-8 signaling, mitosis and DNA-related activities. LPS/IFN-ɣ stimulation caused iNOS and NO induction and morphological activation in both cell lines. Shock wave trauma by the Flyer Plate method caused an inflammatory response and morphological signs of activation in two macrophage cell lines, while iNOS induction appeared to require humoral signaling by LPS/IFN-ɣ. Our findings indicated that direct energy transfer by trauma can activate macrophages directly without humoral mediators, which comprises a novel activation mechanism of macrophages.

Functional Teas from the Leaves of Arbutus unedo: Phenolic Content, Antioxidant Activity, and Detection of Efficient Radical Scavengers.

PubMed

Erkekoglou, Ioannis; Nenadis, Nikolaos; Samara, Efrosini; Mantzouridou, Fani Th

2017-06-01

The phenolic content/composition and antioxidant activity of hot/cold infusion and decoction from the leaves of Arbutus unedo were studied for the first time. 1,1-diphenyl-2-picrylhydrazyl (DPPH ● ), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS ●+ ), crocin-bleaching, copper-reducing, and liposome accelerated oxidation assays were used for the evaluation of the activity in vitro. In vivo, the extracts were examined for their ability to protect S. cerevisiae cells from H 2 O 2 induced oxidative stress. An on-line high-performance liquid chromatography-DPPH ● assay was applied to identify potent radical scavengers and comment on their contribution to the total activity. The addition of leaves to boiling water (decoction) was the most appropriate practice to apply since the highest phenol intake (220.2 mg gallic acid/cup served) was obtained. Additionally, its antioxidant activity was equal or superior to that of the other extracts. Flavonols (~51-61 mg/g dry extract) were the main phenols in all the extracts, with quercitrin accounting for ~20% of the total phenol amount. The on-line DPPH ● method verified the high potency of the decoction and indicated as the most active radical scavengers, two galloylquinic acid derivatives and myricitrin, accounting for ~28-45% and ~11-13% of the total scavenging, respectively. Present data may contribute to the future exploitation of A. unedo leaves by the food industry for health-promoting herbal tea preparations and dietary supplements.

The first total synthesis and biological evaluation of marine natural products ma'edamines A and B.

PubMed

Saha, Sanjay; Venkata Ramana Reddy, Ch; Chiranjeevi, T; Addepally, Uma; Chinta Rao, T S; Patro, Balaram

2013-02-15

We have developed the first total syntheses of marine natural products ma'edamines A (18) and B (20). Structurally, they contain a pyrazine-2-(1H)-one core and were screened for antiproliferative activity on several cancer cell lines. Out of the six cell lines tested, ma'edamines A and B showed significant cytotoxicity against human colon cancer line COLO 205 (IC(50) 7.9 and 10.3 μM, respectively), breast cancer cell line MCF-7 (IC(50): 6.9 and 10.5 μM, respectively) and human lung adenocarcinoma cell line A549 (IC(50): 12.2 and 15.4 μM, respectively). The apoptotic effect of ma'edamines was confirmed by comet assay. Hence ma'edamines are likely to be useful as leads for development of a new class of anti-cancer agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

Anti-Cancer Activity of Resveratrol and Derivatives Produced by Grapevine Cell Suspensions in a 14 L Stirred Bioreactor.

PubMed

Nivelle, Laetitia; Hubert, Jane; Courot, Eric; Jeandet, Philippe; Aziz, Aziz; Nuzillard, Jean-Marc; Renault, Jean-Hugues; Clément, Christophe; Martiny, Laurent; Delmas, Dominique; Tarpin, Michel

2017-03-16

In the present study, resveratrol and various oligomeric derivatives were obtained from a 14 L bioreactor culture of elicited grapevine cell suspensions (Vitis labrusca L.). The crude ethyl acetate stilbene extract obtained from the culture medium was fractionated by centrifugal partition chromatography (CPC) using a gradient elution method and the major stilbenes contained in the fractions were subsequently identified by using a 13 C-NMR-based dereplication procedure and further 2D NMR analyses including HSQC, HMBC, and COSY. Beside δ-viniferin (2), leachianol F (4) and G (4'), four stilbenes (resveratrol (1), ε-viniferin (5), pallidol (3) and a newly characterized dimer (6)) were recovered as pure compounds in sufficient amounts to allow assessment of their biological activity on the cell growth of three different cell lines, including two human skin malignant melanoma cancer cell lines (HT-144 and SKMEL-28) and a healthy human dermal fibroblast HDF line. Among the dimers obtained in this study, the newly characterized resveratrol dimer (6) has never been described in nature and its biological potential was evaluated here for the first time. ε-viniferin as well as dimer (6) showed IC 50 values on the three tested cell lines lower than the ones exerted by resveratrol and pallidol. However, activities of the first two compounds were significantly decreased in the presence of fetal bovine serum although that of resveratrol and pallidol was not. The differential tumor activity exerted by resveratrol on healthy and cancer lines was also discussed.

First-line treatment disruption among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.

PubMed

Tang, Derek H; Li, Nanxin; Du, Ella X; Peeples, Miranda; Chu, Lihao; Xie, Jipan; Barghout, Victoria

2017-12-01

This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US. Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database. Patients were required to have continuous quarterly activity (defined as ≥1 pharmacy or medical claim) for 12 months prior to and 1 month after the initiation of the index therapy (index date). Treatment disruption was defined as a treatment gap of ≥60 days or adding an agent after the original therapy. Kaplan-Meier analyses were conducted to estimate treatment disruption rates during the 6 months following the index date. Patients without treatment disruption were censored at the end of continuous quarterly activity or end of data. A total of 8,160 and 2,153 eligible patients initiated endocrine therapy or chemotherapy as their first-line mBC treatment, with a median follow-up of 6.7 and 7.6 months, respectively. The three most prevalent metastatic sites were bone (28.1-42.2%), liver (8.8-17.3%), and lung (8.6-9.5%). Overall, 37.7% (n = 3,074) of patients receiving endocrine therapy and 86.1% (n = 1,852) of patients receiving chemotherapy encountered treatment disruption at 6 months (log-rank test p < .05). Treatment disruption rates of first-line therapies were sub-optimal among post-menopausal women with HR+/HER2- mBC, primarily driven by chemotherapy users. New therapies or interventions are needed to reduce treatment disruption in this patient population.

Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia.

PubMed

Itchaki, Gilad; Brown, Jennifer R

2018-01-01

Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.

Xanthatin and xanthinosin from the burs of Xanthium strumarium L. as potential anticancer agents.

PubMed

Ramírez-Erosa, Irving; Huang, Yaoge; Hickie, Robert A; Sutherland, Ronald G; Barl, Branka

2007-11-01

Xanthatin and xanthinosin, 2 sesquiterpene lactones isolated from the burs of Xanthiun strumarium L. (cocklebur), showed moderate to high in vitro cytotoxic activity in the human cancer cell lines WiDr ATCC (colon), MDA-MB-231 ATCC (breast), and NCI-417 (lung). Xanthatin and xanthinosin were purified as the result of a multi-screening bioassay-guided study of wild plant species of the family Asteraceae, collected from various sites in Saskatchewan, Canada. Seventy-five extracts at a single concentration of 100 microg/mL were evaluated for in vitro cytotoxicity to the human cancer cell lines used. The chloroform extract of Carduus nutans L. (nodding thistle) aerial parts (IC50, 9.3 microg/mL) and the hexane extract of Echinacea angustifolia DC. (narrow-leaved purple coneflower) root (IC50, 4.0 microg/mL) were moderately to highly cytotoxic to the lung cancer cell line. The chloroform extracts of X. strumarium L. burs and Tanacetum vulgare L. (tansy) aerial parts exhibited the highest cytotoxicity for all cell lines tested; their IC50 values, obtained from multidose testing, ranged from 0.1 to 6.2 microg/mL (X. strumarium) and from 2.4 to 9.1 microg/mL (T. vulgare). Further purification of the chloroform fraction of X. strumarium yielded xanthatin and xanthinosin in high yields. This is the first time that these compounds have been reported in the burs of X. strumarium. Their IC50 values are also reported herein.

Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First-Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States.

PubMed

Huang, Min; Lou, Yanyan; Pellissier, James; Burke, Thomas; Liu, Frank Xiaoqing; Xu, Ruifeng; Velcheti, Vamsidhar

2017-08-01

Our objectives were to evaluate the cost effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy as first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) that expresses high levels of programmed death ligand-1 (PD-L1) [tumour proportion score (TPS) ≥50%], from a US third-party public healthcare payer perspective. We conducted a partitioned-survival model with a cycle length of 1 week and a base-case time horizon of 20 years. Parametric models were fitted to Kaplan-Meier estimates of time on treatment, progression-free survival and overall survival from the KEYNOTE-024 randomized clinical trial (patients aged ≥18 years with stage IV NSCLC, TPS ≥50%, without epidermal growth factor receptor (EGFR)-activating mutations or anaplastic lymphoma kinase (ALK) translocations who received no prior systemic chemotherapy) and validated with long-term registry data. Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, year 2016 values) for drug acquisition/administration, adverse events and clinical management were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. In the base-case scenario, pembrolizumab resulted in an expected gain of 1.31 life-years (LYs) and 1.05 QALYs and an incremental cost of $US102,439 compared with SoC. The incremental cost per QALY gain was $US97,621/QALY and the incremental cost per LY gain was $US78,344/LY. Pembrolizumab is projected to be a cost-effective option compared with SoC platinum-based chemotherapy as first-line treatment in adults with metastatic NSCLC expressing high levels of PD-L1.

Development of On-Line High Performance Liquid Chromatography (HPLC)-Biochemical Detection Methods as Tools in the Identification of Bioactives

PubMed Central

Malherbe, Christiaan J.; de Beer, Dalene; Joubert, Elizabeth

2012-01-01

Biochemical detection (BCD) methods are commonly used to screen plant extracts for specific biological activities in batch assays. Traditionally, bioactives in the most active extracts were identified through time-consuming bio-assay guided fractionation until single active compounds could be isolated. Not only are isolation procedures often tedious, but they could also lead to artifact formation. On-line coupling of BCD assays to high performance liquid chromatography (HPLC) is gaining ground as a high resolution screening technique to overcome problems associated with pre-isolation by measuring the effects of compounds post-column directly after separation. To date, several on-line HPLC-BCD assays, applied to whole plant extracts and mixtures, have been published. In this review the focus will fall on enzyme-based, receptor-based and antioxidant assays. PMID:22489144

Alu expression in human cell lines and their retrotranspositional potential.

PubMed

Oler, Andrew J; Traina-Dorge, Stephen; Derbes, Rebecca S; Canella, Donatella; Cairns, Brad R; Roy-Engel, Astrid M

2012-06-20

The vast majority of the 1.1 million Alu elements are retrotranspositionally inactive, where only a few loci referred to as 'source elements' can generate new Alu insertions. The first step in identifying the active Alu sources is to determine the loci transcribed by RNA polymerase III (pol III). Previous genome-wide analyses from normal and transformed cell lines identified multiple Alu loci occupied by pol III factors, making them candidate source elements. Analysis of the data from these genome-wide studies determined that the majority of pol III-bound Alus belonged to the older subfamilies Alu S and Alu J, which varied between cell lines from 62.5% to 98.7% of the identified loci. The pol III-bound Alus were further scored for estimated retrotransposition potential (ERP) based on the absence or presence of selected sequence features associated with Alu retrotransposition capability. Our analyses indicate that most of the pol III-bound Alu loci candidates identified lack the sequence characteristics important for retrotransposition. These data suggest that Alu expression likely varies by cell type, growth conditions and transformation state. This variation could extend to where the same cell lines in different laboratories present different Alu expression patterns. The vast majority of Alu loci potentially transcribed by RNA pol III lack important sequence features for retrotransposition and the majority of potentially active Alu loci in the genome (scored high ERP) belong to young Alu subfamilies. Our observations suggest that in an in vivo scenario, the contribution of Alu activity on somatic genetic damage may significantly vary between individuals and tissues.

Fe XXV and Fe XXVI Diagnostics of the Black Hole and Accretion Disk in Active Galaxies: Chandra Time-Resolved Spectroscopy of NGC 7314

NASA Technical Reports Server (NTRS)

Yaqoob, Tahir; George, Ian M.; Kallman, Timothy R.; Padmanabhan, Urmila; Weaver, Kimberly A.; Turner, T. Jane

2003-01-01

We report the detection of Fe xxv and Fe XXVI Ka emission lines from a Chandra High Energy Grating Spectrometer (HETGS) observation of the narrow-line Seyfert 1 galaxy NGC 7314, made simultaneously with RXTE. The lines are redshifted (cz approximately 1500 kilometers per second) relative to the systemic velocity and unresolved by the gratings. We argue that the lines originate in a near face-on (less than 7 deg) disk having a radial line emissivity flatter than r(exp -2). Line emission from ionization states of Fe in the range approximately Fe I a up to Fe XXVI is observed. The ionization balance of Fe responds to continuum variations on timescales less than 12.5 ks, supporting an origin of the lines close to the X-ray source. We present additional, detailed diagnostics from this rich data set. These results identify NGC 7314 as a key source to study in the future if we are to pursue reverberation mapping of space-time near black-hole event horizons. This is because it is first necessary to understand the ionization structure of accretion disks and the relation between the X-ray continuum and Fe Ka line emission. However, we also describe how our results are suggestive of a means of measuring black-hole spin without a knowledge of the relation between the continuum and line emission. Finally, these data emphasize that one can study strong gravity with narrow (as opposed to very broad) disk lines. In fact narrow lines offer higher precision, given sufficient energy resolution.

The Case for Optically Thick High-Velocity Broad-Line Region Gas in Active Galactic Nuclei

NASA Astrophysics Data System (ADS)

Snedden, Stephanie A.; Gaskell, C. Martin

2007-11-01

A combined analysis of the profiles of the main broad quasar emission lines in both Hubble Space Telescope and optical spectra shows that while the profiles of the strong UV lines are quite similar, there is frequently a strong increase in the Lyα/Hα ratio in the high-velocity gas. We show that the suggestion that the high-velocity gas is optically thin presents many problems. We show that the relative strengths of the high-velocity wings arise naturally in an optically thick BLR component. An optically thick model successfully explains the equivalent widths of the lines, the Lyα/Hα ratios and flatter Balmer decrements in the line wings, the strengths of C III] and the λ1400 blend, and the strong variability in flux of high-velocity, high-ionization lines (especially He II and He I).

Using CO as a Physical Probe of the SF Activity in the Planck-Herschel Selected Hyper Luminous Infrared Galaxies

NASA Astrophysics Data System (ADS)

Harrington, Kevin

2018-01-01

Multi-J CO line studies are essential for quantifying the physical properties of the star-forming ISM, yet it is observationally expensive to detect those faint CO emission lines at high redshift. Our eight Planck-Herschel selected galaxies, with apparent LIR > 1013‑14 L⊙, serve as the best laboratories to conduct such a CO spectral line energy distribution analysis at high-z. Using our GBT and LMT (Jup = 1-3) measurements, we trace the bulk molecular gas mass, finding relatively large star formation efficiencies (as traced by the LIR-to-L’CO(1‑0) ratio) consistent with a starburst mode of activity. With our mid-J (Jup = 4-8) CO line measurements, obtained with the IRAM 30m telescope, we find gas excitation conditions ranging from sub-thermal SMGs to highly excited local starbursts out to Jup = 5-8. The consistently high velocity-integrated line intensities at Jup = 5-8 indicates the presence a warm/dense component responsible for exciting the higher-J CO lines, therefore we use coupled non-LTE large velocity gradient and dust radiative transfer models to begin characterising the two-component molecular ISM in these strongly lensed systems.

Tyrosine kinase inhibition: A therapeutic target for the management of chronic-phase chronic myeloid leukemia

PubMed Central

Jabbour, Elias J; Cortes, Jorge E; Kantarjian, Hagop M

2014-01-01

Chronic myeloid leukemia (CML) is a hematologic neoplasm with a progressive, ultimately terminal, disease course. In most cases, CML arises owing to the aberrant formation of a chimeric gene for a constitutively active tyrosine kinase. Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target transforming the prognosis of patients with CML. New tyrosine kinase inhibitors (TKIs) continue to improve the management of CML, offering alternative options for those resistant to or intolerant of standard TKIs. Here we review the pathobiology of CML and explore emerging strategies to optimize the management of chronic-phase CML, particularly first-line treatment. PMID:24236822

Electrical Experiments. VT-214-12-2. Part II. A-C Across the Line Control.

ERIC Educational Resources Information Center

Connecticut State Dept. of Education, Hartford. Div. of Vocational Education.

Designed for high school electronics students, this second document in a series of six electrical learning activity packages focuses on alternating current across-the-line control. An introductory section gives the objective for the activities, an introduction, and an outline of the content. The remainder of the activity book is comprised of…

Dolutegravir for first-line antiretroviral therapy in low-income and middle-income countries: uncertainties and opportunities for implementation and research.

PubMed

Dorward, Jienchi; Lessells, Richard; Drain, Paul K; Naidoo, Kogieleum; de Oliveira, Tulio; Pillay, Yogan; Abdool Karim, Salim S; Garrett, Nigel

2018-06-05

A new first-line antiretroviral therapy (ART) regimen containing dolutegravir is being rolled out in low-income and middle-income countries (LMICs). In studies from predominantly high-income settings, dolutegravir-based regimens had superior efficacy, tolerability, and durability compared with existing first-line regimens. However, several questions remain about the roll out of dolutegravir in LMICs, where most people with HIV are women of reproductive age, tuberculosis prevalence can be high, and access to viral load and HIV drug resistance testing is limited. Findings from cohort studies suggest that dolutegravir is safe when initiated in pregnancy, but more data are needed to determine the risk of adverse birth outcomes when dolutegravir-based regimens are initiated before conception. Increasing access to viral load testing to monitor the effectiveness of dolutegravir remains crucial, but the best strategy to manage patients with viraemia is unclear. Furthermore, evidence to support the effectiveness of dolutegravir when given with tuberculosis treatment is scarce, particularly in programmatic settings in LMICs. Lastly, whether nucleoside reverse transcriptase inhibitor resistance will affect the long-term efficacy of dolutegravir-based regimens in first-line, and potentially second-line, ART is unknown. Clinical trials, cohorts, and surveillance of HIV drug resistance will be necessary to answer these questions and to maximise the benefits of this new regimen. Copyright © 2018 Elsevier Ltd. All rights reserved.

Diagnosis and Treatment Strategy of Achalasia Subtypes and Esophagogastric Junction Outflow Obstruction Based on High-Resolution Manometry.

PubMed

Ihara, Eikichi; Muta, Kazumasa; Fukaura, Keita; Nakamura, Kazuhiko

2017-01-01

Based on Chicago Classification version 3.0, the disorders of esophagogastric junction outflow obstruction (EGJOO) include achalasia (types I, II and III) and EGJOO. Although no curative treatments are currently available for the treatment of the disorders of EGJOO, medical treatments, endoscopic pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), and per-oral endoscopic myotomy (POEM) are usually the sought-after modes of treatment. Since the etiology and pathogenesis might vary depending on the types of EGJOO disorders, treatment strategies should be considered based on those subtypes. Based on the accumulated evidences, the treatment strategies of our institution are as follows: effects of medical treatments on achalasia are limited. Either PD or LHM/POEM can be considered a first-line in achalasia type I, according to the patient's wish. PD and POEM can be considered first-line in achalasia types II and III, respectively. Conversely, In EGJOO, medical treatments including drugs like acotiamide and/or diltiazem can be tested as a first-line, and PD and POEM will be considered second and third-line treatments, respectively. Key Messages: The classification of subtypes based on high-resolution manometry will help us consider which treatment option can be selected as a first-line treatment depending upon the subtypes of disorders of EGJOO. Acotiamide has the potential to cure patients with EGJOO. © 2016 S. Karger AG, Basel.

Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study.

PubMed

Oudard, Stéphane; Geoffrois, Lionnel; Guillot, Aline; Chevreau, Christine; Deville, Jean-Laurent; Falkowski, Sabrina; Boyle, Helen; Baciuchka, Marjorie; Gimel, Pierre; Laguerre, Brigitte; Laramas, Mathieu; Pfister, Christian; Topart, Delphine; Rolland, Frédéric; Legouffe, Eric; Denechere, Gwénaël; Amela, Eric Yaovi; Abadie-Lacourtoisie, Sophie; Gross-Goupil, Marine

2016-07-01

To assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC). This observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge. Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90-100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported. Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cost-effectiveness of treating multidrug-resistant tuberculosis.

PubMed

Resch, Stephen C; Salomon, Joshua A; Murray, Megan; Weinstein, Milton C

2006-07-01

Despite the existence of effective drug treatments, tuberculosis (TB) causes 2 million deaths annually worldwide. Effective treatment is complicated by multidrug-resistant TB (MDR TB) strains that respond only to second-line drugs. We projected the health benefits and cost-effectiveness of using drug susceptibility testing and second-line drugs in a lower-middle-income setting with high levels of MDR TB. We developed a dynamic state-transition model of TB. In a base case analysis, the model was calibrated to approximate the TB epidemic in Peru, a setting with a smear-positive TB incidence of 120 per 100,000 and 4.5% MDR TB among prevalent cases. Secondary analyses considered other settings. The following strategies were evaluated: first-line drugs administered under directly observed therapy (DOTS), locally standardized second-line drugs for previously treated cases (STR1), locally standardized second-line drugs for previously treated cases with test-confirmed MDR TB (STR2), comprehensive drug susceptibility testing and individualized treatment for previously treated cases (ITR1), and comprehensive drug susceptibility testing and individualized treatment for all cases (ITR2). Outcomes were costs per TB death averted and costs per quality-adjusted life year (QALY) gained. We found that strategies incorporating the use of second-line drug regimens following first-line treatment failure were highly cost-effective compared to strategies using first-line drugs only. In our base case, standardized second-line treatment for confirmed MDR TB cases (STR2) had an incremental cost-effectiveness ratio of 720 dollars per QALY (8,700 dollars per averted death) compared to DOTS. Individualized second-line drug treatment for MDR TB following first-line failure (ITR1) provided more benefit at an incremental cost of 990 dollars per QALY (12,000 dollars per averted death) compared to STR2. A more aggressive version of the individualized treatment strategy (ITR2), in which both new and previously treated cases are tested for MDR TB, had an incremental cost-effectiveness ratio of 11,000 dollars per QALY (160,000 dollars per averted death) compared to ITR1. The STR2 and ITR1 strategies remained cost-effective under a wide range of alternative assumptions about treatment costs, effectiveness, MDR TB prevalence, and transmission. Treatment of MDR TB using second-line drugs is highly cost-effective in Peru. In other settings, the attractiveness of strategies using second-line drugs will depend on TB incidence, MDR burden, and the available budget, but simulation results suggest that individualized regimens would be cost-effective in a wide range of situations.

Socio-economic status influences access to second-line disease modifying treatment in Relapsing Remitting Multiple Sclerosis patients

PubMed Central

Dejardin, Olivier; Droulon, Karine; Launoy, Guy; Defer, Gilles

2018-01-01

Objective In MS, Socio-Economic status (SES) may influence healthcare and access to disease-modifying treatments (DMTs). Optimising delays to switch patients to a second-line DMT may hamper disease progression most effectively and achieve long term disease control. The objective of this study is to identify the influence of SES on the delay between first and second line DMT in RRMS patients, in Western-Normandy, France. Methods The association between SES and the delay to access a second-line DMT were studied using data from the MS registry of Western-Normandy including 733 patients with a diagnosis of RRMS during the period in question [1982–2011]. We used the European Deprivation Index (EDI), a score with a rank level inversely related to SES. We performed multivariate adjusted Cox models for studying EDI effect on the delay between first and second line DMT. Results No significant influence of SES was observed on delay to access a second-line DMT if first-line DMT exposure time was less than 5 years. After 5 years from initiation of first-line treatment the risk of accessing a second-line DMT is 3 times higher for patients with lower deprivation indices (1st quintile of EDI) ([HR] 3.14 95%CI [1.72–5.72], p-value<0.001) compared to patients with higher values (EDI quintiles 2 to 5). Interpretation In RRMS, a high SES may facilitate access to a second-line DMT a few years after first-line DMT exposure. Greater consideration should also be given to the SES of MS patients as a risk factor in therapeutic healthcare issues throughout medical follow-up. PMID:29390025

Evidence for a first-order liquid-liquid transition in high-pressure hydrogen from ab initio simulations.

PubMed

Morales, Miguel A; Pierleoni, Carlo; Schwegler, Eric; Ceperley, D M

2010-07-20

Using quantum simulation techniques based on either density functional theory or quantum Monte Carlo, we find clear evidence of a first-order transition in liquid hydrogen, between a low conductivity molecular state and a high conductivity atomic state. Using the temperature dependence of the discontinuity in the electronic conductivity, we estimate the critical point of the transition at temperatures near 2,000 K and pressures near 120 GPa. Furthermore, we have determined the melting curve of molecular hydrogen up to pressures of 200 GPa, finding a reentrant melting line. The melting line crosses the metalization line at 700 K and 220 GPa using density functional energetics and at 550 K and 290 GPa using quantum Monte Carlo energetics.

Involvement of NK cells against tumors and parasites.

PubMed

Papazahariadou, M; Athanasiadis, G I; Papadopoulos, E; Symeonidou, I; Hatzistilianou, M; Castellani, M L; Bhattacharya, K; Shanmugham, L N; Conti, P; Frydas, S

2007-01-01

Host resistance against pathogens depends on a complex interplay of innate and adaptive immune mechanisms. Acting as an early line of defence, the immune system includes activation of neutrophils, tissue macrophages, monocytes, dendritic cells, eosinophils and natural killer (NK) cells. NK cells are lymphoid cells that can be activated without previous stimulation and are therefore like macrophages in the first line of defence against tumor cells and a diverse range of pathogens. NK cells mediate significant activity and produce high levels of proinflammatory cytokines in response to infection. Their cytotoxicity production is induced principally by monocyte-, macrophage- and dendritic cell-derived cytokines, but their activation is also believed to be cytokine-mediated. Recognition of infection by NK cells is accomplished by numerous activating and inhibitory receptors on the NK cells' surface that selectively trigger the cytolytic activity in a major histocompability complex-independent manner. NK cells have trypanocidal activity of fibroblast cells and mediate direct destruction of extracellular epimastigote and trypomastigote forms of T. cruzi and T. lewisi in vitro; moreover, they kill plasmodia-infected erythrocytes directly through cell-cell interaction. This review provides a more detailed analysis of how NK cells recognize and respond to parasites and how they mediate cytotoxicity against tumor cells. Also the unique role of NK cells in innate immunity to infection and the relationship between parasites and carcinogenesis are discussed.

Cytotoxic sesquiterpene lactones from the leaves of Vernonia guineensis Benth. (Asteraceae)

PubMed Central

Toyang, Ngeh J.; Wabo, Hippolyte K.; Ateh, Eugene N.; Davis, Harry; Tane, Pierre; Sondengam, Luc B.; Bryant, Joseph; Verpoorte, Rob

2015-01-01

Ethnopharmacological relevance Vernonia guineensis Benth. (Asteraceae) preparations are used in folk medicine in Cameroon to treat a number of ailments, including prostate cancer and malaria, and is used as an anthelmintic, adaptogen and antidote. The aim of this study was to continue the validation of the activity of Vernonia guineensis Benth. extracts and isolated molecules against cancer cell lines following the previous isolation of an anti-prostate cancer sugar ester from the root extract. Materials and methods Acetone extracts of Vernonia guineensis Benth. leaves were tested for activity against 10 cancer cell lines (Breast—MDA-MB-231, Breast—MCF-7, Colon—HCT-116, Leukemia—HL-60, Lung—A549, Melanoma—A375, Ovarian—OVCAR3, Pancreas—Mia-paca, Prostate—PC-3 and Prostate—DU-145). The acetone extract was subjected to bioactivity guided fractionation. Anti-proliferation and clonogenic activity of the isolated compounds were tested. The WST-1 assay was used for the anti-proliferation activity, while the standard clonogenic test was used to determine the clonogenic activity. Results The acetone extract of Vernonia guineensis Benth. demonstrated in vitro activity ranging from IC50 4–26 mg/mL against the 10 cell lines. Activity guided fractionation of this extract yielded two sesquiterpene lactones, isolated for the first time from the genus Vernonia. The compounds were characterized using spectroscopic experiments, including a combination of 1D and 2D NMR data. Vernopicrin (1) and Vernomelitensin (2) demonstrated in vitro activity against human cancer cell lines with IC50 ranging from 0.35–2.04 μM (P < 0.05) and 0.13–1.5 μM (P < 0.05), respectively, between the most and least sensitive cell lines for each compound. Vernopicrin was most active against the human melanoma (A375) cell line and least active against the lung cancer (A549) cell line, while Vernomelitensin was also most active against the human melanoma (A375) cell line and least active against the breast cancer (MCF-7) cell line. Both compounds also demonstrated anticlonogenic activity. Conclusion The cytotoxicity demonstrated by the crude extract and isolated sesquiterpenes against cancer cell lines highlights the medicinal potential of V. guineensis. The selective anti-proliferation and dose dependent anticlonogenic activities suggest that the identified sesquiterpenes could be potential antitumor agents.. PMID:23376285

Potent in vitro anticancer activity of metacycloprodigiosin and undecylprodigiosin from a sponge-derived actinomycete Saccharopolyspora sp. nov.

PubMed

Liu, Rui; Cui, Cheng-Bin; Duan, Lin; Gu, Qian-Qun; Zhu, Wei-Ming

2005-12-01

Bioassay-guided fractionation of CHCl3 extract from the fermentation broth of a sponge Mycale plumose-derived actinomycete Saccharopolyspora sp. nov., led to the isolation of two known prodigiosin analogs--metacycloprodigiosin (1) and undecylprodigiosin (2). These compounds exhibited significant cytotoxic activities against five cancer cell lines: P388, HL60, A-549, BEL-7402, and SPCA4. This is the first report on the significant cytotoxicity of metacycloprodigiosin (1) against human cancer cell lines.

First charge breeding results at CARIBU EBIS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kondrashev, S., E-mail: kondrashev@anl.gov; Barcikowski, A., E-mail: kondrashev@anl.gov; Dickerson, C., E-mail: kondrashev@anl.gov

The Electron Beam Ion Source (EBIS) developed to breed CARIBU radioactive beams at ATLAS is currently in the off-line commissioning stage. The beam commissioning is being performed using a low emittance surface ionization source producing singly-charged cesium ions. The primary goal of the off-line commissioning is the demonstration of high-efficiency charge breeding in the pulsed injection mode. An overview of the final design of the CARIBU EBIS charge breeder, the off-line commissioning installation and the first results on charge breeding of stable cesium ions are presented and discussed.

Impurity profiling of liothyronine sodium by means of reversed phase HPLC, high resolution mass spectrometry, on-line H/D exchange and UV/Vis absorption.

PubMed

Ruggenthaler, M; Grass, J; Schuh, W; Huber, C G; Reischl, R J

2017-09-05

For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT 3 Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT 4 Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system. Furthermore, the mass-spectrometric CID-fragmentation of specific related substances was discussed and rationalized by detailed fragmentation pathways. Moreover, the UV/Vis absorption characteristics of the API and selected impurities were investigated to corroborate chemical structure assignments derived from MS data. Copyright © 2017 Elsevier B.V. All rights reserved.

A Chandra Observation of the Ultraluminous Infrared Galaxy IRAS 19254-7245 (The Superantennae): X-Ray Emission from the Compton-Thick Active Galactic Nucleus and the Diffuse Starburst

NASA Technical Reports Server (NTRS)

Jia, Jianjun; Ptak, Andrew; Heckman, Timothy M.; Braito, Valentina; Reeves, James

2012-01-01

We present a Chandra observation of IRAS 19254-7245, a nearby ultraluminous infrared galaxy also known as the Superantennae. The high spatial resolution of Chandra allows us to disentangle for the first time the diffuse starburst (SB) emission from the embedded Compton-thick active galactic nucleus (AGN) in the southern nucleus. No AGN activity is detected in the northern nucleus. The 2-10 keV spectrum of the AGN emission is fitted by a flat power law (TAU = 1.3) and an He-like Fe Kalpha line with equivalent width 1.5 keV, consistent with previous observations. The Fe K line profile could be resolved as a blend of a neutral 6.4 keV line and an ionized 6.7 keV (He-like) or 6.9 keV (H-like) line. Variability of the neutral line is detected compared with the previous XMM-Newton and Suzaku observations, demonstrating the compact size of the iron line emission. The spectrum of the galaxy-scale extended emission excluding the AGN and other bright point sources is fitted with a thermal component with a best-fit kT of approximately 0.8 keV. The 2-10 keV luminosity of the extended emission is about one order of magnitude lower than that of the AGN. The basic physical and structural properties of the extended emission are fully consistent with a galactic wind being driven by the SB. A candidate ultraluminous X-ray source is detected 8 south of the southern nucleus. The 0.3 - 10 keV luminosity of this off-nuclear point source is approximately 6 x 10(exp 40) erg per second if the emission is isotropic and the source is associated with the Superantennae.

[Norfloxacin: a broad-spectrum quinolone for superficial eye infections].

PubMed

Grosset, J

1990-09-01

Norfloxacin is a synthetic antibiotic belonging to the fluoroquinolone class. At present, an oral formulation is available and indicated for the treatment of urinary tract infections. Because of the properties of norfloxacin, a 0.3% norfloxacin ophtalmic solution may be used by ophtalmologists. The molecular target of norfloxacin is DNA gyrase that regulates DNA replication. Norfloxacin is a broad spectrum antibiotic. A flurin atome in position 6 is responsible for the broad spectrum of activity as compared with the first generation quinolones. MICs of norfloxacin against Haemophilus influenzae, Neisseria gonorrhoeae, Staphylococcus aureus, Pseudomonas aeruginosa, and enterbacteriaceae are low or intermediate. Norfloxacin is a bactericidal drug of which MBCs are equivalent to or twice as high as MICs against the majority of organisms. The proportion of norfloxacin resistant strains is limited and, at present, no plasmid resistance has been observed. This explains the activity of norfloxacin against clinical isolates whose drug resistance is plasmid-mediated. Norfloxacin resistance is chromosomic, but the mutation rate is low. There is no cross-resistance between quinolones and other classes of drug, with the exception of drug resistance related to changes in the bacterial outer membrane proteins. A low decrease in norfloxacin susceptibility is observed in case of resistance to first generation quinolones. The above-mentioned properties make norfloxacin in ophtalmic solution a first line drug for treatment of superficial ocular infections and a second line drug for treatment of infections due to organisms resistant to other drugs.

High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines.

PubMed

Chowdhury, Subir K R; Gemin, Adam; Singh, Gurmit

2005-08-12

Most malignant cells are highly glycolytic and produce high levels of reactive oxygen species (ROS) compared to normal cells. Mitochondrial glycerophosphate dehydrogenase (mGPDH) participates in the reoxidation of cytosolic NADH by delivering reducing equivalents from this molecule into the electron transport chain, thus sustaining glycolysis. Here, we investigate the role of mGPDH in maintaining an increased rate of glycolysis and evaluate glycerophosphate-dependent ROS production in prostate cancer cell lines (LNCaP, DU145, PC3, and CL1). Immunoblot, polarographic, and spectrophotometric analyses revealed that mGPDH abundance and activity was significantly elevated in prostate cancer cell lines when compared to the normal prostate epithelial cell line PNT1A. Furthermore, both the glycolytic capacity and glycerophosphate-dependent ROS production was increased 1.68- to 4.44-fold and 5- to 7-fold, respectively, in prostate cancer cell lines when compared to PNT1A cells. Overall, these data demonstrate that mGPDH is involved in maintaining a high rate of glycolysis and is an important site of electron leakage leading to ROS production in prostate cancer cells.

IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Benhui; Yang Xianzi; Department of Medical Oncology, Taihe Hospital, Yunyang Medical College, Shiyan, Hubei 442000

2008-05-02

IL-4-induced Stat6 signaling is active in a variety of cell types and plays a role in cell proliferation/growth and resistance to apoptosis. Using EMSA, we identified differential IL-4/Stat6 activities in colorectal cancer cell lines, HT-29 being active Stat6{sup high} phenotype and Caco-2 being defective Stat6{sup null} phenotype, respectively. Active Stat6{sup high} HT-29 cells exhibited resistance to apoptosis by flowcytometry and aggressive metastasis by Transwell assay compared with defective Stat6{sup null} Caco-2 cells. Comparing one another using RT-PCR, Stat6{sup high} HT-29 cells expressed more mRNA of anti-apoptotic and pro-metastatic genes Survivin, MDM2, and TMPRSS4, while Stat6{sup null} Caco-2 cells expressed moremore » mRNA of pro-apoptotic and anti-metastatic genes BAX, CAV1, and P53, respectively. This is the first study describing correlations of IL-4/Stat6 activities with apoptosis and metastasis in colon cancer. These findings, together with the observation of constitutive Stat6 activation in many human malignancies, suggest that Stat6 activities could be a biomarker for cancer cell's invasive/metastatic capability.« less

Summer learning and its implications: insights from the Beginning School Study.

PubMed

Alexander, Karl L; Entwisle, Doris R; Olson, Linda Steffel

2007-01-01

There is perhaps no more pressing issue in school policy today than the achievement gap across social lines. Achievement differences between well-to-do children and poor children and between disadvantaged racial and ethnic minorities and majority whites are large when children first begin school, and they increase over time. Despite years of study and an abundance of good intentions, these patterned achievement differences persist, but who is responsible, and how are schools implicated? The increasing gap seems to suggest that schools are unable to equalize educational opportunity or, worse still, that they actively handicap disadvantaged children. But a seasonal perspective on learning yields a rather different impression. Comparing achievement gains separately over the school year and the summer months reveals that much of the achievement gap originates over the summer period, when children are not in school. The authors review Beginning School Study research on differential summer learning across social lines (that is, by family socioeconomic level) and its implications for later schooling outcomes, including high school curriculum placements, high school dropout, and college attendance. These studies document the extent to which these large summer learning differences impede the later educational progress of children of low socioeconomic status. Practical implications are discussed, including the need for early and sustained interventions to prevent the achievement gap from opening wide in the first place and for high-quality summer programming focused on preventing differential summer learning loss.

Exploiting the Genetic Diversity of Maize Using a Combined Metabolomic, Enzyme Activity Profiling, and Metabolic Modeling Approach to Link Leaf Physiology to Kernel Yield

PubMed Central

Yesbergenova-Cuny, Zhazira; Simons, Margaret; Chardon, Fabien; Armengaud, Patrick; Quilleré, Isabelle; Cukier, Caroline; Gibon, Yves; Limami, Anis M.; Nicolas, Stéphane; Brulé, Lenaïg; Lea, Peter J.; Maranas, Costas D.; Hirel, Bertrand

2017-01-01

A combined metabolomic, biochemical, fluxomic, and metabolic modeling approach was developed using 19 genetically distant maize (Zea mays) lines from Europe and America. Considerable differences were detected between the lines when leaf metabolic profiles and activities of the main enzymes involved in primary metabolism were compared. During grain filling, the leaf metabolic composition appeared to be a reliable marker, allowing a classification matching the genetic diversity of the lines. During the same period, there was a significant correlation between the genetic distance of the lines and the activities of enzymes involved in carbon metabolism, notably glycolysis. Although large differences were observed in terms of leaf metabolic fluxes, these variations were not tightly linked to the genome structure of the lines. Both correlation studies and metabolic network analyses allowed the description of a maize ideotype with a high grain yield potential. Such an ideotype is characterized by low accumulation of soluble amino acids and carbohydrates in the leaves and high activity of enzymes involved in the C4 photosynthetic pathway and in the biosynthesis of amino acids derived from glutamate. Chlorogenates appear to be important markers that can be used to select for maize lines that produce larger kernels. PMID:28396554

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

PubMed

Ghasemi, Farhad; Black, Morgan; Sun, Ren X; Vizeacoumar, Frederick; Pinto, Nicole; Ruicci, Kara M; Yoo, John; Fung, Kevin; MacNeil, Danielle; Palma, David A; Winquist, Eric; Mymryk, Joe S; Ailles, Laurie A; Datti, Alessandro; Barrett, John W; Boutros, Paul C; Nichols, Anthony C

2018-05-25

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs . HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC.

A Required Rotation in Clinical Laboratory Management for Pathology Residents: Five-Year Experience at Hofstra Northwell School of Medicine.

PubMed

Rishi, Arvind; Hoda, Syed T; Crawford, James M

2016-01-01

Leadership and management training during pathology residency have been identified repeatedly by employers as insufficient. A 1-month rotation in clinical laboratory management (CLM) was created for third-year pathology residents. We report on our experience and assess the value of this rotation. The rotation was one-half observational and one-half active. The observational component involved being a member of department and laboratory service line leadership, both at the departmental and institutional level. Observational participation enabled learning of both the content and principles of leadership and management activities. The active half of the rotation was performance of a project intended to advance the strategic trajectory of the department and laboratory service line. In our program that matriculates 4 residents per year, 20 residents participated from April 2010 through December 2015. Their projects either activated a new priority area or helped propel an existing strategic priority forward. Of the 16 resident graduates who had obtained their first employment or a fellowship position, 9 responded to an assessment survey. The majority of respondents (5/9) felt that the rotation significantly contributed to their ability to compete for a fellowship or their first employment position. The top reported benefits of the rotation included people management; communication with staff, departmental, and institutional leadership; and involvement in department and institutional meetings and task groups. Our 5-year experience demonstrates both the successful principles by which the CLM rotation can be established and the high value of this rotation to residency graduates.

Rapid screening of bioactive compounds from natural products by integrating 5-channel parallel chromatography coupled with on-line mass spectrometry and microplate based assays.

PubMed

Zhang, Yufeng; Xiao, Shun; Sun, Lijuan; Ge, Zhiwei; Fang, Fengkai; Zhang, Wen; Wang, Yi; Cheng, Yiyu

2013-05-13

A high throughput method was developed for rapid screening and identification of bioactive compounds from traditional Chinese medicine, marine products and other natural products. The system, integrated with five-channel chromatographic separation and dual UV-MS detection, is compatible with in vitro 96-well microplate based bioassays. The stability and applicability of the proposed method was validated by testing radical scavenging capability of a mixture of seven known compounds (rutin, dihydroquercetin, salvianolic acid A, salvianolic acid B, glycyrrhizic acid, rubescensin A and tangeretin). Moreover, the proposed method was successfully applied to the crude extracts of traditional Chinese medicine and a marine sponge from which 12 bioactive compounds were screened and characterized based on their anti-oxidative or anti-tumor activities. In particular, two diterpenoid derivatives, agelasine B and (-)-agelasine D, were identified for the first time as anti-tumor compounds from the sponge Agelas mauritiana, showing a considerable activity toward MCF-7 cells (IC50 values of 7.84±0.65 and 10.48±0.84 μM, respectively). Our findings suggested that the integrated system of 5-channel parallel chromatography coupled with on-line mass spectrometry and microplate based assays can be a versatile and high efficient approach for the discovery of active compounds from natural products. Copyright © 2013 Elsevier B.V. All rights reserved.

The Biological Activities of Sesterterpenoid-Type Ophiobolins.

PubMed

Tian, Wei; Deng, Zixin; Hong, Kui

2017-07-18

Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A-W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure-activity relationship to lay the foundation for the future developments and applications of these promising molecules.

"RED" Matters When Naming "CAR": The Cascading Activation of Nontarget Properties

ERIC Educational Resources Information Center

Roux, Sébastien; Bonin, Patrick

2016-01-01

Seven experiments tested, whether when naming a colored object (e.g., "CAR"), its color (e.g., "red") is phonologically encoded. In the first experiment, adults had to say aloud the names of colored line drawings of objects that were each displayed among 3 black-and-white line drawings (Experiment 1a) or that were presented…

First Year Sedimentological Characteristics and Morphological Evolution of an Artificial Berm at Fort Myers Beach, Florida

DTIC Science & Technology

2011-06-17

collected in the berm area. In the control areas, surface sediment samples were taken at approximately the toe of the dune (where present...In the berm area, surface sediment samples were taken at approximately the toe of the dune (where 29   present), backbeach, high tide line, mean...samples were taken at approximately the toe of the dune (where present), backbeach, high tide line, mean sea level, low tide line, 2 ft water depth

Impact of active geomagnetic conditions on stimulated radiation during ionospheric second electron gyroharmonic heating

NASA Astrophysics Data System (ADS)

Bordikar, M. R.; Scales, W. A.; Mahmoudian, A.; Kim, H.; Bernhardt, P. A.; Redmon, R.; Samimi, A. R.; Brizcinski, S.; McCarrick, M. J.

2014-01-01

Recently, narrowband emissions ordered near the H+ (proton) gyrofrequency (fcH) were reported in the stimulated electromagnetic emission (SEE) spectrum during active geomagnetic conditions. This work presents new observations and theoretical analysis of these recently discovered emissions. These emission lines are observed in the stimulated electromagnetic emission (SEE) spectrum when the transmitter is tuned near the second electron gyroharmonic frequency (2fce) during recent ionospheric modification experiments at the High Frequency Active Auroral Research (HAARP) facility near Gakona, Alaska. The spectral lines are typically shifted below and above the pump wave frequency by harmonics of a frequency roughly 10% less than fcH (≈ 800 Hz) with a narrow emission bandwidth less than the O+ gyrofrequency (≈ 50 Hz). However, new observations and analysis of emission lines ordered by a frequency approximately 10% greater than fcH are presented here for the first time as well. The interaction altitude for the heating for all the observations is in the range of 160 km up to 200 km. As described previously, proton precipitation due to active geomagnetic conditions is considered as the reason for the presence of H+ ions known to be a minor background constituent in this altitude region. DMSP satellite observations over HAARP during the heating experiments and ground-based magnetometer and riometer data validate active geomagnetic conditions. The theory of parametric decay instability in multi-ion component plasma including H+ ions as a minority species described in previous work is expanded in light of simultaneously observed preexisting SEE features to interpret the newly reported observations. Impact of active geomagnetic conditions on the SEE spectrum as a diagnostic tool for proton precipitation event characterization is discussed.

Spermidine/spermine N1-acetyltransferase (SSAT) activity in human small-cell lung carcinoma cells following transfection with a genomic SSAT construct.

PubMed

Murray-Stewart, Tracy; Applegren, Nancy B; Devereux, Wendy; Hacker, Amy; Smith, Renee; Wang, Yanlin; Casero, Robert A

2003-07-15

Spermidine/spermine N (1)-acetyltransferase (SSAT) activity is typically highly inducible in non-small-cell lung carcinomas in response to treatment with anti-tumour polyamine analogues, and this induction is associated with subsequent cell death. In contrast, cells of the small-cell lung carcinoma (SCLC) phenotype generally do not respond to these compounds with an increase in SSAT activity, and usually are only moderately affected with respect to growth. The goal of the present study was to produce an SSAT-overexpressing SCLC cell line to further investigate the role of SSAT in response to these anti-tumour analogues. To accomplish this, NCI-H82 SCLC cells were stably transfected with plasmids containing either the SSAT genomic sequence or the corresponding cDNA sequence. Individual clones were selected based on their ability to show induced SSAT activity in response to exposure to a polyamine analogue, and an increase in the steady-state SSAT mRNA level. Cells transfected with the genomic sequence exhibited a significant increase in basal SSAT mRNA expression, as well as enhanced SSAT activity, intracellular polyamine pool depletion and growth inhibition following treatment with the analogue N (1), N (11)-bis(ethyl)norspermine. Cells containing the transfected cDNA also exhibited an increase in the basal SSAT mRNA level, but remained phenotypically similar to vector control cells with respect to their response to analogue exposure. These studies indicate that both the genomic SSAT sequence and polyamine analogue exposure play a role in the transcriptional and post-transcriptional regulation and subsequent induction of SSAT activity in these cells. Furthermore, this is the first production of a cell line capable of SSAT protein induction from a generally unresponsive parent line.

Unsplit bipolar pulse forming line

DOEpatents

Rhodes, Mark A [Pleasanton, CA

2011-05-24

A bipolar pulse forming transmission line module and system for linear induction accelerators having first, second, third, and fourth planar conductors which form a sequentially arranged interleaved stack having opposing first and second ends, with dielectric layers between the conductors. The first and second planar conductors are connected to each other at the first end, and the first and fourth planar conductors are connected to each other at the second end via a shorting plate. The third planar conductor is electrically connectable to a high voltage source, and an internal switch functions to short at the first end a high voltage from the third planar conductor to the fourth planar conductor to produce a bipolar pulse at the acceleration axis with a zero net time integral. Improved access to the switch is enabled by an aperture through the shorting plate and the proximity of the aperture to the switch.

Magnetometric and gravimetric surveys in fault detection over Acambay System

NASA Astrophysics Data System (ADS)

García-Serrano, A.; Sanchez-Gonzalez, J.; Cifuentes-Nava, G.

2013-05-01

In commemoration of the centennial of the Acambay intraplate earthquake of November 19th 1912, we carry out gravimetric and magnetometric surveys to define the structure of faults caused by this event. The study area is located approximately 11 km south of Acambay, in the Acambay-Tixmadeje fault system, where we performed two magnetometric surveys, the first consisting of 17 lines with a spacing of 35m between lines and 5m between stations, and the second with a total of 12 lines with the same spacing, both NW. In addition to these two lines we performed gravimetric profiles located in the central part of each magnetometric survey, with a spacing of 25m between stations, in order to correlate the results of both techniques, the lengths of such profiles were of 600m and 550m respectively. This work describes the data processing including directional derivatives, analytical signal and inversion, by means of which we obtain results of magnetic variations and anomaly traits highly correlated with those faults. It is of great importance to characterize these faults given the large population growth in the area and settlement houses on them, which involves a high risk in the security of the population, considering that these are active faults and cannot be discard earthquakes associated with them, so it is necessary for the authorities and people have relevant information to these problem.

How fast do quasar emission lines vary? First results from a program to monitor the Balmer lines of the Palomar-Green Quasars

NASA Technical Reports Server (NTRS)

Maoz, Dan; Smith, Paul S.; Jannuzi, Buell T.; Kaspi, Shai; Netzer, Hagai

1994-01-01

We have monitored spectrophotometrically a subsample (28) of the Palomar-Green Bright Quasar Sample for 2 years in order to test for correlations between continuum and emission-line variations and to determine the timescales relevant to mapping the broad-line regions of high-luminosity active galactic nuclei (AGNs). Half of the quasars showed optical continuum variations with amplitudes in the range 20-75%. The rise and fall time for the continuum variations is typically 0.5-2 years. In most of the objects with continuum variations, we detect correlated variations in the broad H-alpha and H-beta emission lines. The amplitude of the line variations is usually 2-4 times smaller than the optical continuum fluctuations. We present light curves and analyze spectra for six of the variable quasars with 1000-10,000 A luminosity in the range 0.3-4 x 10(exp 45) ergs/s. In four of these objects the lines respond to the continuum variations with a lag that is smaller than or comparable to our typical sampling interval (a few months). Although continued monitoring is required to confirm these results and increase their accuracy, the present evidence indicates that quasars with the above luminosities have broad-line regions smaller than about 1 1t-yr. Two of the quasars monitored show no detectable line variations despite relatively large-amplitude continuum changes. This could be a stronger manifestation of the low-amplitude line-response phenomenon we observe in the other quasars.

PBS TeacherLine National Survey of Teacher Professional Development, 2005-2006

ERIC Educational Resources Information Center

Hezel Associates (NJ1), 2007

2007-01-01

PBS TeacherLine, an initiative funded under the U.S. Department of Education's Ready To Teach program, is designed to provide high-quality online professional development for K-12 teachers. Through the first five-year grant cycle, ending in 2005, PBS TeacherLine produced approximately 100 online facilitated courses in reading, mathematics,…

Magnetic Structure of Sites of Braiding in Hi-C Active Region

NASA Technical Reports Server (NTRS)

Tiwari, S. K.; Alexander, C. E.; Winebarger, A.; Moore, R. L.

2014-01-01

High-resolution Coronal Imager (Hi-C) observations of an active region (AR) corona, at a spatial resolution of 0.2 arcsec, have offered the first direct evidence of field lines braiding, which could deliver sufficient energy to heat the AR corona by current dissipation via magnetic reconnection, a proposal given by Parker three decades ago. The energy required to heat the corona must be transported from the photosphere along the field lines. The mechanism that drives the energy transport to the corona is not yet fully understood. To investigate simultaneous magnetic and intensity structure in and around the AR in detail, we use SDO/HMI+AIA data of + / - 2 hours around the 5 minute Hi-C flight. In the case of the QS, work done by convection/granulation on the inter-granular feet of the coronal field lines probably translates into the heat observed in the corona. In the case of the AR, as here, there could be flux emergence, cancellation/submergence, or shear flows generating large stress and tension in coronal field loops which is released as heat in the corona. However, to the best of our knowledge, there is no observational evidence available to these processes. We investigate the changes taking place in the photospheric feet of the magnetic field involved with brightenings in the Hi-C AR corona. Using HMI 45s magnetograms of four hours we find that, out of the two Hi-C sub-regions where the braiding of field lines were recently detected, flux emergence takes place in one region and flux cancellation in the other. The field in these sub-regions are highly sheared and have apparent high speed plasma flows at their feet. Therefore, shearing flows plausibly power much of the coronal and transition region heating in these areas of the AR. In addition, the presence of large flux emergence/cancellation strongly suggests that the work done by these processes on the pre-existing field also drives much of the observed heating.

A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

PubMed

Pinheiro, Eloan Dos Santos; Antunes, Octavio Augusto Ceva; Fortunak, Joseph M D

2008-09-01

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for "advanced salvage" drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for "lowest income" countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.

Understanding the rotation of coronal holes

NASA Astrophysics Data System (ADS)

Wang, Y.-M.; Sheeley, N. R., Jr.

1993-09-01

In an earlier study we found that the rotation of coronal holes could be understood on the basis of a nearly current-free coronal field, with the holes representing open magnetic regions. In this paper we illustrate the model by focusing on the case of CH1, the rigidly rotating boot-shaped hole observed by Skylab. We show that the interaction between the polar fields and the flux associated with active regions produces distortions in the coronal field configuration and thus in the polar-hole boundaries; these distortions corotate with the perturbing nonaxisymmetric flux. In the case of CH1, positive-polarity field lines in the northern hemisphere 'collided' with like-polarity field lines fanning out from a decaying active region complex located just below the equator, producing a midlatitude corridor of open field lines rotating at the rate of the active region complex. Sheared coronal holes result when nonaxisymmetric flux is present at high latitudes, or equivalently, when the photospheric neutral line extends to high latitudes. We demonstrate how a small active region, rotating at the local photospheric rate, can drift through a rigidly rotating hole like CH1. Finally, we discuss the role of field-line reconnection in maintaining a quasi-potential coronal configuration.

Abundance Variations and Flows in Plage Regions Observed with CDS/SOHO

NASA Astrophysics Data System (ADS)

Rank, G.; Bagalá, L. G.; Czaykowska, A.; Haerendel, G.

1999-10-01

We present results from CDS/SOHO observations of the spotless active region NOAA-8208, obtained on 28th April 1998 near disk center. MDI images show a bipolar magnetic configuration. The regions of enhanced He I emission correspond to the areas with strong magnetic flux and also with bright plage areas seen in Ca II and H-alpha images. A high correlation is found between intensity maps of the transition region lines He I (logTmax = 4.3), O III (logTmax = 5.0), and O V (logTmax = 5.4). The line-of-sight velocities of He I reveal a strong downflow in the plage areas. Further, the line-of-sight velocities of He I, O III, and O V are well correlated, showing that the downflow pattern exists up to temperatures of about 0.25 MK. At higher temperatures (Mg VIII at logTmax = 5.8) this flow is not detected, suggesting that material streams into the plage region from sideways in the high transition region. Maps of the electron density in the transition region have been constructed from several line ratios yielding densities of about 9.0 cm-3 in the plage regions, about dex 0.5 cm-3 higher compared to the surrounding. To study the spatial variation of the first ionization potential (FIP) effect, the abundance ratio has been mapped for the ion ratio MgVI/NeVI. The ratio is highly variable on spatial scales down to a few arcsec from photospheric values to enhancements of a factor of 10. The strongest FIP enhancements are not correlated with transition region line emission, but are found outside of the plage regions. Some areas of strong FIP enhancement appear stretched and elongated, suggesting that the material is confined in loop-like structures.

Determination of active components of Ginkgo biloba in human urine by capillary high-performance liquid chromatography/mass spectrometry with on-line column-switching purification.

PubMed

Ding, Shujing; Dudley, Ed; Chen, Lijuan; Plummer, Sue; Tang, Jiandong; Newton, Russell P; Brenton, A Gareth

2006-01-01

Ginkgo biloba is one of the most popular herbal nutritional supplements, with terpene lactones and flavonoids being the two major active components. An on-line purification high-performance liquid chromatography/mass spectrometry (HPLC/MS) method was successfully developed for the quantitative determination of flavonoids and terpene lactones excreted in human urine after ingesting the herbal supplement. Satisfactory separation was obtained using a C18 capillary column made in-house with sample clean-up and pre-concentration achieved using a C18 pre-column with column switching. High selectivity and limits of detection of 1-18 ng/mL were achieved using a selected ion monitoring (SIM) scan in negative ion mode; the on-line solid-phase extraction (SPE) recovery of the active components in Ginkgo biloba determined in this study was greater than 75%. Copyright 2006 John Wiley & Sons, Ltd.

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

PubMed

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.

Lyman-Alpha Observations of High Radial Velocity Stars

NASA Astrophysics Data System (ADS)

Bookbinder, Jay

1990-12-01

H I LYMAN -ALPHA (LY-A) IS ONE OF THE MOST IMPORTANT LINES EMITTED BY PLASMA IN THE TEMPERATURE RANGE OF 7000 TO 10 TO THE FIFTH POWER K IN LATE-TYPE STARS. IT IS A MAJOR COMPONENT OF THE TOTAL RADIATIVE LOSS RATE, AND IT PLAYS A CRUCIAL ROLE IN DETERMINING THE ATMOSPHERIC STRUCTURE AND IN FLUORESCING OTHER UV LINES. YET IT IS ALSO THE LEAST STUDIED MAJOR LINE IN THE FAR UV, BECAUSE MOST OF THE LINE FLUX IS ABSORBED BY THE ISM ALONG THE LINE OF SIGHT AND BECAUSE IT IS STRONGLY COMTAMINATED BY THE GEOCORONAL BACKGROUND. A KNOWLEDGE OF THE Ly-A PROFILE IS ALSO IMPORTANT FOR STUDIES OF DEUTERIUM IN THE INTERSTELLAR MEDIUM. BY OBSERVING HIGH RADIAL VELOCITY STARS WE WILL OBTAIN FOR THE FIRST TIME HIGH RESOLUTION SPECTRA OF THE CORE OF A STELLAR H I LYMAN-A EMISSION LINE PROFILE.

Assessing the effects of underground mining activities on high-voltage overhead power lines

NASA Astrophysics Data System (ADS)

Gusev, Vladimir; Zhuravlyov, Alexei; Maliukhina, Elena

2017-11-01

This paper introduces a technique for predictive assessment of changes in the position of power transmission towers and condition of overhead power lines, located in the zone of influence of displacements and deformations of the Earth's surface caused by mining activities. A special approach for monitoring the technical condition of towers and cables is proposed. It is intended to address the issue of controlling the condition of transmission lines that are under the influence of underground mining activities and to checkmate such impact.

Use of Third Line Antiretroviral Therapy in Latin America

PubMed Central

Cesar, Carina; Shepherd, Bryan E.; Jenkins, Cathy A.; Ghidinelli, Massimo; Castro, Jose Luis; Veloso, Valdiléa Gonçalves; Cortes, Claudia P.; Padgett, Denis; Crabtree-Ramirez, Brenda; Gotuzzo, Eduardo; Fink, Valeria; Duran, Adriana; Sued, Omar; McGowan, Catherine C.; Cahn, Pedro

2014-01-01

Background Access to highly active antiretroviral therapy (HAART) is expanding in Latin America. Many patients require second and third line therapy due to toxicity, tolerability, failure, or a combination of factors. The need for third line HAART, essential for program planning, is not known. Methods Antiretroviral-naïve patients ≥18 years who started first HAART after January 1, 2000 in Caribbean, Central and South America Network (CCASAnet) sites in Argentina, Brazil, Honduras, Mexico, and Peru were included. Clinical trials participants were excluded. Third line HAART was defined as use of darunavir, tipranavir, etravirine, enfuvirtide, maraviroc or raltegravir. Need for third line HAART was defined as virologic failure while on second line HAART. Results Of 5853 HAART initiators followed for a median of 3.5 years, 310 (5.3%) failed a second line regimen and 44 (0.8%) received a third line regimen. Cumulative incidence of failing a 2nd or starting a 3rd line regimen was 2.7% and 6.0% three and five years after HAART initiation, respectively. Predictors at HAART initiation for failing a second or starting a third line included female sex (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.18–2.00, p = 0.001), younger age (HR = 2.76 for 20 vs. 40 years, 95% CI 1.86–4.10, p<0.001), and prior AIDS (HR = 2.17, 95% CI 1.62–2.90, p<0.001). Conclusions Third line regimens may be needed for at least 6% of patients in Latin America within 5 years of starting HAART, a substantial proportion given the large numbers of patients on HAART in the region. Improved accessibility to third line regimens is warranted. PMID:25221931

Electrical and Biological Effects of Transmission Lines: A Review.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jack M.

1989-06-01

This review describes the electrical properties of a-c and d-c transmission lines and the resulting effects on plants, animals, and people. Methods used by BPA to mitigate undesirable effects are also discussed. Although much of the information in this review pertains to high-voltage transmission lines, information on distribution lines and electrical appliances is included. The electrical properties discussed are electric and magnetic fields and corona: first for alternating-current (a-c) lines, then for direct current (d-c).

Pursuing Lines of Flight: Enacting Equity-Based Preservice Teacher Learning in First-Year Teaching

ERIC Educational Resources Information Center

Strom, Katie; Martin, Adrian D.

2016-01-01

This article examines how one first-year physics teacher translated his inquiry-based, socially just pre-professional learning into classroom practice in his first several months of teaching, using rhizomatics, a non-linear theory of social activity, as a theoretical and methodological frame. This case highlights the complexity of enacting a…

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

PubMed

Santini, Daniele; Vincenzi, Bruno; Adamo, Vincenzo; Addeo, Raffaele; Fusco, Vittorio; Russo, Antonio; Montemurro, Filippo; Roato, Ilaria; Redana, Stefania; Lanzetta, Gaetano; Satolli, Maria Antonietta; Berruti, Alfredo; Leoni, Valentina; Galluzzo, Sara; Antimi, Mauro; Ferraro, Giuseppa; Rossi, Maura; Del Prete, Salvatore; Valerio, Maria Rosaria; Marra, Monica; Caraglia, Michele; Tonini, Giuseppe

2011-06-01

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Search and Studies of Active Galaxies Using Multiwavelength Data

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.; Gyulzadyan, M. V.; Abrahamyan, H. V.; Paronyan, G. M.; Mikayelyan, G. A.

2017-07-01

The Byurakan Astrophysical Observatory (BAO) during its history has always been one of the centres for surveys and studies of active galaxies. Here we review our search and studies of active galaxies during last 30 years using various wavelength ranges, as well as some recent related works. These projects since late 1980s were focused on multiwavelength search and studies of AGN and Starbursts. 1103 blue stellar objects (BSOs) on the basis of their UV-excess were selected using Markarian Survey (First Byurakan Survey, FBS) plates and Markarian's criteria used for the galaxies. 1577 IRAS point sources were optically identified using FBS low-dispersion spectra and many AGN, SB and high-luminosity IR galaxies (LIRG/ULIRG) were discovered. 2791 ROSAT FSC sources were optically identified using Hamburg Quasar Survey (HQS) low-dispersion spectra and many AGN were discovered by follow-up observations. Fine analysis of emission line spectra was carried out using spectral line decomposition software to establish true profiles and calculate physical parameters for the emitting regions. Multiwavelength approach allowed revealing many new AGN and SB and obtaining a number of interesting relations using their observational characteristics and physical properties.

An on-line high-performance liquid chromatography-diode-array detector-electrospray ionization-ion-trap-time-of-flight-mass spectrometry-total antioxidant capacity detection system applying two antioxidant methods for activity evaluation of the edible flowers from Prunus mume.

PubMed

Zhang, Xiaoxia; Lin, Zongtao; Fang, Jinggui; Liu, Meixian; Niu, Yanyan; Chen, Shizhong; Wang, Hong

2015-10-02

An on-line high-performance liquid chromatography-diode-array detector-electrospray ionization-ion-trap-time-of-flight-mass spectrometry-total antioxidant capacity detection (HPLC-DAD-ESI-IT-TOF-MS-TACD) system was created for identification and evaluation of antioxidants in Prunus (P.) mume flowers. Applying this system, the HPLC fingerprint, ultraviolet (UV) spectra, mass fragmentations, active profiles against 1,1-diphenylpicryl-2-hydrazyl radical (DPPH•) scavenging activity and ferric reducing antioxidant power (FRAP) of each complex sample were obtained simultaneously after one injection. Synchronous structure identification and activities screening of complex samples were thus accomplished. In this study, 78 compounds were identified from P. mume flowers by their chromatographic behaviors, UV spectra and MS data with the assistance of standard compounds and literature reports. The DPPH and FRAP activity of 24 samples (23 different P. mume varieties and 1 related herbal medicine) were then quantified by their detailed activity profiles from the on-line system, and by the total activity of each sample extract from off-line 96-well plate method. As a result, 21 and 32 compounds in the on-line system showed anti-oxidative effects against DPPH and FRAP, respectively. The established on-line system is efficient, sensitive and reliable to tell the DPPH and FRAP antioxidant activities of individual compound in complex samples, and therefore would be a useful and promising technique for antioxidant screening from different food and medicinal matrices. Copyright © 2015 Elsevier B.V. All rights reserved.

Outcome Evaluation of Active Support Training in Taiwan

ERIC Educational Resources Information Center

Chou, Yueh-Ching; Harman, Anthony D.; Lin, Chwen-Jen; Lee, Wan-ping; Chang, Shu-chuan; Lin, Mei-Ling

2011-01-01

Active Support was implemented for the first time in Taiwan in March, 2009. This study aims to evaluate whether the supervisors and front line managers of residential services receiving Active Support Training (AST) caused a positive impact on their users with intellectual disabilities (ID) while comparing this with their counterparts with ID…

First Detections of the [NII] 122 Micrometer Line at High Redshift: Demonstrating the Utility of the Line for Studying Galaxies in the Early Universe

NASA Technical Reports Server (NTRS)

Ferkinhoff, Carl; Brisbin, Drew; Nikola, Thomas; Parshley, Stephen C.; Stacey, Gordon J.; Phillips, Thomas G.; Falgarone, Edith; Benford, Dominic J.; Staguhn, Johannes G.; Tucker, Carol E.

2011-01-01

We report the first detections of the [NIl] 122 {\\mu} m line from a high redshift galaxy. The line was strongly (> 6{\\sigma}) detected from SMMJ02399-0136, and HI413+ 117 (the Cloverleaf QSO) using the Redshift(z) and Early Universe Spectrometer (ZEUS) on the CSO. The lines from both sources are quite bright with line-to-FIR continuum luminosity ratios that are approx.7.0x10(exp -4) (Cloverleaf) and 2.1x10(exp -3) (SMMJ02399). With ratios 2-10 times larger than the average value for nearby galaxies, neither source exhibits the line-to-continuum deficits seen in nearby sources. The line strengths also indicate large ionized gas fractions, approx.8 to 17% of the molecular gas mass. The [OIII]/[NII] line ratio is very sensitive to the effective temperature of ionizing stars and the ionization parameter for emission arising in the narrow-line region (NLR) of an AGN. Using our previous detection of the [01II] 88 {\\mu}m line, the [OIII]/ [NIl] line ratio for SMMJ02399-0136 indicates the dominant source of the line emission is either stellar HII regions ionized by 09.5 stars, or the NLR of the AGN with ionization parameter 10g(U) = -3.3 to -4.0. A composite system, where 30 to 50% of the FIR lines arise in the NLR also matches the data. The Cloverleaf is best modeled by a superposition of approx.200 M82like starbursts accounting for all of the FIR emission and 43% of the [NIl] line. The remainder may come from the NLR. This work demonstrates the utility of the [NIl] and [OIII] lines in constraining properties of the ionized medium.

Coronal Structures in Cool Stars

NASA Technical Reports Server (NTRS)

Oliversen, Ronald (Technical Monitor); Dupree, Andrea K.

2004-01-01

Many papers have been published that further elucidate the structure of coronas in cool stars as determined from EUVE, HST, FUSE, Chandra, and XMM-Newton observations. In addition we are exploring the effects of coronas on the He I 1083081 transition that is observed in the infrared. Highlights of these are summarized below including publications during this reporting period and presentations. Ground-based magnetic Doppler imaging of cool stars suggests that active stars have active regions located at high latitudes on their surface. We have performed similar imaging in X-ray to locate the sites of enhanced activity using Chandra spectra. Chandra HETG observations of the bright eclipsing contact binary 44i Boo and Chandra LETG observations for the eclipsing binary VW Cep show X-ray line profiles that are Doppler-shifted by orbital motion. After careful analysis of the spectrum of each binary, a composite line-profile is constructed by adding the individual spectral lines. This high signal-to-noise ratio composite line-profile yields orbital velocities for these binaries that are accurate to 30 km/sec and allows their orbital motion to be studied at higher time resolutions. In conjunction with X-ray lightcurves, the phase-binned composite line-profiles constrain coronal structures to be small and located at high latitudes. These observations and techniques show the power of the Doppler Imaging Technique applied to X-ray line emission.

Discovery of starspots on Vega. First spectroscopic detection of surface structures on a normal A-type star

NASA Astrophysics Data System (ADS)

Böhm, T.; Holschneider, M.; Lignières, F.; Petit, P.; Rainer, M.; Paletou, F.; Wade, G.; Alecian, E.; Carfantan, H.; Blazère, A.; Mirouh, G. M.

2015-05-01

Context. The theoretically studied impact of rapid rotation on stellar evolution needs to be compared with these results of high-resolution spectroscopy-velocimetry observations. Early-type stars present a perfect laboratory for these studies. The prototype A0 star Vega has been extensively monitored in recent years in spectropolarimetry. A weak surface magnetic field was detected, implying that there might be a (still undetected) structured surface. First indications of the presence of small amplitude stellar radial velocity variations have been reported recently, but the confirmation and in-depth study with the highly stabilized spectrograph SOPHIE/OHP was required. Aims: The goal of this article is to present a thorough analysis of the line profile variations and associated estimators in the early-type standard star Vega (A0) in order to reveal potential activity tracers, exoplanet companions, and stellar oscillations. Methods: Vega was monitored in quasi-continuous high-resolution echelle spectroscopy with the highly stabilized velocimeter SOPHIE/OHP. A total of 2588 high signal-to-noise spectra was obtained during 34.7 h on five nights (2 to 6 of August 2012) in high-resolution mode at R = 75 000 and covering the visible domain from 3895-6270 Å. For each reduced spectrum, least square deconvolved equivalent photospheric profiles were calculated with a Teff = 9500 and log g = 4.0 spectral line mask. Several methods were applied to study the dynamic behaviour of the profile variations (evolution of radial velocity, bisectors, vspan, 2D profiles, amongst others). Results: We present the discovery of a spotted stellar surface on an A-type standard star (Vega) with very faint spot amplitudes ΔF/Fc ~ 5 × 10-4. A rotational modulation of spectral lines with a period of rotation P = 0.68 d has clearly been exhibited, unambiguously confirming the results of previous spectropolarimetric studies. Most of these brightness inhomogeneities seem to be located in lower equatorial latitudes. Either a very thin convective layer can be responsible for magnetic field generation at small amplitudes, or a new mechanism has to be invoked to explain the existence of activity tracing starspots. At this stage it is difficult to disentangle a rotational from a stellar pulsational origin for the existing higher frequency periodic variations. Conclusions: This first strong evidence that standard A-type stars can show surface structures opens a new field of research and ask about a potential link with the recently discovered weak magnetic field discoveries in this category of stars. Based on observations obtained with the SOPHIE spectrograph at the 2 m OHP telescope operated by the Institut National des Sciences de l'Univers (INSU) of the Centre National de la Recherche Scientifique of France (CNRS).

Open-field behavior of house mice selectively bred for high voluntary wheel-running.

PubMed

Bronikowski, A M; Carter, P A; Swallow, J G; Girard, I A; Rhodes, J S; Garland, T

2001-05-01

Open-field behavioral assays are commonly used to test both locomotor activity and emotionality in rodents. We performed open-field tests on house mice (Mus domesticus) from four replicate lines genetically selected for high voluntary wheel-running for 22 generations and from four replicate random-bred control lines. Individual mice were recorded by video camera for 3 min in a 1-m2 open-field arena on 2 consecutive days. Mice from selected lines showed no statistical differences from control mice with respect to distance traveled, defecation, time spent in the interior, or average distance from the center of the arena during the trial. Thus, we found little evidence that open-field behavior, as traditionally defined, is genetically correlated with wheel-running behavior. This result is a useful converse test of classical studies that report no increased wheel-running in mice selected for increased open-field activity. However, mice from selected lines turned less in their travel paths than did control-line mice, and females from selected lines had slower travel times (longer latencies) to reach the wall. We discuss these results in the context of the historical open-field test and newly defined measures of open-field activity.

Bipolar pulse forming line

DOEpatents

Rhodes, Mark A.

2008-10-21

A bipolar pulse forming transmission line module for linear induction accelerators having first, second, third, fourth, and fifth planar conductors which form an interleaved stack with dielectric layers between the conductors. Each conductor has a first end, and a second end adjacent an acceleration axis. The first and second planar conductors are connected to each other at the second ends, the fourth and fifth planar conductors are connected to each other at the second ends, and the first and fifth planar conductors are connected to each other at the first ends via a shorting plate adjacent the first ends. The third planar conductor is electrically connectable to a high voltage source, and an internal switch functions to short a high voltage from the first end of the third planar conductor to the first end of the fourth planar conductor to produce a bipolar pulse at the acceleration axis with a zero net time integral. Improved access to the switch is enabled by an aperture through the shorting plate and the proximity of the aperture to the switch.

The 2-79 keV X-ray Spectrum of the Circinus Galaxy with NuSTAR, XMM-Newton and Chandra: a Fully Compton-Thick Active Galactic Nucleus

DOE PAGES

Arevalo, P.; Bauer, F. E.; Puccetti, S.; ...

2014-07-30

Here, the Circinus galaxy is one of the closest obscured active galactic nuclei (AGNs), making it an ideal target for detailed study. Combining archival Chandra and XMM-Newton data with new NuSTAR observations, we model the 2-79 keV spectrum to constrain the primary AGN continuum and to derive physical parameters for the obscuring material. Chandra's high angular resolution allows a separation of nuclear and off-nuclear galactic emission. In the off-nuclear diffuse emission, we find signatures of strong cold reflection, including high equivalent-width neutral Fe lines. This Compton-scattered off-nuclear emission amounts to 18% of the nuclear flux in the Fe line region,more » but becomes comparable to the nuclear emission above 30 keV. The new analysis no longer supports a prominent transmitted AGN component in the observed band. We find that the nuclear spectrum is consistent with Compton scattering by an optically thick torus, where the intrinsic spectrum is a power law of photon index Γ = 2.2-2.4, the torus has an equatorial column density of N H = (6-10) × 10 24 cm –2, and the intrinsic AGN 2-10 keV luminosity is (2.3-5.1) × 10 42 erg s –1. These values place Circinus along the same relations as unobscured AGNs in accretion rate versus Γ and L X versus L IR phase space. NuSTAR's high sensitivity and low background allow us to study the short timescale variability of Circinus at X-ray energies above 10 keV for the first time. Here, the lack of detected variability favors a Compton-thick absorber, in line with the spectral fitting results.« less

Evidence for a first-order liquid-liquid transition in high-pressure hydrogen from ab initio simulations

PubMed Central

Morales, Miguel A.; Pierleoni, Carlo; Schwegler, Eric; Ceperley, D. M.

2010-01-01

Using quantum simulation techniques based on either density functional theory or quantum Monte Carlo, we find clear evidence of a first-order transition in liquid hydrogen, between a low conductivity molecular state and a high conductivity atomic state. Using the temperature dependence of the discontinuity in the electronic conductivity, we estimate the critical point of the transition at temperatures near 2,000 K and pressures near 120 GPa. Furthermore, we have determined the melting curve of molecular hydrogen up to pressures of 200 GPa, finding a reentrant melting line. The melting line crosses the metalization line at 700 K and 220 GPa using density functional energetics and at 550 K and 290 GPa using quantum Monte Carlo energetics. PMID:20566888

Line-dependent veiling in very active classical T Tauri stars

NASA Astrophysics Data System (ADS)

Rei, A. C. S.; Petrov, P. P.; Gameiro, J. F.

2018-02-01

Context. The T Tauri stars with active accretion disks show veiled photospheric spectra. This is supposedly due to non-photospheric continuum radiated by hot spots beneath the accretion shocks at stellar surface and/or chromospheric emission lines radiated by the post-shocked gas. The amount of veiling is often considered as a measure of the mass-accretion rate. Aim. We analysed high-resolution photospheric spectra of accreting T Tauri stars LkHα 321, V1331 Cyg, and AS 353A with the aim of clarifying the nature of the line-dependent veiling. Each of these objects shows a strong emission line spectrum and powerful wind features indicating high rates of accretion and mass loss. Methods: Equivalent widths of hundreds of weak photospheric lines were measured in the observed spectra of high quality and compared with those in synthetic spectra of appropriate models of stellar atmospheres. Results: The photospheric spectra of the three T Tauri stars are highly veiled. We found that the veiling is strongly line-dependent: larger in stronger photospheric lines and weak or absent in the weakest ones. No dependence of veiling on excitation potential within 0 to 5 eV was found. Different physical processes responsible for these unusual veiling effects are discussed in the framework of the magnetospheric accretion model. Conclusions: The observed veiling has two origins: (1) an abnormal structure of stellar atmosphere heated up by the accreting matter, and (2) a non-photospheric continuum radiated by a hot spot with temperature lower than 10 000 K. The true level of the veiling continuum can be derived by measuring the weakest photospheric lines with equivalent widths down to ≈10 mÅ. A limited spectral resolution and/or low signal-to-noise ratio results in overestimation of the veiling continuum. In the three very active stars, the veiling continuum is a minor contributor to the observed veiling, while the major contribution comes from the line-dependent veiling.

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study.

PubMed

Zhou, C C; Bai, C X; Guan, Z Z; Jiang, G L; Shi, Y K; Wang, M Z; Wu, Y L; Zhang, Y P; Zhu, Y Z

2014-05-01

Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively. The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported.

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa

PubMed Central

Knight, Gwenan M.; Gomez, Gabriela B.; Dodd, Peter J.; Dowdy, David; Zwerling, Alice; Wells, William A.; Cobelens, Frank; Vassall, Anna; White, Richard G.

2015-01-01

Background A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. Method An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015–2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. Results It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). Conclusion The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa. PMID:26717007

Transmission Line Security Monitor

ScienceCinema

None

2017-12-09

The Transmission Line Security Monitor is a multi-sensor monitor that mounts directly on high-voltage transmission lines to detect, characterize and communicate terrorist activity, human tampering and threatening conditions around support towers. For more information about INL's critical infrastructure protection research, visit http://www.facebook.com/idahonationallaboratory.

Bright Points and Subflares in UV Lines and in X-Rays

NASA Technical Reports Server (NTRS)

Rovira, M.; Schmieder, B.; Demoulin, P.; Simnett, G. M.; Hagyard, M. J.; Reichmann, E.; Tandberg-Hanssen, E.

1998-01-01

We have analysed an active region which was observed in Halpha (MSDP), UV lines (SMM/UVSP), and in X rays (SMM/HXIS). In this active region there were only a few subflares and many small bright points visible in UV and in X rays. Using an extrapolation based on the Fourier transform we have computed magnetic field lines connecting different photospheric magnetic polarities from ground-based magnetograms. Along the magnetic inversion lines we find 2 different zones: 1. a high shear region (less than 70 degrees) where subflares occur 2. a low shear region along the magnetic inversion line where UV bright points are observed.

Germ-Line Recombination Activity of the Widely Used hGFAP-Cre and Nestin-Cre Transgenes

PubMed Central

Zhang, Jiong; Dublin, Pavel; Griemsmann, Stephanie; Klein, Alexandra; Brehm, Ralph; Bedner, Peter; Fleischmann, Bernd K.; Steinhäuser, Christian; Theis, Martin

2013-01-01

Herein we demonstrate with PCR, immunodetection and reporter gene approaches that the widely used human Glial Fibrillary Acidic Protein (hGFAP)-Cre transgene exhibits spontaneous germ-line recombination activity in leading to deletion in brain, heart and tail tissue with high frequency. The ectopic activity of hGFAP-Cre requires a rigorous control. We likewise observed that a second widely used nestin-Cre transgene shows germ-line deletion. Here we describe procedures to identify mice with germ-line recombination mediated by the hGFAP-Cre and nestin-Cre transgenes. Such control is essential to avoid pleiotropic effects due to germ-line deletion of loxP-flanked target genes and to maintain the CNS-restricted deletion status in transgenic mouse colonies. PMID:24349371

Start Your Engines...Start Your Year!

ERIC Educational Resources Information Center

Adair, Lila M.; Loveless, Garry C.

1994-01-01

Provides a first-week activity in which student groups brainstorm and build cars to win a race. Includes rules, suggestions, time line, and evaluation methods. Notes that many misconceptions may arise from the activity but these are dealt with in the next few weeks of class. (MVL)

How We Identify and Manage Patients with Inadequately Controlled Polycythemia Vera.

PubMed

Reiter, Andreas; Harrison, Claire

2016-10-01

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by an overactive Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway through mutations in JAK2 exons 12 or 14 (JAK2 V617F). The dominant clinical characteristics include erythrocytosis (with or without leukocytosis/thrombocytosis), thrombotic events, and symptoms. Increased risk of mortality is mainly caused by thrombotic events and progression to post-polycythemia vera myelofibrosis (PPV-MF) or secondary acute myeloid leukemia (sAML). The most important prognostic factors include age and a history of thrombotic events, although recent evidence has indicated that leukocytosis and additional cytogenetic aberrations may also be of significant prognostic value. First-line therapies include aspirin and phlebotomies, which significantly reduce the incidence of thrombotic events and prolong survival. Cytoreductive treatment with hydroxyurea (approved) and conventional or pegylated interferon-α (effective, but not approved in many countries) is initiated for high-risk or inadequately controlled disease, e.g., uncontrolled hematocrit, leukocytosis, thrombocytosis, thrombotic events, splenomegaly, or symptoms. However, some patients may not receive initial benefit from first-line therapy or may become resistant or intolerant in due course. Although second-line treatment options are limited, clinical trials have shown the efficacy of ruxolitinib toward improving blood counts, enlarged spleen, and symptoms and potentially reducing thrombotic events. Identification of patients with uncontrolled PV is important for clinical care, as such patients have a high risk of complications, and future studies with JAK inhibitors or other agents alone or in combination are needed to test their potential to reduce rates of thrombotic events and transformation to PPV-MF or sAML.

Antiretroviral therapy in children: recent advances.

PubMed

Lodha, Rakesh; Manglani, Mamta

2012-12-01

Availability and successful use of various antiretroviral drugs has transformed HIV/AIDS from an incurable to a treatable chronic condition. The antiretroviral therapy can successfully suppress viral replication and preserve the immune system for many years. The implementation of antiretroviral therapy program in resource limited settings using the 'public health approach' of the World Health Organization has had a dramatic impact on the lives of millions of HIV infected individuals. Antiretroviral therapy (ART) in children has many challenges: use of appropriate formulations, regular need for modification of doses as the child grows, adherence issues, etc. To reduce the high morbidity and mortality in HIV infected children, it is currently recommended that all HIV infected children less than 24 mo should receive ART; in older children the indications are based on clinical and/or immunological criteria. Highly active antiretroviral therapy regimens include at least 3 antiretroviral drugs. The first line therapy recommended for children is a combination of two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor. Infants who have had exposure to nevirapine should receive a combination of two nucleoside reverse transcriptase inhibitors and a protease inhibitor; the protease inhibitor of choice is ritonavir boosted lopinavir. The success of therapy is dependent on >95 % adherence. The second line regimen, used when the first line therapy fails, is based on a protease inhibitor. The ongoing research focuses on simplification of regimen, discovery of more potent drugs, availability of more pediatric formulations, treatment of drug resistant strains etc. The optimal indications for initiation of therapy in children, are also being studied.

Immortalization of chicken preadipocytes by retroviral transduction of chicken TERT and TR

PubMed Central

Wang, Wei; Zhang, Tianmu; Wu, Chunyan; Wang, Shanshan; Wang, Yuxiang; Wang, Ning

2017-01-01

The chicken is an important agricultural animal and model for developmental biology, immunology and virology. Excess fat accumulation continues to be a serious problem for the chicken industry. However, chicken adipogenesis and obesity have not been well investigated, because no chicken preadipocyte cell lines have been generated thus far. Here, we successfully generated two immortalized chicken preadipocyte cell lines through transduction of either chicken telomerase reverse transcriptase (chTERT) alone or in combination with chicken telomerase RNA (chTR). Both of these cell lines have survived >100 population doublings in vitro, display high telomerase activity and have no sign of replicative senescence. Similar to primary chicken preadipocytes, these two cell lines display a fibroblast-like morphology, retain the capacity to differentiate into adipocytes, and do not display any signs of malignant transformation. Isoenzyme analysis and PCR-based analysis confirmed that these two cell lines are of chicken origin and are free from inter-species contamination. To our knowledge, this is the first report demonstrating the generation of immortal chicken cells by introduction of chTERT and chTR. Our established chicken preadipocyte cell lines show great promise as an in vitro model for the investigation of chicken adipogenesis, lipid metabolism, and obesity and its related diseases, and our results also provide clues for immortalizing other avian cell types. PMID:28486516

Active Tuberculosis among Homeless Persons, Toronto, Ontario, Canada, 1998–2007

PubMed Central

Rea, Elizabeth; McDermaid, Cameron; Stuart, Rebecca; Chambers, Catharine; Wang, Jun; Chan, Angie; Gardam, Michael; Jamieson, Frances; Yang, Jae; Hwang, Stephen W.

2011-01-01

While tuberculosis (TB) in Canadian cities is increasingly affecting foreign-born persons, homeless persons remain at high risk. To assess trends in TB, we studied all homeless persons in Toronto who had a diagnosis of active TB during 1998–2007. We compared Canada-born and foreign-born homeless persons and assessed changes over time. We identified 91 homeless persons with active TB; they typically had highly contagious, advanced disease, and 19% died within 12 months of diagnosis. The proportion of homeless persons who were foreign-born increased from 24% in 1998–2002 to 39% in 2003–2007. Among foreign-born homeless persons with TB, 56% of infections were caused by strains not known to circulate among homeless persons in Toronto. Only 2% of infections were resistant to first-line TB medications. The rise in foreign-born homeless persons with TB strains likely acquired overseas suggests that the risk for drug-resistant strains entering the homeless shelter system may be escalating. PMID:21392424

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas.

PubMed

Pham, Lan V; Huang, Shengjian; Zhang, Hui; Zhang, Jun; Bell, Taylor; Zhou, Shouhao; Pogue, Elizabeth; Ding, Zhiyong; Lam, Laura; Westin, Jason; Davis, R Eric; Young, Ken H; Medeiros, L Jeffrey; Ford, Richard J; Nomie, Krystle; Zhang, Leo; Wang, Michael

2018-04-17

Purpose: B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. Clin Cancer Res; 1-14. ©2018 AACR. ©2018 American Association for Cancer Research.

A Study of a Compound Solar Eruption with Two Consecutive Erupting Magnetic Structures

NASA Astrophysics Data System (ADS)

Dhakal, Suman K.; Chintzoglou, Georgios; Zhang, Jie

2018-06-01

We report a study of a compound solar eruption that was associated with two consecutively erupting magnetic structures and correspondingly two distinct peaks, during impulsive phase, of an M-class flare (M8.5). Simultaneous multi-viewpoint observations from SDO, GOES and STEREO-A show that this compound eruption originated from two pre-existing sigmoidal magnetic structures lying along the same polarity inversion line. Observations of the associated pre-existing filaments further show that these magnetic structures are lying one on top of the other, separated by 12 Mm in height, in a so-called “double-decker” configuration. The high-lying magnetic structure became unstable and erupted first, appearing as an expanding hot channel seen at extreme ultraviolet wavelengths. About 12 minutes later, the low-lying structure also started to erupt and moved at an even faster speed compared to the high-lying one. As a result, the two erupting structures interacted and merged with each other, appearing as a single coronal mass ejection in the outer corona. We find that the double-decker configuration is likely caused by the persistent shearing motion and flux cancellation along the source active region’s strong-gradient polarity inversion line. The successive destabilization of these two separate but closely spaced magnetic structures, possibly in the form of magnetic flux ropes, led to a compound solar eruption. The study of the compound eruption provides a unique opportunity to reveal the formation process, initiation, and evolution of complex eruptive structures in solar active regions.

Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

PubMed

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico

2014-01-01

The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

Determining inclinations of active galactic nuclei via their narrow-line region kinematics

NASA Astrophysics Data System (ADS)

Fischer, Travis Cody

Active Galactic Nuclei (AGN) are axisymmetric systems to first order; their observed properties are likely strong functions of inclination with respect to our line of sight. However, except for a few special cases, the specific inclinations of individual AGN are unknown. We have developed a promising technique for determining the inclinations of nearby AGN by mapping the kinematics of their narrow-line regions (NLRs), which are easily resolved with Hubble Space Telescope (HST) [O III] imaging and long-slit spectra from the Space Telescope Imaging Spectrograph (STIS). Our studies indicate that NLR kinematics dominated by radial outflow can be fit with simple biconical outflow models that can be used to determine the inclination of the bicone axis, and hence the obscuring torus, with respect to our line of sight. We present NLR analysis of 53 Seyfert galaxies and resultant inclinations from models of 17 individual AGN with clear signatures of biconical outflow. From these AGN, which we can for the first time assess the effect of inclination on other observable properties in radio-quiet AGN, including the discovery of a distinct correlation between AGN inclination and X-ray column density. INDEX WORDS: AGN, Seyfert galaxies, NLR, Outflows, Kinematics, Bicones, Unified Model Graduation.

Quantitative High-throughput Luciferase Screening in Identifying CAR Modulators

PubMed Central

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2017-01-01

Summary The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR. PMID:27518621

Portable open-path optical remote sensing (ORS) Fourier transform infrared (FTIR) instrumentation miniaturization and software for point and click real-time analysis

NASA Astrophysics Data System (ADS)

Zemek, Peter G.; Plowman, Steven V.

2010-04-01

Advances in hardware have miniaturized the emissions spectrometer and associated optics, rendering them easily deployed in the field. Such systems are also suitable for vehicle mounting, and can provide high quality data and concentration information in minutes. Advances in software have accompanied this hardware evolution, enabling the development of portable point-and-click OP-FTIR systems that weigh less than 16 lbs. These systems are ideal for first-responders, military, law enforcement, forensics, and screening applications using optical remote sensing (ORS) methodologies. With canned methods and interchangeable detectors, the new generation of OP-FTIR technology is coupled to the latest forward reference-type model software to provide point-and-click technology. These software models have been established for some time. However, refined user-friendly models that use active, passive, and solar occultation methodologies now allow the user to quickly field-screen and quantify plumes, fence-lines, and combustion incident scenarios in high-temporal-resolution. Synthetic background generation is now redundant as the models use highly accurate instrument line shape (ILS) convolutions and several other parameters, in conjunction with radiative transfer model databases to model a single calibration spectrum to collected sample spectra. Data retrievals are performed directly on single beam spectra using non-linear classical least squares (NLCLS). Typically, the Hitran line database is used to generate the initial calibration spectrum contained within the software.

Involvement of dopamine in the differences in sexual behaviour between Roman high and low avoidance rats: an intracerebral microdialysis study.

PubMed

Sanna, Fabrizio; Piludu, Maria Antonietta; Corda, Maria Giuseppa; Melis, Maria Rosaria; Giorgi, Osvaldo; Argiolas, Antonio

2015-03-15

Outbred Roman high- (RHA) and low-avoidance (RLA) rats are selected for respectively rapid vs. poor acquisition of the active avoidance response and display different copulatory patterns when exposed to a sexually receptive female, with RHA rats showing more robust sexual motivation and better performance than RLA rats also after repeated sexual activity. Here we show that the distinct patterns of sexual behaviour of the Roman lines are correlated with differences in the activity of the dopaminergic mesolimbic system, which plays a key role in sexual motivation and copulatory performance. Thus, differential increases in the concentrations of dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid, occurred in dialysates obtained from the nucleus accumbens shell of naïve and sexually experienced Roman rats during the anticipatory and consummatory phases of sexual activity. These differences were particularly evident between sexually naïve RHA and RLA rats and tended to diminish but still persisted between sexually experienced rats, as did the differences in sexual behaviour. Analysis of the biochemical and behavioural findings showed that, while in RHA rats sexual experience caused a shift in the changes in both the dopaminergic activity and copulation towards the first period of the sexual test, in RLA rats sexual experience increased dopaminergic activity and copulation throughout the entire test. Therefore, this study adds experimental support to the view that the different sexual patterns of the Roman lines are due, at least in part, to a more robust functional tone of the mesolimbic dopaminergic system of RHA rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Consequences of hot gas in the broad line region of active galactic nuclei

NASA Technical Reports Server (NTRS)

Kallman, T.; Mushotzky, R.

1985-01-01

Models for hot gas in the broad line region of active galactic nuclei are discussed. The results of the two phase equilibrium models for confinement of broad line clouds by Compton heated gas are used to show that high luminosity quasars are expected to show Fe XXVI L alpha line absorption which will be observed with spectrometers such as those planned for the future X-ray spectroscopy experiments. Two phase equilibrium models also predict that the gas in the broad line clouds and the confining medium may be Compton thick. It is shown that the combined effects of Comptonization and photoabsorption can suppress both the broad emission lines and X-rays in the Einstein and HEAO-1 energy bands. The observed properties of such Compton thick active galaxies are expected to be similar to those of Seyfert 2 nuclei. The implications for polarization and variability are also discussed.

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

PubMed Central

Santarpia, Mariacarmela; Daffinà, Maria Grazia; D’Aveni, Alessandro; Marabello, Grazia; Liguori, Alessia; Giovannetti, Elisa; Karachaliou, Niki; Gonzalez Cao, Maria; Rosell, Rafael; Altavilla, Giuseppe

2017-01-01

The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations. PMID:28740365

Discovery of Ultra-fast Outflows in a Sample of Broad-line Radio Galaxies Observed with Suzaku

NASA Astrophysics Data System (ADS)

Tombesi, F.; Sambruna, R. M.; Reeves, J. N.; Braito, V.; Ballo, L.; Gofford, J.; Cappi, M.; Mushotzky, R. F.

2010-08-01

We present the results of a uniform and systematic search for blueshifted Fe K absorption lines in the X-ray spectra of five bright broad-line radio galaxies observed with Suzaku. We detect, for the first time in radio-loud active galactic nuclei (AGNs) at X-rays, several absorption lines at energies greater than 7 keV in three out of five sources, namely, 3C 111, 3C 120, and 3C 390.3. The lines are detected with high significance according to both the F-test and extensive Monte Carlo simulations. Their likely interpretation as blueshifted Fe XXV and Fe XXVI K-shell resonance lines implies an origin from highly ionized gas outflowing with mildly relativistic velocities, in the range v ~= 0.04-0.15c. A fit with specific photoionization models gives ionization parameters in the range log ξ ~= 4-5.6 erg s-1 cm and column densities of N H ~= 1022-1023 cm-2. These characteristics are very similar to those of the ultra-fast outflows (UFOs) previously observed in radio-quiet AGNs. Their estimated location within ~0.01-0.3 pc of the central super-massive black hole suggests a likely origin related with accretion disk winds/outflows. Depending on the absorber covering fraction, the mass outflow rate of these UFOs can be comparable to the accretion rate and their kinetic power can correspond to a significant fraction of the bolometric luminosity and is comparable to their typical jet power. Therefore, these UFOs can play a significant role in the expected feedback from the AGN to the surrounding environment and can give us further clues on the relation between the accretion disk and the formation of winds/jets in both radio-quiet and radio-loud AGNs.

Selection and breeding of honey bees for higher or lower collection of avocado nectar.

PubMed

Afik, Ohad; Dag, Arnon; Yeselson, Yelena; Schaffer, Arthur; Shafir, Sharoni

2010-04-01

Intensive activity of honey bees, Apis mellifera L., is essential for high fruit set in avocado, Persea americana Mill., orchards, but even when hives are located inside the orchard, many bees still search for alternative blooms. We tested for a possible genetic component for a preference of avocado bloom relative to competing bloom. The honey from each hive was extracted at the end of the avocado bloom and the concentration of perseitol, a carbohydrate that is unique to avocado, was analyzed as a measure for avocado foraging. During the first year, five bee strains were compared in three different sites in Israel. Significant differences were found between strains in honey perseitol concentrations, suggesting differences in their efficiency as avocado pollinators, although these differences were site dependent. At two sites, colonies with the highest and lowest perseitol concentrations were selected as parental "high" and "low" lines. Queens were raised from the selected colonies and were instrumentally inseminated by drones from other colonies of this line. During the second and third years, colonies with inseminated queens were introduced to the avocado orchards, together with the selected colonies still surviving from the previous year. Colonies of the high line had greater perseitol concentrations than those of the low line. Selected colonies that survived from the previous year performed consistently vis-à-vis perseitol concentration, in the second year of testing. Heritability value of 0.22 was estimated based on regression of offspring on midparent. The results reveal a heritable component for willingness of honey bees to collect avocado nectar.

The Second-generation z (Redshift) and Early Universe Spectrometer. I. First-light Observation of a Highly Lensed Local-ulirg Analog at High-z

NASA Astrophysics Data System (ADS)

Ferkinhoff, Carl; Brisbin, Drew; Parshley, Stephen; Nikola, Thomas; Stacey, Gordon J.; Schoenwald, Justin; Higdon, James L.; Higdon, Sarah J. U.; Verma, Aprajita; Riechers, Dominik; Hailey-Dunsheath, Steven; Menten, Karl M.; Güsten, Rolf; Weiß, Axel; Irwin, Kent; Cho, Hsiao M.; Niemack, Michael; Halpern, Mark; Amiri, Mandana; Hasselfield, Matthew; Wiebe, D. V.; Ade, Peter A. R.; Tucker, Carol E.

2014-01-01

We recently commissioned our new spectrometer, the second-generation z(Redshift) and Early Universe Spectrometer (ZEUS-2) on the Atacama Pathfinder Experiment telescope. ZEUS-2 is a submillimeter grating spectrometer optimized for detecting the faint and broad lines from distant galaxies that are redshifted into the telluric windows from 200 to 850 μm. It uses a focal plane array of transition-edge sensed bolometers, the first use of these arrays for astrophysical spectroscopy. ZEUS-2 promises to be an important tool for studying galaxies in the years to come because of its synergy with Atacama Large Millimeter Array and its capabilities in the short submillimeter windows that are unique in the post-Herschel era. Here, we report on our first detection of the [C II] 158 μm line with ZEUS-2. We detect the line at z ~ 1.8 from H-ATLAS J091043.1-000322 with a line flux of (6.44 ± 0.42) × 10-18 W m-2. Combined with its far-IR luminosity and a new Herschel-PACS detection of the [O I] 63 μm line, we model the line emission as coming from a photo-dissociation region with far-ultraviolet radiation field, G ~ 2 × 104 G 0, gas density, n ~ 1 × 103 cm-3 and size between ~0.4 and 1 kpc. On the basis of this model, we conclude that H-ATLAS J091043.1-000322 is a high-redshift analog of a local ultra-luminous IR galaxy; i.e., it is likely the site of a compact starburst caused by a major merger. Further identification of these merging systems is important for constraining galaxy formation and evolution models.

1,1-Diphenyl-2-picrylhydrazyl radical-scavenging compounds from soybean miso and antiproliferative activity of isoflavones from soybean miso toward the cancer cell lines.

PubMed

Hirota, A; Taki, S; Kawaii, S; Yano, M; Abe, N

2000-05-01

Guided by their DPPH radical-scavenging activity, nine compounds were isolated from soybean miso. Of these, 8-hydroxydaidzein, 8-hydroxygenistein and syringic acid had as high DPPH radical-scavenging activity as that of alpha-tocopherol. The antiproliferative activity of four of the isolated isoflavones toward three cancer cell lines was examined. 8-Hydroxygenistein showed the highest activity (IC50=5.2 microM) toward human promyelocytic leukemia cells (HL-60).

High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chowdhury, Subir K.R.; Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Hamilton, Ont., L8N 3Z5; Gemin, Adam

Most malignant cells are highly glycolytic and produce high levels of reactive oxygen species (ROS) compared to normal cells. Mitochondrial glycerophosphate dehydrogenase (mGPDH) participates in the reoxidation of cytosolic NADH by delivering reducing equivalents from this molecule into the electron transport chain, thus sustaining glycolysis. Here, we investigate the role of mGPDH in maintaining an increased rate of glycolysis and evaluate glycerophosphate-dependent ROS production in prostate cancer cell lines (LNCaP, DU145, PC3, and CL1). Immunoblot, polarographic, and spectrophotometric analyses revealed that mGPDH abundance and activity was significantly elevated in prostate cancer cell lines when compared to the normal prostate epithelialmore » cell line PNT1A. Furthermore, both the glycolytic capacity and glycerophosphate-dependent ROS production was increased 1.68- to 4.44-fold and 5- to 7-fold, respectively, in prostate cancer cell lines when compared to PNT1A cells. Overall, these data demonstrate that mGPDH is involved in maintaining a high rate of glycolysis and is an important site of electron leakage leading to ROS production in prostate cancer cells.« less

Effect of three fatty acids from the leaf extract of Tiliacora triandra on P-glycoprotein function in multidrug-resistant A549RT-eto cell line

PubMed Central

Kaewpiboon, Chutima; Winayanuwattikun, Pakorn; Yongvanich, Tikamporn; Phuwapraisirisan, Preecha; Assavalapsakul, Wanchai

2014-01-01

Background: Cancer cells have the ability to develop resistance to chemotherapy drugs, which then leads to a reduced effectiveness and success of the treatment. Multidrug resistance (MDR) involves the resistance in the same cell/tissue to a diverse range of drugs of different structures. One of the characteristics of MDR is an overexpression of P-glycoprotein (P-gp), which causes the efflux of the accumulated drug out of the cell. The MDR human non-small cell lung carcinoma cell line with a high P-gp expression level (A549RT-eto) was used to investigate the bioactive compounds capable of reversing the etoposide resistance in this cell line. Materials and Methods: The leaves of Tiliacora triandra were sequentially extracted with hexane, dichloromethane, methanol and water. Only the hexane extract reduced the etoposide resistance of the A549RT-eto cell line, and was further fractionated by column chromatography using the TLC-pattern and the restoration of etoposide sensitivity as the selection criteria. Results: The obtained active fraction (F22) was found by nuclear magnetic resonance and gas chromatography-mass spectroscopy analyses to be comprised of a 49.5:19.6:30.9 (w/w/w) mixture of hexadecanoic: octadecanoic acid: (Z)-6-octadecenoic acids. This stoichiometric mixture was recreated using pure fatty acids (MSFA) and gave a similar sensitization to etoposide and enhanced the relative rate of rhodamine-123 accumulation to a similar extent as F22, supporting the action via reducing P-gp activity. In contrast, the fatty acids alone did not show this effect. Conclusion: This is the first report of the biological activity from the leaves of T. triandra as a potential source of a novel chemosensitizer. PMID:25298673

Effect of three fatty acids from the leaf extract of Tiliacora triandra on P-glycoprotein function in multidrug-resistant A549RT-eto cell line.

PubMed

Kaewpiboon, Chutima; Winayanuwattikun, Pakorn; Yongvanich, Tikamporn; Phuwapraisirisan, Preecha; Assavalapsakul, Wanchai

2014-08-01

Cancer cells have the ability to develop resistance to chemotherapy drugs, which then leads to a reduced effectiveness and success of the treatment. Multidrug resistance (MDR) involves the resistance in the same cell/tissue to a diverse range of drugs of different structures. One of the characteristics of MDR is an overexpression of P-glycoprotein (P-gp), which causes the efflux of the accumulated drug out of the cell. The MDR human non-small cell lung carcinoma cell line with a high P-gp expression level (A549RT-eto) was used to investigate the bioactive compounds capable of reversing the etoposide resistance in this cell line. The leaves of Tiliacora triandra were sequentially extracted with hexane, dichloromethane, methanol and water. Only the hexane extract reduced the etoposide resistance of the A549RT-eto cell line, and was further fractionated by column chromatography using the TLC-pattern and the restoration of etoposide sensitivity as the selection criteria. The obtained active fraction (F22) was found by nuclear magnetic resonance and gas chromatography-mass spectroscopy analyses to be comprised of a 49.5:19.6:30.9 (w/w/w) mixture of hexadecanoic: octadecanoic acid: (Z)-6-octadecenoic acids. This stoichiometric mixture was recreated using pure fatty acids (MSFA) and gave a similar sensitization to etoposide and enhanced the relative rate of rhodamine-123 accumulation to a similar extent as F22, supporting the action via reducing P-gp activity. In contrast, the fatty acids alone did not show this effect. This is the first report of the biological activity from the leaves of T. triandra as a potential source of a novel chemosensitizer.

Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitro.

PubMed

Fairhall, Emma A; Leitch, Alistair C; Lakey, Anne F; Probert, Philip M E; Richardson, Gabriella; De Santis, Carol; Wright, Matthew C

2018-05-22

The rodent pancreatic AR42J-B13 (B-13) cell line differentiates into non-replicative hepatocyte-like cells in response to glucocorticoid mediated via the glucocorticoid receptor (GR). The aims of this study were to identify a human cell line that responds similarly and investigate the mechanisms underpinning any alteration in differentiation. Exposing the human pancreatic adenocarcinoma (HPAC) cell line to 1-10 µM concentrations of dexamethasone (DEX) resulted an inhibition of proliferation, suppressed carcinoembryonic antigen expression, limited expression of pancreatic acinar and hepatic gene expression and significant induction of the constitutively-expressed hepatic CYP3A5 mRNA transcript. These changes were associated with a pulse of genomic DNA methylation and suppressed notch signalling activity. HPAC cells expressed high levels of GR transcript in contrast to other nuclear receptors - such as the glucocorticoid-activated pregnane X receptor (PXR) - and GR transcriptional function was activated by DEX in HPAC cells. Expression of selected hepatocyte transcripts in response to DEX was blocked by co-treatment with the GR antagonist RU486. These data indicate that the HPAC response to glucocorticoid exposure includes an inhibition in proliferation, alterations in notch signalling and a limited change in the expression of genes associated with an acinar and hepatic phenotype. This is the first demonstration of a human cell responding to similarly to the rodent B-13 cell regarding formation of hepatocyte-like cells in response to glucocorticoid. Identifying and modulating the ablating factor(s) may enhance the hepatocyte-like forming capacity of HPAC cells after exposure to glucocorticoid and generate an unlimited in vitro supply of human hepatocytes for toxicology studies and a variety of clinical applications. Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

First 2017-total-eclipse results from the Williams College team

NASA Astrophysics Data System (ADS)

Pasachoff, J.; Dantowitz, R.; Rusin, V.; Seiradakis, J. H.; Voulgaris, A.; Seaton, D. B.; Davis, A. B.; Lu, M.; Sliski, D.; Ladd, E. F.; Economou, T.; Peñaloza-Murillo, M. A.; Nagle-McNaughton, T.

2017-12-01

We report on a wide range of observations we carried out during the total solar eclipse of August 21, 2017. Our main site was on the campus of Willamette University, Salem, Oregon, at which we had a variety of telescopes, spectrographs, cameras, a grism, and terrestrial-atmospheric measuring devices. Our goals included differentiating between models of coronal heating through measuring power-spectra of coronal loops in the [Fe XIV] and [Fe X] emission lines at multi-Hertz cadence with a frame-transfer CCD and otherwise; following coronal structure over the solar-activity cycle; comparing the results of a full-MHD prediction with actual coronal streamers; studying the dynamics of coronal plumes given the minimum phase of the solar-activity cycle; measuring the variation of the corona over the solar-activity cycle from our continuing measurements of the green-line/red-line intensity ratio; studying a variety of additional coronal emisson lines; high-resolution coronal imaging compared with overlapping images from space coronagraphs aboard SoHO and STEREO; comparing with AIA/SDO, HMO/SDO, SUVI/GOES-16, and SWAP/PROBA2 space images; and more. Our research has been supported in large part by grants from the Committee for Research and Exploration of the National Geographic Society and from the Solar Terrestrial Program of the Atmospheric and Geospace Sciences Division of the National Science Foundation, with additional support from Sigma Xi. Additional support for undergraduate participation came from the NSF, the NASA Massachusetts Space Grant Consortium, and the Clare Booth Luce Foundation, with travel support from the Freeman Foote Fund, the Rob Spring Fund, the Brandi Fund, and other sources at Williams College.

Antiproliferative Activity of Cyanophora paradoxa Pigments in Melanoma, Breast and Lung Cancer Cells

PubMed Central

Baudelet, Paul-Hubert; Gagez, Anne-Laure; Bérard, Jean-Baptiste; Juin, Camille; Bridiau, Nicolas; Kaas, Raymond; Thiéry, Valérie; Cadoret, Jean-Paul; Picot, Laurent

2013-01-01

The glaucophyte Cyanophora paradoxa (Cp) was chemically investigated to identify pigments efficiently inhibiting malignant melanoma, mammary carcinoma and lung adenocarcinoma cells growth. Cp water and ethanol extracts significantly inhibited the growth of the three cancer cell lines in vitro, at 100 µg·mL−1. Flash chromatography of the Cp ethanol extract, devoid of c-phycocyanin and allophycocyanin, enabled the collection of eight fractions, four of which strongly inhibited cancer cells growth at 100 µg·mL−1. Particularly, two fractions inhibited more than 90% of the melanoma cells growth, one inducing apoptosis in the three cancer cells lines. The detailed analysis of Cp pigment composition resulted in the discrimination of 17 molecules, ten of which were unequivocally identified by high resolution mass spectrometry. Pheophorbide a, β-cryptoxanthin and zeaxanthin were the three main pigments or derivatives responsible for the strong cytotoxicity of Cp fractions in cancer cells. These data point to Cyanophora paradoxa as a new microalgal source to purify potent anticancer pigments, and demonstrate for the first time the strong antiproliferative activity of zeaxanthin and β-cryptoxanthin in melanoma cells. PMID:24189278

Natural Immunity to HIV: a delicate balance between strength and control.

PubMed

Poudrier, Johanne; Thibodeau, Valérie; Roger, Michel

2012-01-01

Understanding how the mucosal immune system in the human female reproductive tract might prevent or facilitate HIV infection has important implications for the design of effective interventions. We and others have established cohorts of highly-exposed, HIV-seronegative individuals, such as HIV-uninfected commercial sex workers, who have remained HIV-negative after more than 5 years of active prostitution. Observations obtained in studies of such individuals, who represent a model of natural immunity to HIV, indicate that HIV resistance may be associated with the host's capacity to preserve systemic integrity by constraining immune activity and controlling inflammatory conditions at the mucosal point of entry. This likely necessitates the orchestration of balanced, first-line and adaptive immune responses.

Effect of HK2, PKM2 and LDHA on Cetuximab efficacy in metastatic colorectal cancer.

PubMed

Wang, Haohua; Peng, Roujun; Chen, Xiuxing; Jia, Rui; Huang, Chunyue; Huang, Yuanyuan; Xia, Liangping; Guo, Guifang

2018-04-01

Although hexokinase (HK) 2, pyruvate kinase muscle (PKM) isozyme 2 and lactate dehydrogenase (LDH) A predict the efficacy of medicines in various solid tumors, their ability to predict the efficacy of cetuximab in metastatic colorectal cancer (mCRC) remains unclear. mCRC patients with pathological specimens who received cetuximab and chemotherapy from 2005 to 2015 in the present institution were enrolled. Immunohistochemistry was used to detect HK2, PKM2 and LDHA expression. SPSS20 was used for statistical analysis. A total of 68 patients were included; 33 received cetuximab plus chemotherapy as first-line therapy, and the rest, as second- or later-line therapy. HK2 expression levels were increased in cancer compared with normal tissue (75.4% vs. 40%; P<0.001), however PKM2 (P=0.243) and LDHA (P=0.067) expression levels were not. For progression-free survival (PFS) with first-line cetuximab plus chemotherapy, patients with high HK2 expression exhibited longer PFS compared with those with low HK2 expression (23.9 months vs. 6.9 months; P=0.021). However, this positive association was absent in 35 cases administered first-line chemotherapy alone (13.4 months vs. 13.5 months; P=0.539). LDHA expression was associated with the PFS of patients receiving first-line chemotherapy (18.3 and 10.1 months for high and low expression, respectively; P=0.005), whereas this association was absent in cetuximab plus chemotherapy cases (19.9 months vs. 12 months; P=0.522). Furthermore, high LDHA expression correlated with high overall response rate (ORR) (72.2% vs. 15.4%, P=0.006) for chemotherapy, however not disease control rate (DCR) (P=0.074). Neither DCR nor ORR were associated with HK2 expression. PKM2 expression did not affect PFS, DCR or ORR. LDHA expression (P=0.005), pathological differentiation (P=0.019) and synchronous/metachronous metastasis (P=0.014) were independent predictive factors of PFS for all first-line patients, and tumor differentiation (P=0.002) was associated with overall survival (OS) in multivariate analysis. HK2, PKM2 and LDHA did not impact OS. It was concluded that HK2 expression was increased in colorectal cancer tissue and may predict cetuximab efficacy and LDHA for chemotherapy treatment of mCRC.

Stellar Laboratories: New GeV and Ge VI Oscillator Strengths and their Validation in the Hot White Dwarf RE0503-289

NASA Technical Reports Server (NTRS)

Rauch, T.; Werner, K.; Biemont, E.; Quinet, P.; Kruk, J. W.

2013-01-01

State-of-the-art spectral analysis of hot stars by means of non-LTE model-atmosphere techniques has arrived at a high level of sophistication. The analysis of high-resolution and high-S/N spectra, however, is strongly restricted by the lack of reliable atomic data for highly ionized species from intermediate-mass metals to trans-iron elements. Especially data for the latter has only been sparsely calculated. Many of their lines are identified in spectra of extremely hot, hydrogen-deficient post-AGB stars. A reliable determination of their abundances establishes crucial constraints for AGB nucleosynthesis simulations and, thus, for stellar evolutionary theory. Aims. In a previous analysis of the UV spectrum of RE 0503-289, spectral lines of highly ionized Ga, Ge, As, Se, Kr, Mo, Sn, Te, I, and Xe were identified. Individual abundance determinations are hampered by the lack of reliable oscillator strengths. Most of these identified lines stem from Ge V. In addition, we identified Ge VI lines for the first time. We calculated Ge V and Ge VI oscillator strengths in order to reproduce the observed spectrum. Methods. We newly calculated Ge V and Ge VI oscillator strengths to consider their radiative and collisional bound-bound transitions in detail in our non-LTE stellar-atmosphere models for the analysis of the Ge IV-VI spectrum exhibited in high-resolution and high-S/N FUV (FUSE) and UV (ORFEUS/BEFS, IUE) observations of RE 0503-289. Results. In the UV spectrum of RE 0503-289, we identify four Ge IV, 37 Ge V, and seven Ge VI lines. Most of these lines are identified for the first time in any star. We can reproduce almost all Ge IV, GeV, and Ge VI lines in the observed spectrum of RE 0503-289 (T(sub eff) = 70 kK, log g = 7.5) at log Ge = -3.8 +/- 0.3 (mass fraction, about 650 times solar). The Ge IV/V/VI ionization equilibrium, that is a very sensitive T(sub eff) indicator, is reproduced well. Conclusions. Reliable measurements and calculations of atomic data are a prerequisite for stellar-atmosphere modeling. Our oscillator-strength calculations have allowed, for the first time, Ge V and Ge VI lines to be successfully reproduced in a white dwarf s (RE 0503-289) spectrum and to determine its photospheric Ge abundance.

Synthesis, anticancer and antibacterial activity of salinomycin N-benzyl amides.

PubMed

Antoszczak, Michał; Maj, Ewa; Napiórkowska, Agnieszka; Stefańska, Joanna; Augustynowicz-Kopeć, Ewa; Wietrzyk, Joanna; Janczak, Jan; Brzezinski, Bogumil; Huczyński, Adam

2014-11-25

A series of 12 novel monosubstituted N-benzyl amides of salinomycin (SAL) was synthesized for the first time and characterized by NMR and FT-IR spectroscopic methods. Molecular structures of three salinomycin derivatives in the solid state were determined using single crystal X-ray method. All compounds obtained were screened for their antiproliferative activity against various human cancer cell lines as well as against the most problematic bacteria strains such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), and Mycobacterium tuberculosis. Novel salinomycin derivatives exhibited potent anticancer activity against drug-resistant cell lines. Additionally, two N-benzyl amides of salinomycin revealed interesting antibacterial activity. The most active were N-benzyl amides of SAL substituted at -ortho position and the least anticancer active derivatives were those substituted at the -para position.

Behavioral Traits are Affected by Selective Breeding for Increased Wheel-Running Behavior in Mice

PubMed Central

Jónás, I.; Schubert, K. A.; Reijne, A. C.; Scholte, J.; Garland, T.; Gerkema, M. P.; Scheurink, A. J. W.; Nyakas, C.

2010-01-01

Voluntary physical activity may be related to personality traits. Here, we investigated these relations in two mouse lines selectively bred for high voluntary wheel-running behavior and in one non-selected control line. Selection lines were more explorative and “information gathering” in the open-field test, either with increased upright positions or horizontal locomotion toward the middle ring. Furthermore, one of the selection lines had an increased risk-taking behavior relative to the control line in approaching a novel object placed in the center of the open field. However, anxiety behavior was increased in selection lines during the plus-maze test. Maze learning was not statistically different among lines, but routine behavior was increased in both selection lines when the maze exit after 2 days of testing was displaced. Specifically, in the displaced maze, selected mice traveled more frequently to the old, habituated exit, bypassing the new exit attached to their home cage. Although the generality of the results would need to be confirmed in future studies including all eight lines in the selection experiment, the increased routine and exploratory behavior (at least in the lines used in the present study) may be adaptive to sustain high activity levels. PMID:20369280

Flare activity and photospheric analysis of Proxima Centauri

NASA Astrophysics Data System (ADS)

Pavlenko, Y.; Suárez Mascareño, A.; Rebolo, R.; Lodieu, N.; Béjar, V. J. S.; González Hernández, J. I.

2017-10-01

Context. We present the analysis of emission lines in high-resolution optical spectra of the planet-host star Proxima Centauri (Proxima) classified as a M5.5V. Aims: We carry out a detailed analysis of the observed spectra to get a better understanding of the physical conditions of the atmosphere of this star. Methods: We identify the emission lines in a series of 147 high-resolution optical spectra of the star at different levels of activity and compare them with the synthetic spectra computed over a wide spectral range. Results: Our synthetic spectra computed with the PHOENIX 2900/5.0/0.0 model atmosphere fits the observed spectral energy distribution from optical to near-infrared quite well. However, modelling strong atomic lines in the blue spectrum (3900-4200 Å) requires implementing additional opacity. We show that high-temperature layers in Proxima Centauri consist of at least three emitting parts: a) a stellar chromosphere where numerous emission lines form; we suggest that some emission cores of strong absorption lines of metals form there; b) flare regions above the chromosphere, where hydrogen Balmer lines up to high transition levels (10-2) form; and c) a stellar wind component with Vr = -30 km s-1 seen in some Balmer lines as blueshifted emission lines. We believe that the observed He line at 4026 Å in emission can be formed in that very hot region. Conclusions: We show that the real structure of the atmosphere of Proxima is rather complicated. The photosphere of the star is best fit by a normal M5 dwarf spectrum. On the other hand, emission lines form in the chromosphere, flare regions, and extended hot envelope. The movies are available at http://www.aanda.org

Design and vibration control of vehicle engine mount activated by MR fluid and piezoelectric actuator

NASA Astrophysics Data System (ADS)

Lee, D. Y.; Park, Y. K.; Choi, S. B.; Lee, H. G.

2009-07-01

An engine is one of the most dominant noise and vibration sources in vehicle systems. Therefore, in order to resolve noise and vibration problems due to engine, various types of engine mounts have been proposed. This work presents a new type of active engine mount system featuring a magneto-rheological (MR) fluid and a piezostack actuator. As a first step, six degrees-of freedom dynamic model of an in-line four-cylinder engine which has three points mounting system is derived by considering the dynamic behaviors of MR mount and piezostack mount. In the configuration of engine mount system, two MR mounts are installed for vibration control of roll mode motion whose energy is very high in low frequency range, while one piezostack mount is installed for vibration control of bounce and pitch mode motion whose energy is relatively high in high frequency range. As a second step, linear quadratic regulator (LQR) controller is synthesized to actively control the imposed vibration. In order to demonstrate the effectiveness of the proposed active engine mount, vibration control performances are evaluated under various engine operating speeds (wide frequency range).

Antioxidant potential, cytotoxic activity and total phenolic content of Alpinia pahangensis rhizomes

PubMed Central

2013-01-01

Background Alpinia pahangensis, a wild ginger distributed in the lowlands of Pahang, Malaysia, is used by the locals to treat flatulence. In this study, the antioxidant and cytotoxic activities of the crude aqueous methanol and fractionated extracts of Alpinia pahangensis against five different cancer and one normal cell lines were investigated. The total phenolic content of each extract and its fractions were also quantified. This is the first report on the antioxidant and cytotoxic activities of Alpinia pahangensis extract. Methods In the current study, the crude methanol and fractionated extract of the rhizomes of Alpinia pahangensis were investigated for their antioxidant activity using four different assays namely, the DPPH scavenging activity, superoxide anion scavenging, β-carotene bleaching and reducing power assays whilst their phenolic contents were measured by the Folin-Ciocalteu’s method. In vitro neutral red cytotoxicity assay was employed to evaluate the cytotoxic activity against five different cancer cell lines, colon cancer (HCT 116 and HT-29), cervical cancer (Ca Ski), breast cancer (MCF7) and lung cancer (A549) cell lines, and one normal cell line (MRC-5). The extract that showed high cytotoxic activity was further investigated for its chemical constituents by GC-MS (gas chromatography–mass spectrometry) analysis. Results The ethyl acetate fraction showed the strongest DPPH radical scavenging (0.35 ± 0.094 mg/ml) and SOD activities (51.77 ± 4.9%) whilst the methanol extract showed the highest reducing power and also the strongest antioxidant activity in the β-carotene bleaching assays in comparison to other fractions. The highest phenolic content was found in the ethyl acetate fraction, followed by the crude methanol extract, hexane and water fractions. The results showed a positive correlation between total phenolic content with DPPH radical scavenging capacities and SOD activities. The hexane fraction showed potent cytotoxic effect against KB, Ca Ski and HCT 116 cell lines with IC50 of 5.8 ± 0.1 and 9.1 ± 2.0 ug/ml, respectively. The major components of hexane fraction analysed by GC-MS analysis were mostly methyl esters. Conclusions The current study suggests that the methanol extract and ethyl acetate fraction of A. pahangensis is a potential source of natural antioxidant for protective as well as prevention of life-threatening diseases. The hexane fraction of A. pahangensis may have the potential to be developed into therapeutic option for treating cancer. PMID:24083445

Characteristics of Coplanar Waveguide on Sapphire for High Temperature Applications (25 to 400 degrees C)

NASA Technical Reports Server (NTRS)

Ponchak, George E.; Jordan, Jennifer L.; Scardelletti, Maximilian; Stalker, Amy R.

2007-01-01

This paper presents the characteristics of coplanar waveguide transmission lines fabricated on R-plane sapphire substrates as a function of temperature across the temperature range of 25 to 400 C. Effective permittivity and attenuation are measured on a high temperature probe station. Two techniques are used to obtain the transmission line characteristics, a Thru-Reflect-Line calibration technique that yields the propagation coefficient and resonant stubs. To a first order fit of the data, the effective permittivity and the attenuation increase linearly with temperature.

Predictive factors for structural remission using abatacept: results from the ABROAD study.

PubMed

Murakami, Kosaku; Sekiguchi, Masahiro; Hirata, Shintaro; Fujii, Takao; Matsui, Kiyoshi; Morita, Satoshi; Ohmura, Koichiro; Kawahito, Yutaka; Nishimoto, Norihiro; Mimori, Tsuneyo; Sano, Hajime

2018-05-29

To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde's modified total Sharp score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = 0.007) and slower radiographic progression (shown as "baseline mTSS/year <3", OR = 3.727, p = 0.004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Band-9 ALMA Observations of the [N II] 122 μm Line and FIR Continuum in Two High-z galaxies.

NASA Astrophysics Data System (ADS)

Ferkinhoff, Carl; Brisbin, Drew; Nikola, Thomas; Stacey, Gordon J.; Sheth, Kartik; Hailey-Dunsheath, Steve; Falgarone, Edith

2015-06-01

We present Atacama Large Millimeter Array (ALMA) observations of two high-redshift systems (SMMJ02399-0136 at z 1 ˜ 2.8 and the Cloverleaf QSO at z 1 ˜ 2.5) in their rest-frame 122 μm continuum (ν sky ˜ 650 GHz, λ sky ˜ 450 μm) and [N ii] 122 μm line emission. The continuum observations with a synthesized beam of ˜0.″ 25 resolve both sources and recover the expected flux. The Cloverleaf is resolved into a partial Einstein ring, while SMMJ02399-0136 is unambiguously separated into two components: a point source associated with an active galactic nucleus and an extended region at the location of a previously identified dusty starburst. We detect the [N ii] line in both systems, though significantly weaker than our previous detections made with the first generation z (Redshift) and Early Universe Spectrometer. We show that this discrepancy is mostly explained if the line flux is resolved out due to significantly more extended emission and longer ALMA baselines than expected. Based on the ALMA observations we determine that ≥75% of the total [N ii] line flux in each source is produced via star formation. We use the [N ii] line flux that is recovered by ALMA to constrain the N/H abundance, ionized gas mass, hydrogen- ionizing photon rate, and star formation rate. In SMMJ02399-0136 we discover it contains a significant amount (˜1000 M ⊙ yr-1) of unobscured star formation in addition to its dusty starburst and argue that SMMJ02399-0136 may be similar to the Antennae Galaxies (Arp 244) locally. In total these observations provide a new look at two well-studied systems while demonstrating the power and challenges of Band-9 ALMA observations of high-z systems.

[Construction and validation of a short scale of perception of barriers for the physical activity in adolescents].

PubMed

Cabanas-Sánchez, Verónica; Tejero-González, Carlos M; Veiga, Oscar L

2012-01-01

One of the main problems of health in the first world is the increase of physical inactivity. In this respect, adolescence has been identified as a critic period with high decline of physical activity. Therefore, a relevant line of research is the understanding of this social phenomenon. The aim of this study was to design a scale to assess perceived barriers to physical activity on adolescents. A convenience sample of 160 Spanish adolescents (84 girls), between 12 and 18 years old, was recruited for this study. Firstly, there were designed 40 items whose pertinence was evaluated through content validation by experts. Later, the participants were divided in two randomized groups, and Exploratory Factor Analysis and Confirmatory Factor Analysis were performed to define a short scale of 12 items. Cronbach Alfa Coefficent was used to evaluate internal consistence of the instrument. The scale reports four dimensions: incompatibility barriers (2 items), self-concept barriers (4 items), amotivation barriers (4 items) and social barriers (2 items). The scale showed enough construct validity (χ2=60.78; d.f.=48; p=0.100; GFI=0.88; CFI=0.94; RMSEA=0.58) and high internal reliability (α=0.80). Moreover, the scale was able to explain 67% of the data variance. The Short Scale of Perceived Barriers to Physical Activity in Adolescents is a valid and reliable instrument.

Development of Live-working Robot for Power Transmission Lines

NASA Astrophysics Data System (ADS)

Yan, Yu; Liu, Xiaqing; Ren, Chengxian; Li, Jinliang; Li, Hui

2017-07-01

Dream-I, the first reconfigurable live-working robot for power transmission lines successfully developed in China, has the functions of autonomous walking on lines and accurately positioning. This paper firstly described operation task and object of the robot; then designed a general platform, an insulator replacement end and a drainage plate bolt fastening end of the robot, presented a control system of the robot, and performed simulation analysis on operation plan of the robot; and finally completed electrical field withstand voltage tests in a high voltage hall as well as online test and trial on actual lines. Experimental results show that by replacing ends of manipulators, the robot can fulfill operation tasks of live replacement of suspension insulators and live drainage plate bolt fastening.

Structure and kinematics of the broad-line regions in active galaxies from IUE variability data

NASA Technical Reports Server (NTRS)

Koratkar, Anuradha P.; Gaskell, C. Martin

1991-01-01

IUE archival data are used here to investigate the structure nad kinematics of the broad-line regions (BLRs) in nine AGN. It is found that the centroid of the line-continuum cross-correlation functions (CCFs) can be determined with reasonable reliability. The errors in BLR size estimates from CCFs for irregularly sampled light curves are fairly well understood. BLRs are found to have small luminosity-weighted radii, and lines of high ionization tend to be emitted closer to the central source than lines of low ionization, especially for low-luminosity objects. The motion of the gas is gravity-dominated with both pure inflow and pure outflow of high-velocity gas being excluded at a high confidence level for certain geometries.

Antiproliferative activity of Haematoxylum brasiletto H. Karst

PubMed Central

Bello-Martínez, J; Jiménez-Estrada, M; Rosas-Acevedo, JL; Avila-Caballero, LP; Vidal-Gutierrez, M; Patiño-Morales, C; Ortiz-Sánchez, E; Robles-Zepeda, RE

2017-01-01

Background: Haematoxylum brasiletto is a tree that grows in Central America, commonly known as “Palo de Brasil,” which is used in the traditional medicine for the treatment of cancer and gastric ulcers. Objective: The aim of this study was to isolate the compounds responsible for antiproliferative activity of H. brasiletto. Materials and Methods: A bioassay-guided fractionation of ethanol extract of H. brasiletto was performed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide cell proliferation assay to measure the antiproliferative activity on six human cancer cell lines (A549, LS180, HeLa, SiHa, MDA-MB-231, and NCI-H1299) and one human noncancer cell line (ARPE-19). The ethanol extract was partitioned with hexane, dichloromethane, and ethyl acetate. The active dichloromethane fraction was fractioned by silica-column chromatography, and active subfractions were separated using preparative-thin layer chromatography. The chemical structure of an isolated compound was elucidated with different chemical and spectroscopic methods. Results: The flavonoid brazilin (1) was isolated from the heartwood of H. brasiletto. The measurement of antiproliferative activity showed that brazilin can inhibit the growth of SiHa, MDA-MB-231, A549, and NCI-H1299 cell lines by 50% at doses of 44.3, 48.7, 45.4, and 48.7 μM, respectively. Furthermore, the flavonoid showed a high antiproliferative activity on LS 180 and HeLa with IC50 values of 62.2 and 71.9 μM, respectively. Brazilin also exhibited a high antiproliferative activity on the human noncancer cell line ARPE-19 with an IC50 value of 37.9 μM. Conclusions: Brazilin: (6aS, 11bR)-7,11b-Dihidro-6H-indeno[2,1-c] cromeno-3,6a, 9,10-tetrol was isolated; this compound demonstrated antiproliferative activity against several human cancer cell lines. This work demonstrated that brazilin, a flavonoid isolated and characterized of H. brasiletto, has antiproliferative activity against cancer cell lines. SUMMARY The flavonoid brazilin was isolated from the heartwood of H. brasilettoBrazilin is able to inhibit the growth of SiHa, MDA-MB-231, A549 and NCI- H1299 cancerous cell linesBrazilin exhibited a moderate antiproliferative activity on the human non-cancer cell line ARPE-19Brazilin demonstrated to have antiproliferative activity against human cancer cell lines and could be a potential source of anticancer agents. Abbreviations used: MTT: [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium]; FBS: Fetal bovine serum; TLC: Thin layer chromatography. PMID:28808394

First results from the Goddard High-Resolution spectrograph - High-resolution observations of the 1942 A resonance line of HG II in the chemically peculiar B star, Chi Lupi

NASA Technical Reports Server (NTRS)

Leckrone, David S.; Wahlgren, Glenn M.; Johansson, Sveneric G.

1991-01-01

The Goddard High-Resolution Spectrograph on the HST has been used to obtain high S/N observations of the sharp-lined, Hg- and Pt-rich B-type star, Chi Lupi, with a resolving power of 87,000. The observations reveal a level of spectroscopic detail never before observed at ultraviolet wavelengths for any star other than the sun. Concentrating on the region around the resonance line of Hg II at 1942 A, the profile and central position of this line confirm beyond doubt that the Hg isotope anomaly in Chi Lupi is real and extreme, with Hg being heavily concentrated in the form of Hg-204. The problems in atomic physics which impair the accurate analysis of spectra of this quality are emphasized.

Designing an Online Social Support Platform Through Co-Creation with Seniors.

PubMed

Rochat, Jessica; Nap, Henk Herman; Ricci, Arnaud; Cornelisse, Lotte; Lukkien, Dirk; Lovis, Christian; Ehrler, Frédéric

2018-01-01

The high number of seniors that feels excluded of society highlights the necessity to promote active ageing. This intention can be supported through online platforms that encourage participation in social activities. The goal of the present study was to identify design principles of online support platforms for seniors through focus groups and to ideate the platform through co-creation sessions. The results show that a social platform for seniors must, among other, help to foster contact between users, and must provide services and meaningful activities. A first mock-up of the platform's design has been created based on the co-creation sessions and will be iteratively evaluated and enhanced in future studies in four countries across Europe. Our findings are in line with those of other studies demonstrating that seniors attach importance to trustworthiness and need to maintain social ties.

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

PubMed Central

Dunn, Linda A.; Burgess, Anita G.; Krauer, Kenia G.; Eckmann, Lars; Vanelle, Patrice; Crozet, Maxime D.; Gillin, Frances D.; Upcroft, Peter; Upcroft, Jacqueline A.

2010-01-01

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID90 values around 100 μM (MTR-susceptible isolates typically have an ID90 of 5–12.8 μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells. PMID:20456926

Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.

PubMed

Cantini, Fabrizio; Niccoli, Laura; Nannini, Carlotta; Cassarà, Emanuele; Kaloudi, Olga; Giulio Favalli, Ennio; Becciolini, Andrea; Biggioggero, Martina; Benucci, Maurizio; Li Gobbi, Francesca; Grossi, Valentina; Infantino, Maria; Meacci, Francesca; Manfredi, Mariangela; Guiducci, Serena; Bellando-Randone, Silvia; Matucci-Cerinic, Marco; Foti, Rosario; Di Gangi, Marcella; Mosca, Marta; Tani, Chiara; Palmieri, Fabrizio; Goletti, Delia

2016-04-01

A multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), was constituted to formulate evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictor biomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host-related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs. Some variables, including the patients' preference, the indication for anti-TNF monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. Further, evidence of a better cost-effectiveness profile for etanercept (ETN) and biosimilar infliximab (IFX) in RA was found. Any biologic may be employed in absence of choice driving factors in RA. Otherwise, a high infection risk or LTBI positivity drive the choice toward abatacept (ABA), tocilizumab (TCZ), or ETN. TCZ should be the first choice if monotherapy is required. High rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) titers should drive the choice toward TCZ or ABA, while in patients at high CVD risk anti-TNF choice, with preference for ETN, seems appropriate. Presence of anterior uveitis or inflammatory bowel disease drives the choice to monoclonal antibody anti-TNFs (MoAb anti-TNFs). In PsA, ustekinumab (UTK), and to a lesser extent ETN, represents the first choice in patients at high infection and TB risk. Anti-TNFs or UTK choice is guided by skin or articular disease severity, enthesitis, and dactylitis, whereas ETN should be preferred if metabolic syndrome or high CV risk complicate PsA. Taking in account of multiple choice driving variables, first-line biologic therapy may be optimized in patients with RA, SpA, and PsA. Copyright © 2016 Elsevier Inc. All rights reserved.

Managing toxic shock syndrome with antibiotics.

PubMed

Annane, Djillali; Clair, Bernard; Salomon, Jérôme

2004-08-01

Toxic shock syndrome (TSS) is a serious disorder with a worldwide prevalence of approximately 3/100,000 persons. TSS is mainly caused by Streptococcus pyogenes or Staphylococcus aureus. Thus, beta-lactam and lincosamides, such as clindamycin, are the first-line drugs. Yet, the mortality rate remains unacceptably high; highlighting the role of bacterial toxin-mediated activation of the inflammatory cascade in TSS pathogenesis. Further strategies should be targeted towards interfering with the interaction between bacterial toxins and host T cells. This paper aims to provide an overview of the epidemiology, pathomechanisms, and clinical presentation of TSS, and criteria for selecting drugs among available antibiotics.

Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin

PubMed Central

Cruickshank, M N; Ford, J; Cheung, L C; Heng, J; Singh, S; Wells, J; Failes, T W; Arndt, G M; Smithers, N; Prinjha, R K; Anderson, D; Carter, K W; Gout, A M; Lassmann, T; O'Reilly, J; Cole, C H; Kotecha, R S; Kees, U R

2017-01-01

To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage–response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL. PMID:27443263

Confirmation Of Thick Whim At Z-0.1 In Sculptor Supercluster

NASA Technical Reports Server (NTRS)

Nicastro, Fabrizio

2005-01-01

This grant is associated to an XMM observation of the quasar QSO Q0056-363(PI: Dr. Roberto Maiolino), which is one of the brightest quasars in the X-ray sky, and it lies in the general direction of the Sculptor Supercluster, and behind it. We requested the observation to check a previous hint of existence of an absorption features by highly ionized gas at the redshift of the Supercluster, which we supposed to be the imprint of a Warm-Hot Intergalactic Medium filament connecting the already virialized structures in the Supercluster. The observation suffered a high background, and so the net exposure was considerably reduced compared to the requested exposure. Additionally the quasar turned out to be in a quite low level of activity. These two unfortunate facts made it impossible to confirm or rule-out at high resolution (i.e. with the RGS) the existence of the previously hinted OW1 K-alpha resonant line at the redshift of the Sculptor Supercluster, the new RGS data being sensitive only to equivalent width of unresolved absorption lines of about 30-50 mA at 1-sigma. The data, however, shows a very strong absorption line in a position different from the OVII/OVIII K-alpha at the redshift of the Supercluster. If this line is interpreted as OVII/OVIII K-alpha absorption, the redshift of this WHIM filament would lie in a region of the Universe where no visible virialized concentrations are present. This would confirm the relatively high probability of detecting WHIM filaments in apparent 'void' regions of the Universe (as previously suggested by our first detection of WHIM filaments at z greater than 0 along the line of sight to the blazar Mkn 421). A paper on the non-detection of any WHIM filament at the redshift of the Sculptor Supercluster, as well as on the detection of this putative WHIM filament in a 'void', will be shortly submitted to the ApJ.

A novel dual-functioning ruthenium(II)-arene complex of an anti-microbial ciprofloxacin derivative - Anti-proliferative and anti-microbial activity.

PubMed

Ude, Ziga; Romero-Canelón, Isolda; Twamley, Brendan; Fitzgerald Hughes, Deirdre; Sadler, Peter J; Marmion, Celine J

2016-07-01

7-(4-(Decanoyl)piperazin-1-yl)-ciprofloxacin, CipA, (1) which is an analogue of the antibiotic ciprofloxacin, and its ruthenium(II) complex [Ru(η(6)-p-cymene)(CipA-H)Cl], (2) have been synthesised and the x-ray crystal structures of 1·1.3H2O·0.6CH3OH and 2·CH3OH·0.5H2O determined. The complex adopts a typical pseudo-octahedral 'piano-stool' geometry, with Ru(II) π-bonded to the p-cymene ring and σ-bonded to a chloride and two oxygen atoms of the chelated fluoroquinolone ligand. The complex is highly cytotoxic in the low μM range and is as potent as the clinical drug cisplatin against the human cancer cell lines A2780, A549, HCT116, and PC3. It is also highly cytotoxic against cisplatin- and oxaliplatin-resistant cell lines suggesting a different mechanism of action. The complex also retained low μM cytotoxicity against the human colon cancer cell line HCT116p53 in which the tumour suppressor p53 had been knocked out, suggesting that the potent anti-proliferative properties associated with this complex are independent of the status of p53 (in contrast to cisplatin). The complex also retained moderate anti-bacterial activity in two Escherichia coli, a laboratory strain and a clinical isolate resistant to first, second and third generation β-lactam antibiotics. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The lymphotoxin promoter is stimulated by HTLV-I tax activation of NF-kappa B in human T-cell lines.

PubMed

Paul, N L; Millet, I; Ruddle, N H

1993-07-01

The HTLV-I transcriptional activator tax was used to gain insight into the mechanism of lymphotoxin (LT; TNF-beta) gene induction. Tax-expressing cell lines produce LT biologic activity. An LT promoter (LT-293) CAT construct that contained an NF-kappa B site was active in the LT-producing C81-66-45 cell line, which contains defective HTLV-I but expresses tax. The observation that a mutated LT-kappa B construct (M1-CAT) was inactive in C81-66-45, confirmed the importance of NF-kappa B in LT gene expression. Tax was transfected into HTLV-I-negative human T-cell lines. Jurkat T cells stably expressing tax contained elevated levels of NF-kappa B that directly bound to the LT-kappa B site. Tax co-transfected with reporter constructs into Jurkat cells maximally activated HTLV-I-LTR-CAT and kappa B-fos-CAT and also activated LT-293 to a lesser extent. In JM T cells, tax induced LT-293 activity by two- to four-fold, though there was no induction of M1-CAT. The increase in LT-293 CAT activity mirrored the increase in LT biologic activity seen under these conditions. These studies, the first to demonstrate induction of LT promoter activity over basal levels, indicate that HTLV-I tax causes low-level activation of both endogenous LT and the LT promoter, at least in part through activation of NF-kappa B.

Icotinib Is an Active Treatment of Non-Small-Cell Lung Cancer: A Retrospective Study

PubMed Central

Liu, Yiqian; Liu, Ping; Yin, Yongmei; Guo, Renhua; Lu, Kaihua; Gu, Yanhong; Liu, Lianke; Wang, Jinghua; Wang, Zhaoxia; Røe, Oluf Dimitri; Shu, Yongqian; Zhu, Lingjun

2014-01-01

Background Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC). Methods 82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method. Results Median PFS was 4.0 months (95% CI 2.311–5.689). Median OS was 11.0 months (95% CI 8.537–13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151–11.8) and 3.0 months (95% CI 1.042–4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305–15.695) and 10.0 months (95% CI 7.295–12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18–0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02–0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%). Conclusions Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile. PMID:24836053

Progress of implementation of the World Health Organization strategy for HIV drug resistance control in Latin America and the Caribbean.

PubMed

Ravasi, Giovanni; Jack, Noreen; Alonso Gonzalez, Mónica; Sued, Omar; Pérez-Rosales, María Dolores; Gomez, Bertha; Vila, Marcelo; Riego, Amalia del; Ghidinelli, Massimo

2011-12-01

By the end of 2010, Latin America and the Caribbean (LAC) achieved 63% antiretroviral treatment (ART) coverage. Measures to control HIV drug resistance (HIVDR) at the country level are recommended to maximize the efficacy and sustainability of ART programs. Since 2006, the Pan American Health Organization has supported implementation of the World Health Organization (WHO) strategy for HIVDR prevention and assessment through regional capacity-building activities and direct technical cooperation in 30 LAC countries. By 2010, 85 sites in 19 countries reported early warning indicators, providing information about the extent of potential drivers of drug resistance at the ART site. In 2009, 41.9% of sites did not achieve the WHO target of 100% appropriate first-line prescriptions; 6.3% still experienced high rates (> 20%) of loss to follow-up, and 16.2% had low retention of patients (< 70%) on first-line prescriptions in the first year of treatment. Stock-outs of antiretroviral drugs occurred at 22.7% of sites. Haiti, Guyana, and the Mesoamerican region are planning and implementing WHO HIVDR monitoring surveys or threshold surveys. New HIVDR surveillance tools for concentrated epidemics would promote further scale-up. Extending the WHO HIVDR lab network in Latin America is key to strengthening regional lab capacity to support quality assured HIVDR surveillance. The WHO HIVDR control strategy is feasible and can be rolled out in LAC. Integrating HIVDR activities in national HIV care and treatment plans is key to ensuring the sustainability of this strategy.

High metastaticgastric and breast cancer cells consume oleic acid in an AMPK dependent manner.

PubMed

Li, Shuai; Zhou, Ti; Li, Cen; Dai, Zhiyu; Che, Di; Yao, Yachao; Li, Lei; Ma, Jianxing; Yang, Xia; Gao, Guoquan

2014-01-01

Gastric cancer and breast cancer have a clear tendency toward metastasis and invasion to the microenvironment predominantly composed of adipocytes. Oleic acid is an abundant monounsaturated fatty acid that releases from adipocytes and impinges on different energy metabolism responses. The effect and underlying mechanisms of oleic acid on highly metastatic cancer cells are not completely understood. We reported that AMP-activated protein kinase (AMPK) was obviously activated in highly aggressive carcinoma cell lines treated by oleic acid, including gastric carcinoma HGC-27 and breast carcinoma MDA-MB-231 cell lines. AMPK enhanced the rates of fatty acid oxidation and ATP production and thus significantly promoted cancer growth and migration under serum deprivation. Inactivation of AMPK attenuated these activities of oleic acid. Oleic acid inhibited cancer cell growth and survival in low metastatic carcinoma cells, such as gastric carcinoma SGC7901 and breast carcinoma MCF-7 cell lines. Pharmacological activation of AMPK rescued the cell viability by maintained ATP levels by increasing fatty acid β-oxidation. These results indicate that highly metastatic carcinoma cells could consume oleic acid to maintain malignancy in an AMPK-dependent manner. Our findings demonstrate the important contribution of fatty acid oxidation to cancer cell function.

NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016.

PubMed

Horwitz, Steven M; Zelenetz, Andrew D; Gordon, Leo I; Wierda, William G; Abramson, Jeremy S; Advani, Ranjana H; Andreadis, C Babis; Bartlett, Nancy; Byrd, John C; Fayad, Luis E; Fisher, Richard I; Glenn, Martha J; Habermann, Thomas M; Lee Harris, Nancy; Hernandez-Ilizaliturri, Francisco; Hoppe, Richard T; Kaminski, Mark S; Kelsey, Christopher R; Kim, Youn H; Krivacic, Susan; LaCasce, Ann S; Lunning, Matthew; Nademanee, Auayporn; Press, Oliver; Rabinovitch, Rachel; Reddy, Nishitha; Reid, Erin; Roberts, Kenneth; Saad, Ayman A; Sokol, Lubomir; Swinnen, Lode J; Vose, Julie M; Yahalom, Joachim; Zafar, Nadeem; Dwyer, Mary; Sundar, Hema; Porcu, Pierluigi

2016-09-01

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL. Copyright © 2016 by the National Comprehensive Cancer Network.

Probing Pre-galactic Metal Enrichment with High-redshift Gamma-Ray Bursts

NASA Astrophysics Data System (ADS)

Wang, F. Y.; Bromm, Volker; Greif, Thomas H.; Stacy, Athena; Dai, Z. G.; Loeb, Abraham; Cheng, K. S.

2012-11-01

We explore high-redshift gamma-ray bursts (GRBs) as promising tools to probe pre-galactic metal enrichment. We utilize the bright afterglow of a Population III (Pop III) GRB exploding in a primordial dwarf galaxy as a luminous background source, and calculate the strength of metal absorption lines that are imprinted by the first heavy elements in the intergalactic medium (IGM). To derive the GRB absorption line diagnostics, we use an existing highly resolved simulation of the formation of a first galaxy which is characterized by the onset of atomic hydrogen cooling in a halo with virial temperature >~ 104 K. We explore the unusual circumburst environment inside the systems that hosted Pop III stars, modeling the density evolution with the self-similar solution for a champagne flow. For minihalos close to the cooling threshold, the circumburst density is roughly proportional to (1 + z) with values of about a few cm-3. In more massive halos, corresponding to the first galaxies, the density may be larger, n >~ 100 cm-3. The resulting afterglow fluxes are weakly dependent on redshift at a fixed observed time, and may be detectable with the James Webb Space Telescope and Very Large Array in the near-IR and radio wavebands, respectively, out to redshift z >~ 20. We predict that the maximum of the afterglow emission shifts from near-IR to millimeter bands with peak fluxes from mJy to Jy at different observed times. The metal absorption line signature is expected to be detectable in the near future. GRBs are ideal tools for probing the metal enrichment in the early IGM, due to their high luminosities and featureless power-law spectra. The metals in the first galaxies produced by the first supernova (SN) explosions are likely to reside in low-ionization stages (C II, O I, Si II and Fe II). We show that, if the afterglow can be observed sufficiently early, analysis of the metal lines may distinguish whether the first heavy elements were produced in a pair-instability supernova or a core-collapse (Type II) SN, thus constraining the initial mass function of the first stars.

The requirement for freshly isolated human colorectal cancer (CRC) cells in isolating CRC stem cells.

PubMed

Fan, F; Bellister, S; Lu, J; Ye, X; Boulbes, D R; Tozzi, F; Sceusi, E; Kopetz, S; Tian, F; Xia, L; Zhou, Y; Bhattacharya, R; Ellis, L M

2015-02-03

Isolation of colorectal cancer (CRC) cell populations enriched for cancer stem cells (CSCs) may facilitate target identification. There is no consensus regarding the best methods for isolating CRC stem cells (CRC-SCs). We determined the suitability of various cellular models and various stem cell markers for the isolation of CRC-SCs. Established human CRC cell lines, established CRC cell lines passaged through mice, patient-derived xenograft (PDX)-derived cells, early passage/newly established cell lines, and cells directly from clinical specimens were studied. Cells were FAC-sorted for the CRC-SC markers CD44, CD133, and aldehyde dehydrogenase (ALDH). Sphere formation and in vivo tumorigenicity studies were used to validate CRC-SC enrichment. None of the markers studied in established cell lines, grown either in vitro or in vivo, consistently enriched for CRC-SCs. In the three other cellular models, CD44 and CD133 did not reliably enrich for stemness. In contrast, freshly isolated PDX-derived cells or early passage/newly established CRC cell lines with high ALDH activity formed spheres in vitro and enhanced tumorigenicity in vivo, whereas cells with low ALDH activity did not. PDX-derived cells, early passages/newly established CRC cell lines and cells from clinical specimen with high ALDH activity can be used to identify CRC-SC-enriched populations. Established CRC cell lines should not be used to isolate CSCs.

Development of the 2nd generation z(Redshift) and early universe spectrometer & the study of far-IR fine structure emission in high-z galaxies

NASA Astrophysics Data System (ADS)

Ferkinhoff, Carl

The 2nd generation z (Redshift) and Early Universe Spectrometer (ZEUS-2), is a long-slit echelle-grating spectrometer (R~1000) for observations at submillimeter wavelengths from 200 to 850 microm. Its design is optimized for the detection of redshifted far-infrared spectral lines from galaxies in the early universe. Combining exquisite sensitivity, broad wavelength coverage, and large (˜2.5%) instantaneous bandwidth, ZEUS-2 is uniquely suited for studying galaxies between z˜0.2 and 5---spanning the peaks in both the star formation rate and number of AGN in the universe. ZEUS-2 saw first light at the Caltech Submillimeter Observatory (CSO) in the Spring of 2012 and was commissioned on the Atacama Pathfinder Experiment (APEX) in November 2012. Here we detail the design and performance of ZEUS-2, first however we discuss important science results that are examples of the science enabled by ZEUS-2. Using the first generation z (Redshift) and Early Universe Spectrometer (ZEUS-1) we made the first high-z detections of the [NII] 122 microm and [OIII] 88 microm lines. We detect these lines from starburst galaxies between z ˜2.5 and 4 demonstrating the utility of these lines for characterizing the properties of early galaxies. Specifically we are able to determine the most massive star still on the main sequence, the number of those stars and a lower limit on the mass of ionized gas in the source. Next we present ZEUS-2's first science result. Using ZEUS-2 on APEX we have detected the [CII] 158 microm line from the z = 1.78 galaxy H-ATLAS J091043.1-000322 with a line flux of (6.44 +/- 0.42) ˜ 10-18 W m-2. Combined with its far-infrared luminosity and a new Herschel-PACS detection of the [OI] 63 microm line we are able to conclude that H-ATLAS J091043.1-000322 is a high redshift analogue of a local ultra-luminous infrared galaxy, i.e. it is likely the site of a compact starburst due to a major merger. This detection, combined with the ZEUS-1 observations of the [NII] and [OIII] lines represent examples of work we plan to continue with ZEUS-2. As such, they demonstrate the potential of ZEUS-2 for increasing our understanding of galaxies and galaxy evolution over cosmic time.

Continuous ambulatory peritoneal dialysis is better than automated peritoneal dialysis as first-line treatment in renal replacement therapy.

PubMed

Li, Philip Kam-Tao; Chung, Kwok Yi; Chow, Kai Ming

2007-06-01

This article examines the roles of continuous ambulatory peritoneal dialysis (CAPD) versus automated peritoneal dialysis (APD) as first-line renal replacement therapy. To date, no high-quality large-scale randomized controlled studies have compared CAPD with APD as first-line therapy. However, a discussion on this issue is important so that nephrologists can decide and patients can have a choice of modality on which to start dialysis, especially in the context of health care economics. We review the literature and present Hong Kong as the model of a "CAPD first" policy, an appealing, cost-effective approach for any country. An ideal renal replacement therapy should provide optimal survival, lowest possible risk for comorbidity, highest level of quality of life, and equally important, acceptable cost to society. When we consider this subject in the context that all patients should be started on one first-line modality, the data suggest that a "CAPD first" policy has all these advantages, with APD probably having the edge only with regard to patient preference. The present review highlights preservation of residual renal function, removal and balancing of sodium, incidence of peritonitis, peritoneal membrane transport status, patient rehabilitation, and financial issues in demonstrating that a "CAPD first" policy is the model that should be adopted.

Chromospheric activity on the late-type star V1355 Ori using Lijiang 1.8-m and 2.4-m telescopes

NASA Astrophysics Data System (ADS)

Pi, Qing-Feng; Zhang, Li-Yun; Chang, Liang; Han, Xian-Ming; Lu, Hong-Peng; Zhang, Xi-Liang; Wang, Dai-Mei

2016-10-01

We obtained new high-resolution spectra using the Lijiang 1.8-m and 2.4-m telescopes to investigate the chromospheric activities of V1355 Ori as indicated in the behaviors of Ca ii H&K, Hδ, Hγ, Hβ, Na i D1, D2, Hα and Ca ii infrared triplet (IRT) lines. The observed spectra show obvious emissions above the continuum in Ca ii H&K lines, absorptions in the Hδ, Hγ, Hβ and Na i D1, D2 lines, variable behavior (filled-in absorption, partial emission with a core absorption component or emission above the continuum) in the Hα line, and weak self-reversal emissions in the strong filled-in absorptions of the Ca ii IRT lines. We used a spectral subtraction technique to analyze our data. The results show no excess emission in the Hδ and Hγ lines, very weak excess emissions in the Na i D1, D2 lines, excess emission in the Hβ line, clear excess emission in the Hα line, and excess emissions in the Ca ii IRT lines. The value of the ratio of EW8542/EW8498 is in the range 0.9 to 1.7, which implies that chromospheric activity might have been caused by plage events. The value of the ratio E Hα/E Hβ is above 3, indicating that the Balmer lines would arise from prominence-like material. We also found time variations in light curves associated with equivalent widths of chromospheric activity lines in the Na i D1, D2, Ca ii IRT and Hα lines in particular. These phenomena can be explained by plage events, which are consistent with the behavior of chromospheric activity indicators.

Phase 3 experiments of the JAERI/USDOE collaborative program on fusion blanket neutronics. Volume 1: Experiment

NASA Astrophysics Data System (ADS)

Oyama, Yukio; Konno, Chikara; Ikeda, Yujiro; Maekawa, Fujio; Kosako, Kazuaki; Nakamura, Tomoo; Maekawa, Hiroshi; Youssef, Mahmoud Z.; Kumar, Anil; Abdou, Mohamed A.

1994-02-01

A pseudo-line source has been realized by using an accelerator based D-T point neutron source. The pseudo-line source is obtained by time averaging of continuously moving point source or by superposition of finely distributed point sources. The line source is utilized for fusion blanket neutronics experiments with an annular geometry so as to simulate a part of a tokamak reactor. The source neutron characteristics were measured for two operational modes for the line source, continuous and step-wide modes, with the activation foil and the NE213 detectors, respectively. In order to give a source condition for a successive calculational analysis on the annular blanket experiment, the neutron source characteristics was calculated by a Monte Carlo code. The reliability of the Monte Carlo calculation was confirmed by comparison with the measured source characteristics. The shape of the annular blanket system was a rectangular with an inner cavity. The annular blanket was consist of 15 mm-thick first wall (SS304) and 406 mm-thick breeder zone with Li2O at inside and Li2CO3 at outside. The line source was produced at the center of the inner cavity by moving the annular blanket system in the span of 2 m. Three annular blanket configurations were examined; the reference blanket, the blanket covered with 25 mm thick graphite armor and the armor-blanket with a large opening. The neutronics parameters of tritium production rate, neutron spectrum and activation reaction rate were measured with specially developed techniques such as multi-detector data acquisition system, spectrum weighting function method and ramp controlled high voltage system. The present experiment provides unique data for a higher step of benchmark to test a reliability of neutronics design calculation for a realistic tokamak reactor.

Multiwavelength Search and Studies of Active Galaxies

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.

2016-06-01

Since 1950s, Byurakan Astrophysical Observatory (BAO) has always been one of the centres for surveys and studies of active galaxies. Here I review our search and studies of active galaxies during last 30 years using various wavelength ranges, as well as some recent related works. These projects since late 1980s were focused on multiwavelength search and studies of AGN and Starbursts (SB). 1103 blue stellar objects (BSOs) on the basis of their UV-excess were selected using Markarian Survey (First Byurakan Survey, FBS) plates and Markarian's criteria used for the galaxies. Among many blue stars, QSOs and Seyfert galaxies were found by follow-up observations. 1577 IRAS point sources were optically identified using FBS low-dispersion spectra and many AGN, SB and high-luminosity IR galaxies (LIRG/ULIRG) were discovered. 32 extremely high IR/opt flux ratio galaxies were studies with Spitzer. 2791 ROSAT FSC sources were optically identified using Hamburg Quasar Survey (HQS) low-dispersion spectra and many AGN were discovered by follow-up observations. Fine analysis of emission line spectra was carried out using spectral line decomposition software to establish true profiles and calculate physical parameters for the emitting regions, as well as to study the spectral variability of these objects. X-ray and radio selection criteria were used to find new AGN and variable objects for further studies. Multiwavelength approach allowed revealing many new AGN and SB and obtaining a number of interesting relations using their observational characteristics and physical properties.

KSC-00pp1584

NASA Image and Video Library

2000-10-18

During Super Safety and Health Day at KSC, workers from Florida Power and Light (at left) demonstrate to an interested group of KSC employees how they safely handle high power lines. Safety Day is a full day of NASA-sponsored, KSC and 45th Space Wing events involving a number of health and safety related activities: Displays, vendors, technical paper sessions, panel discussions, a keynote speaker, etc. The entire Center and Wing stand down to participate in the planned events. Safety Day is held annually to proactively increase awareness in safety and health among the government and contractor workforce population. The first guiding principle at KSC is “Safety and Health First.” KSC’s number one goal is to “Assure sound, safe and efficient practices and processes are in place for privatized/commercialized launch site processing.

KSC00pp1584

NASA Image and Video Library

2000-10-18

During Super Safety and Health Day at KSC, workers from Florida Power and Light (at left) demonstrate to an interested group of KSC employees how they safely handle high power lines. Safety Day is a full day of NASA-sponsored, KSC and 45th Space Wing events involving a number of health and safety related activities: Displays, vendors, technical paper sessions, panel discussions, a keynote speaker, etc. The entire Center and Wing stand down to participate in the planned events. Safety Day is held annually to proactively increase awareness in safety and health among the government and contractor workforce population. The first guiding principle at KSC is “Safety and Health First.” KSC’s number one goal is to “Assure sound, safe and efficient practices and processes are in place for privatized/commercialized launch site processing.

NuSTAR Detection of the Blazar B2 1023+25 at Redshift 5.3

NASA Technical Reports Server (NTRS)

Sbarrato, T.; Tagliaferri, G.; Ghisellini, G.; Perri, M.; Puccetti, S.; Balokovic, M.; Nardini, M.; Stern, D.; Boggs, S. E.; Brandt, W. N.;

Role of First-Line Noninvasive Ventilation in Non-COPD Subjects With Pneumonia.

PubMed

Rialp, Gemma; Forteza, Catalina; Muñiz, Daniel; Romero, Maria

2017-09-01

The use of noninvasive ventilation (NIV) in non-COPD patients with pneumonia is controversial due to its high rate of failure and the potentially harmful effects when NIV fails. The purpose of the study was to evaluate outcomes of the first ventilatory treatment applied, NIV or invasive mechanical ventilation (MV), and to identify predictors of NIV failure. Historical cohort study of 159 non-COPD patients with pneumonia admitted to the ICU with ventilatory support. Subjects were divided into 2 groups: invasive MV or NIV. Univariate and multivariate analyses with demographic and clinical data were performed. Analysis of mortality was adjusted for the propensity of receiving first-line invasive MV. One hundred and thirteen subjects received first-line invasive MV and 46 received first-line NIV, of which 27 needed intubation. Hospital mortality was 35, 37 and 56%, respectively, with no significant differences among groups. In the propensity-adjusted analysis (expressed as OR [95% CI]), hospital mortality was associated with age (1.05 [1.02-1.08]), SAPS3 (1.03 [1.00-1.07]), immunosuppression (2.52 [1.02-6.27]) and NIV failure compared to first-line invasive MV (4.3 [1.33-13.94]). Compared with invasive MV, NIV failure delayed intubation (p=.004), and prolonged the length of invasive MV (p=.007) and ICU stay (p=.001). NIV failure was associated with need for vasoactive drugs (OR 7.8 [95% CI, 1.8-33.2], p=.006). In non-COPD subjects with pneumonia, first-line NIV was not associated with better outcome compared with first-line invasive MV. NIV failure was associated with longer duration of MV and hospital stay, and with increased hospital mortality. The use of vasoactive drugs predicted NIV failure. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

The case for inflow of the broad-line region of active galactic nuclei

NASA Astrophysics Data System (ADS)

Gaskell, C. Martin; Goosmann, René W.

2016-02-01

The high-ionization lines of the broad-line region (BLR) of thermal active galactic nuclei (AGNs) show blueshifts of a few hundred km/s to several thousand km/sec with respect to the low-ionization lines. This has long been thought to be due to the high-ionization lines of the BLR arising in a wind of which the far side of the outflow is blocked from our view by the accretion disc. Evidence for and against the disc-wind model is discussed. The biggest problem for the model is that velocity-resolved reverberation mapping repeatedly fails to show the expected kinematic signature of outflow of the BLR. The disc-wind model also cannot readily reproduce the red side of the line profiles of high-ionization lines. The rapidly falling density in an outflow makes it difficult to obtain high equivalent widths. We point out a number of major problems with associating the BLR with the outflows producing broad absorption lines. An explanation which avoids all these problems and satisfies the constraints of both the line profiles and velocity-resolved reverberation-mapping is a model in which the blueshifting is due to scattering off material spiraling inwards with an inflow velocity of half the velocity of the blueshifting. We discuss how recent reverberation mapping results are consistent with the scattering-plus-inflow model but do not support a disc-wind model. We propose that the anti-correlation of the apparent redshifting of Hβ with the blueshifting of C iv is a consequence of contamination of the red wings of Hβ by the broad wings of [O iii].

The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma.

PubMed

Munugalavadla, V; Mariathasan, S; Slaga, D; Du, C; Berry, L; Del Rosario, G; Yan, Y; Boe, M; Sun, L; Friedman, L S; Chesi, M; Leif Bergsagel, P; Ebens, A

2014-01-16

The phosphatidylinositol 3'-kinase (PI3K) pathway is dysregulated in multiple myeloma (MM); we therefore tested a highly selective class I PI3K inhibitor, GDC-0941, for anti-myeloma activity. Functional and mechanistic studies were first performed in MM cell lines, then extended to primary MM patient samples cultured in vitro. GDC-0941 was then assessed as a single agent and in various combinations in myeloma tumor xenograft models. We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells. Mechanistic studies revealed an induction of cell cycle arrest at G0/G1, with decreased phospho-FoxO1/3a levels, decreased cyclin D1 and c-myc expression, and an increase in the cell cycle inhibitor, p27kip. Induction of apoptosis correlated with increased expression of the pro-apoptotic BH3-only protein BIM, cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP). In vitro, GDC-0941 synergized with dexamethasone (Dex) and lenalidomide (combination index values of 0.3-0.4 and 0.4-0.8, respectively); in vivo GDC-0941 has anti-myeloma activity and significantly increases the activity of the standard of care agents in several murine xenograft tumor models (additional tumor growth inhibition of 37-53% (Dex) and 22-72% (lenalidomide)). These data provide a clear therapeutic hypothesis for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.

Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-Treated Agaricus blazei

PubMed Central

Kasai, Hirotake

2007-01-01

We examined the effects of hemicellulase-treated Agaricus blazei (AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth. PMID:17342245

Stimulated Brillouin scattering during electron gyro-harmonic heating at EISCAT

NASA Astrophysics Data System (ADS)

Fu, H. Y.; Scales, W. A.; Bernhardt, P. A.; Briczinski, S. J.; Kosch, M. J.; Senior, A.; Rietveld, M. T.; Yeoman, T. K.; Ruohoniemi, J. M.

2015-08-01

Observations of secondary radiation, stimulated electromagnetic emission (SEE), produced during ionospheric modification experiments using ground-based, high-power, high-frequency (HF) radio waves are considered. The High Frequency Active Auroral Research Program (HAARP) facility is capable of generating narrowband SEE in the form of stimulated Brillouin scatter (SBS) and stimulated ion Bernstein scatter (SIBS) in the SEE spectrum. Such narrowband SEE spectral lines have not been reported using the European Incoherent Scatter (EISCAT) heater facility before. This work reports the first EISCAT results of narrowband SEE spectra and compares them to SEE previously observed at HAARP during electron gyro-harmonic heating. An analysis of experimental SEE data shows observations of emission lines within 100 Hz of the pump frequency, interpreted as SBS, during the 2012 July EISCAT campaign. Experimental results indicate that SBS strengthens as the pump frequency approaches the third electron gyro-harmonic. Also, for different heater antenna beam angles, the CUTLASS radar backscatter induced by HF radio pumping is suppressed near electron gyro-harmonics, whereas electron temperature enhancement weakens as measured by EISCAT/UHF radar. The main features of these new narrowband EISCAT observations are generally consistent with previous SBS measurements at HAARP.

A new ion beam facility based on a 3 MV Tandetron™ at IFIN-HH, Romania

NASA Astrophysics Data System (ADS)

Burducea, I.; Straticiuc, M.; Ghiță, D. G.; Moșu, D. V.; Călinescu, C. I.; Podaru, N. C.; Mous, D. J. W.; Ursu, I.; Zamfir, N. V.

2015-09-01

A 3 MV Tandetron™ accelerator system has been installed and commissioned at the "Horia Hulubei" National Institute for Physics and Nuclear Engineering - IFIN-HH, Măgurele, Romania. The main purpose of this machine is to strengthen applied nuclear physics research ongoing in our institute for more than four decades. The accelerator system was developed by High Voltage Engineering Europa B.V. (HVE) and comprises three high energy beam lines. The first beam line is dedicated to ion beam analysis (IBA) techniques: Rutherford Backscattering Spectrometry - RBS, Nuclear Reaction Analysis - NRA, Particle Induced X-ray and γ-ray Emission - PIXE and PIGE and micro-beam experiments - μ-PIXE. The second beam line is dedicated to high energy ion implantation experiments and the third beam line was designed mainly for nuclear cross-sections measurements used in nuclear astrophysics. A unique feature, the first time in operation at an accelerator facility is the Na charge exchange canal (CEC), which is used to obtain high intensity beams of He- of at least 3 μA. The results of the acceptance tests demonstrate the huge potential of this new facility in various fields, from IBA to radiation hardness studies and from medical or environmental applications to astrophysics. The main features of the accelerator are presented in this paper.

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

PubMed

D'Angelo, Sandra P; Russell, Jeffery; Lebbé, Céleste; Chmielowski, Bartosz; Gambichler, Thilo; Grob, Jean-Jacques; Kiecker, Felix; Rabinowits, Guilherme; Terheyden, Patrick; Zwiener, Isabella; Bajars, Marcis; Hennessy, Meliessa; Kaufman, Howard L

2018-03-22

Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC). To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC. JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing. Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred. Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability. As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at least 3 months was 93% (95% CI, 61%-99%); duration of response of at least 6 months, 83% (95% CI, 46%-96%). First-line avelumab treatment was generally well tolerated, and no treatment-related deaths or grade 4 adverse events occurred. High rates of response to first-line avelumab therapy in patients with distant mMCC build on previously reported antitumor activity after second-line or later treatment, and maturing progression-free survival data suggest that responses are durable. These data further support avelumab's approval in the United States and European Union and use as a standard-of-care treatment for mMCC. clinicaltrials.gov Identifier: NCT02155647.

Activating Cell Death Ligand Signaling Through Proteasome Inhibition

DTIC Science & Technology

2009-05-01

cell system would work and, if not, identify a new system. First, wild-type caspase-8 was stably expressed in the SH -SY-5Y line . SH -SY-5Y caspase-8...little success with the SH -SY-5Y cells we sought to use the I9.2 caspase-8 deficient Jurkat cell line . Our initial data confirmed that the caspase-8...shown that TRAIL can induce apop- tosis in a variety of human tumor cell lines .3,12,13 However, a large number of prostate cancer cells exhibit a

Chandra/HETG Observations of NGC1275

NASA Astrophysics Data System (ADS)

Reynolds, Christopher

2017-09-01

NGC1275 is the active galactic nucleus (AGN) at the heart of the Perseus cluster of galaxies responsible for the mechanical heating of the intracluster medium (ICM) cool core. We propose a deep (500ks) HETG observation of NGC1275, allowing the first high-S/N, high resolution spectrum of this AGN free from contamination by the bright ICM. We will seek the signatures of powerful winds, answering the central question of whether galactic-scale quasar-mode feedback is occuring simultaneously with cluster-scale radio-mode feedback. We also probe circumnuclear gas (i.e. the fuel supply) through the 6.4keV line previously seen by XMM and Hitomi. These issues are crucial unknowns in our models for the evolution of the most massive galaxies and cluster cores.

X-ray Emission Line Spectroscopy of Nearby Galaxies

NASA Astrophysics Data System (ADS)

Wang, Daniel

What are the origins of the diffuse soft X-ray emission from non-AGN galaxies? Preliminary analysis of XMM-Newton RGS spectra shows that a substantial fraction of the emission cannot arise from optically-thin thermal plasma, as commonly assumed, and may originate in charge exchange at the interface with neutral gas. We request the support for a comprehensive observing, data analysis, and modeling program to spectroscopically determine the origins of the emission. First, we will use our scheduled XMM-Newton AO-10 368 ks observations of the nearest compact elliptical galaxy M32 to obtain the first spectroscopic calibration of the cumulative soft X-ray emission from the old stellar population and will develop a spectral model for the charge exchange, as well as analysis tools to measure the spatial and kinematic properties of the X-ray line- emitting plasma. Second, we will characterize the truly diffuse emission from the hot plasma and/or its interplay with the neutral gas in a sample of galactic spheroids and active star forming/starburst regions in nearby galaxies observed by XMM-Newton. In particular, we will map out the spatial distributions of key emission lines and measure (or tightly constrain) the kinematics of hot plasma outflows for a few X-ray-emitting regions with high-quality RGS data. For galaxies with insufficient counting statistics in individual emission lines, we will conduct a spectral stacking analysis to constrain the average properties of the X-ray-emitting plasma. We will use the results of these X-ray spectroscopic analyses, together with complementary X-ray CCD imaging/spectral data and observations in other wavelength bands, to test the models of the emission. In addition to the charge exchange, alternative scenarios such as resonance scattering and relic AGN photo-ionization will also be examined for suitable regions. These studies are important to the understanding of the relationship between the diffuse soft X-ray emission and various high-energy feedback processes of the galaxies.

Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis

PubMed Central

Dheda, Keertan; Gumbo, Tawanda; Gandhi, Neel R; Murray, Megan; Theron, Grant; Udwadia, Zarir; Migliori, G B; Warren, Robin

2017-01-01

Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis—ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing. PMID:24717628

Hi-C Observations of an Active Region Corona, and Investigation of the Underlying Magnetic Structure

NASA Technical Reports Server (NTRS)

Tiwari, Sanjiv K.; Alexander, Caroline E.; Winebarger, Amy R.; Moore, Ronald L.

2014-01-01

Hi-C: first observational evidence of field line braiding in the AR corona; NLFFF extrapolations support. Flux emergence and/or cancellation in the coronal braided region generate large stresses and tension in the coronal field loops which is released as heat in the corona. The field in these sub-regions are highly sheared and have apparent high speed plasma flows, therefore, the contribution from shearing flows to power the coronal and transition region heating can not be ruled out! The spatial resolution of Hi-­C is five times better than AIA. The cadence of Hi-C is 2.5 - 6 times better than AIA. The 193 Å was selected because of the strong emission line of Fe XII (peak formation temperature of 1.5 MK). Hi-­C collected data for 345 s @ 5.4 s cadence. The Hi-C target region was NOAA AR 11520; 11 July 2012, 18:51-18:57 UT. NLFFF extrapolation confirms the braided structure, and free magnetic energy estimates in the given volume.

Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin.

PubMed

Antoszczak, Michał; Maj, Ewa; Stefańska, Joanna; Wietrzyk, Joanna; Janczak, Jan; Brzezinski, Bogumil; Huczyński, Adam

2014-04-01

A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained compounds were found to show potent antiproliferative activity against human cancer cell lines including the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE). Copyright © 2014 Elsevier Ltd. All rights reserved.

Endocannabinoid hydrolases in avian HD11 macrophages identified by chemoproteomics: inactivation by small molecule inhibitors and pathogen-induced downregulation of their activity.

USDA-ARS?s Scientific Manuscript database

The endocannabinoids (eCBs) are endogenous arachidonoyl-containing lipid mediators with important roles in host defense. Macrophages are first-line defenders of the innate immune system and biosynthesize large amounts of eCBs when activated. The cellular levels of eCBs are controlled by the activiti...

Measurements of OH(X2pi) in the stratosphere by high resolution UV spectroscopy

NASA Technical Reports Server (NTRS)

Torr, D. G.; Swift, W.; Fennelly, J.; Liu, G.; Torr, M. R.

1987-01-01

This paper reports the first results obtained using high spectral resolution imaging ultraviolet spectroscopy to observe multiple rotational lines of OH A2 Sigma-X2pi (0-0) band. A 9.2 A spectral segment from 3075.8 A to 3085.0 A is imaged at 0.08 A FWHM spectral resolution, allowing the simultaneous acquisition of six of the brightest OH resonance fluorescence emission lines. The high spectral resolution and low scattered light design of the instrument allows these lines to be detected above the Rayleigh scattered sunlight background. The technique permits remote sensing of stratospheric OH from a high altitude instrument. The instrument was flown to an altitude of 40 km on Aug. 25, 1983, and again on June 12, 1986, on scientific balloons from Palestine, TX. The OH profiles inverted from the limb scans made during these flights are reported here. These profiles represent the first measurements of the temporal variation of OH over an extended height range. The results demonstrate that the technique can be used to monitor OH from orbit.

A pink mouse reports the switch from red to green fluorescence upon Cre-mediated recombination.

PubMed

Hartwich, Heiner; Satheesh, Somisetty V; Nothwang, Hans Gerd

2012-06-14

Targeted genetic modification in the mouse becomes increasingly important in biomedical and basic science. This goal is most often achieved by use of the Cre/loxP system and numerous Cre-driver mouse lines are currently generated. Their initial characterization requires reporter mouse lines to study the in vivo spatiotemporal activity of Cre. Here, we report a dual fluorescence reporter mouse line, which switches expression from the red fluorescent protein mCherry to eGFP after Cre-mediated recombination. Both fluorescent proteins are expressed from the ubiquitously active and strong CAGGS promoter. Among the founders, we noticed a pink mouse line, expressing high levels of the red fluorescent protein mCherry throughout the entire body. Presence of mCherry in the living animal as well as in almost all organs was clearly visible without optical equipment. Upon Cre-activity, mCherry expression was switched to eGFP, demonstrating functionality of this reporter mouse line. The pink mouse presented here is an attractive novel reporter line for fluorescence-based monitoring of Cre-activity. The high expression of mCherry, which is visible to the naked eye, facilitates breeding and crossing, as no genotyping is required to identify mice carrying the reporter allele. The presence of two fluorescent proteins allows in vivo monitoring of recombined and non-recombined cells. Finally, the pink mouse is an eye-catching animal model to demonstrate the power of transgenic techniques in teaching courses.

First Keck Interferometer measurements in self-phase referencing mode: spatially resolving circum-stellar line emission of 48 Lib

NASA Astrophysics Data System (ADS)

Pott, J.-U.; Woillez, J.; Ragland, S.; Wizinowich, P. L.; Eisner, J. A.; Monnier, J. D.; Akeson, R. L.; Ghez, A. M.; Graham, J. R.; Hillenbrand, L. A.; Millan-Gabet, R.; Appleby, E.; Berkey, B.; Colavita, M. M.; Cooper, A.; Felizardo, C.; Herstein, J.; Hrynevych, M.; Medeiros, D.; Morrison, D.; Panteleeva, T.; Smith, B.; Summers, K.; Tsubota, K.; Tyau, C.; Wetherell, E.

2010-07-01

Recently, the Keck interferometer was upgraded to do self-phase-referencing (SPR) assisted K-band spectroscopy at R ~ 2000. This means, combining a spectral resolution of 150 km/s with an angular resolution of 2.7 mas, while maintaining high sensitiviy. This SPR mode operates two fringe trackers in parallel, and explores several infrastructural requirements for off-axis phase-referencing, as currently being implemented as the KI-ASTRA project. The technology of self-phasereferencing opens the way to reach very high spectral resolution in near-infrared interferometry. We present the scientific capabilities of the KI-SPR mode in detail, at the example of observations of the Be-star 48 Lib. Several spectral lines of the cirumstellar disk are resolved. We describe the first detection of Pfund-lines in an interferometric spectrum of a Be star, in addition to Br γ. The differential phase signal can be used to (i) distinguish circum-stellar line emission from the star, (ii) to directly measure line asymmetries tracing an asymetric gas density distribution, (iii) to reach a differential, astrometric precision beyond single-telescope limits sufficient for studying the radial disk structure. Our data support the existence of a radius-dependent disk density perturbation, typically used to explain slow variations of Be-disk hydrogen line profiles.

Detection of boron, cobalt, and other weak interstellar lines toward Zeta Ophiuchi

NASA Technical Reports Server (NTRS)

Federman, S. R.; Sheffer, Y.; Lambert, D. L.; Gilliland, R. L.

1993-01-01

Numerous weak lines from interstellar atomic species toward Zeta Ophiuchi were observed with the Goddard High-Resolution Spectrograph. Of particular note are the first interstellar detection of cobalt and the detection of boron in this sight line. These measurements provide estimates for the amount of depletion for the two elements. Boron, a volatile, and cobalt, a refractory element, display the depletion pattern found by Savage et al. (1992). The abundance of phosphorus in the H II region associated with the star was obtained from a detection of P III. Additional weak lines from S I, C I, Ni II, and Cu II were detected for the first time; these lines provide the basis for refinements in oscillator strength and column density. Analysis of the neutral sulfur data indicates that the atomic gas is more widely distributed than the molecular material in the main component.

Spectroscopic Evidence of Alfvén Wave Damping in the Off-limb Solar Corona

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, G. R., E-mail: girjesh@iucaa.in

We investigate the off-limb active-region and quiet-Sun corona using spectroscopic data. The active region is clearly visible in several spectral lines formed in the temperature range of 1.1–2.8 MK. We derive the electron number density using the line ratio method, and the nonthermal velocity in the off-limb region up to the distance of 140 Mm. We compare density scale heights derived from several spectral line pairs with expected scale heights per the hydrostatic equilibrium model. Using several isolated and unblended spectral line profiles, we estimate nonthermal velocities in the active region and quiet Sun. Nonthermal velocities obtained from warm linesmore » in the active region first show an increase and then later either a decrease or remain almost constant with height in the far off-limb region, whereas nonthermal velocities obtained from hot lines show consistent decrease. However, in the quiet-Sun region, nonthermal velocities obtained from various spectral lines show either a gradual decrease or remain almost constant with height. Using these obtained parameters, we further calculate Alfvén wave energy flux in both active and quiet-Sun regions. We find a significant decrease in wave energy fluxes with height, and hence provide evidence of Alfvén wave damping. Furthermore, we derive damping lengths of Alfvén waves in the both regions and find them to be in the range of 25–170 Mm. Different damping lengths obtained at different temperatures may be explained as either possible temperature-dependent damping or by measurements obtained in different coronal structures formed at different temperatures along the line of sight. Temperature-dependent damping may suggest some role of thermal conduction in the damping of Alfvén waves in the lower corona.« less

International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

PubMed Central

Huth-Kühne, Angela; Baudo, Francesco; Collins, Peter; Ingerslev, Jørgen; Kessler, Craig M.; Lévesque, Hervé; Castellano, Maria Eva Mingot; Shima, Midori; St-Louis, Jean

2009-01-01

Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group. PMID:19336751

Effect of HIV Infection and Highly Active Antiretroviral Therapy on Hearing Function: A Prospective Case-Control Study From Cameroon.

PubMed

Fokouo, Jean Valentin F; Vokwely, Jean Espoir E; Noubiap, Jean Jacques N; Nouthe, Brice Enid; Zafack, Joseline; Minka Ngom, Esthelle Stéphanie; Dalil, Asmaou Bouba; Ngo Nyeki, Adèle-Rose; Bengono, Géneviève; Njock, Richard

2015-05-01

Human immunodeficiency virus (HIV) infection remains a major cause of morbidity and mortality worldwide. Many studies have found a higher prevalence of hearing impairment among HIV-positive individuals. To investigate the effect of HIV and highly active antiretroviral treatment (HAART) on the hearing function in a Cameroonian population. We conducted a prospective case-control study from March 1, 2012, through January 31, 2013. The study took place at the National Social Insurance Fund Hospital in Yaoundé, Cameroon, a public health facility. We included 90 HIV-positive case patients and 90 HIV-negative control patients aged 15 to 49 years without any history of hearing loss or treatment with a known ototoxic drug. The case group was further divided into 3 subgroups: 30 HAART-naive patients, 30 patients receiving first-line HAART, and 30 patients receiving second-line HAART. Hearing function was assessed by pure-tone audiometry and classified according to the criteria of the Bureau International d'Audio-Phonologie. Hearing loss due to HIV and HAART. The HIV-positive patients had more otologic symptoms (hearing loss, dizziness, tinnitus, and otalgia) than HIV-negative patients (41 vs 13, P = .04). There were 49 cases (27.2%) of hearing loss in the HIV-positive group vs 10 (5.6%) in the HIV-negative group (P = .04). Compared with HIV-negative individuals, the odds of hearing loss were higher among HIV-infected HAART-naive patients (right ear: odds ratio [OR], 6.7; 95% CI, 4.3-9.7; P = .004; left ear: OR, 6.2; 95% CI, 3.5-8.3; P = .006), patients receiving first-line HAART (right ear: OR, 5.6; 95% CI, 1.9-10.5; P = .01; left ear: OR, 12.5; 95% CI, 8.5-15.4; P < .001), and patients receiving second-line HAART (right ear: OR, 6.7; 95% CI, 3.3-9.6; P = .004; left ear: OR, 3.7; 95% CI, 3.0-5.0; P = .08). Hearing loss is more frequent in HIV-infected patients compared with uninfected patients. Therefore, HIV-infected patients need special audiologic care. Further studies are needed because controversy remains regarding the factors that lead to ear damage.

Raft cultivation area extraction from high resolution remote sensing imagery by fusing multi-scale region-line primitive association features

NASA Astrophysics Data System (ADS)

Wang, Min; Cui, Qi; Wang, Jie; Ming, Dongping; Lv, Guonian

2017-01-01

In this paper, we first propose several novel concepts for object-based image analysis, which include line-based shape regularity, line density, and scale-based best feature value (SBV), based on the region-line primitive association framework (RLPAF). We then propose a raft cultivation area (RCA) extraction method for high spatial resolution (HSR) remote sensing imagery based on multi-scale feature fusion and spatial rule induction. The proposed method includes the following steps: (1) Multi-scale region primitives (segments) are obtained by image segmentation method HBC-SEG, and line primitives (straight lines) are obtained by phase-based line detection method. (2) Association relationships between regions and lines are built based on RLPAF, and then multi-scale RLPAF features are extracted and SBVs are selected. (3) Several spatial rules are designed to extract RCAs within sea waters after land and water separation. Experiments show that the proposed method can successfully extract different-shaped RCAs from HR images with good performance.

Identification, Expression Analysis, and Target Prediction of Flax Genotroph MicroRNAs Under Normal and Nutrient Stress Conditions

PubMed Central

Melnikova, Nataliya V.; Dmitriev, Alexey A.; Belenikin, Maxim S.; Koroban, Nadezhda V.; Speranskaya, Anna S.; Krinitsina, Anastasia A.; Krasnov, George S.; Lakunina, Valentina A.; Snezhkina, Anastasiya V.; Sadritdinova, Asiya F.; Kishlyan, Natalya V.; Rozhmina, Tatiana A.; Klimina, Kseniya M.; Amosova, Alexandra V.; Zelenin, Alexander V.; Muravenko, Olga V.; Bolsheva, Nadezhda L.; Kudryavtseva, Anna V.

2016-01-01

Cultivated flax (Linum usitatissimum L.) is an important plant valuable for industry. Some flax lines can undergo heritable phenotypic and genotypic changes (LIS-1 insertion being the most common) in response to nutrient stress and are called plastic lines. Offspring of plastic lines, which stably inherit the changes, are called genotrophs. MicroRNAs (miRNAs) are involved in a crucial regulatory mechanism of gene expression. They have previously been assumed to take part in nutrient stress response and can, therefore, participate in genotroph formation. In the present study, we performed high-throughput sequencing of small RNAs (sRNAs) extracted from flax plants grown under normal, phosphate deficient and nutrient excess conditions to identify miRNAs and evaluate their expression. Our analysis revealed expression of 96 conserved miRNAs from 21 families in flax. Moreover, 475 novel potential miRNAs were identified for the first time, and their targets were predicted. However, none of the identified miRNAs were transcribed from LIS-1. Expression of seven miRNAs (miR168, miR169, miR395, miR398, miR399, miR408, and lus-miR-N1) with up- or down-regulation under nutrient stress (on the basis of high-throughput sequencing data) was evaluated on extended sampling using qPCR. Reference gene search identified ETIF3H and ETIF3E genes as most suitable for this purpose. Down-regulation of novel potential lus-miR-N1 and up-regulation of conserved miR399 were revealed under the phosphate deficient conditions. In addition, the negative correlation of expression of lus-miR-N1 and its predicted target, ubiquitin-activating enzyme E1 gene, as well as, miR399 and its predicted target, ubiquitin-conjugating enzyme E2 gene, was observed. Thus, in our study, miRNAs expressed in flax plastic lines and genotrophs were identified and their expression and expression of their targets was evaluated using high-throughput sequencing and qPCR for the first time. These data provide new insights into nutrient stress response regulation in plastic flax cultivars. PMID:27092149

Efficient production of a gene mutant cell line through integrating TALENs and high-throughput cell cloning.

PubMed

Sun, Changhong; Fan, Yu; Li, Juan; Wang, Gancheng; Zhang, Hanshuo; Xi, Jianzhong Jeff

2015-02-01

Transcription activator-like effectors (TALEs) are becoming powerful DNA-targeting tools in a variety of mammalian cells and model organisms. However, generating a stable cell line with specific gene mutations in a simple and rapid manner remains a challenging task. Here, we report a new method to efficiently produce monoclonal cells using integrated TALE nuclease technology and a series of high-throughput cell cloning approaches. Following this method, we obtained three mTOR mutant 293T cell lines within 2 months, which included one homozygous mutant line. © 2014 Society for Laboratory Automation and Screening.

Echo Mapping of Active Galactic Nuclei

NASA Technical Reports Server (NTRS)

Peterson, B. M.; Horne, K.

2004-01-01

Echo mapping makes use of the intrinsic variability of the continuum source in active galactic nuclei to map out the distribution and kinematics of line-emitting gas from its light travel time-delayed response to continuum changes. Echo mapping experiments have yielded sizes for the broad line-emitting region in about three dozen AGNs. The dynamics of the line-emitting gas seem to be dominated by the gravity of the central black hole, enabling measurement of the black-hole masses in AGNs. We discuss requirements for future echo-mapping experiments that will yield the high quality velocity-delay maps of the broad-line region that are needed to determine its physical nature.

FGFR signaling regulates resistance of head and neck cancer stem cells to cisplatin.

PubMed

McDermott, Sarah C; Rodriguez-Ramirez, Christie; McDermott, Sean P; Wicha, Max S; Nör, Jacques E

2018-05-18

Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have poor prognosis with less than 1-year median survival. Platinum-based chemotherapy remains the first-line treatment for HNSCC. The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. A small population of CSC exists within HNSCC that are relatively resistant to chemotherapy and clinically predicted to contribute to tumor recurrence. These head and neck CSCs (HNCSC) are identified by high cell-surface expression of CD44 and high intracellular activity of aldehyde dehydrogenase (ALDH) and termed ALDH high CD44 high . Here, we performed microarray analysis in two HNSCC cell lines (UM-SCC-1, UM-SCC-22B) to investigate molecular pathways active in untreated and cisplatin-resistant ALDH high CD44 high cells. Gene set enrichment analysis and iPathway analysis identified signaling pathways with major implications to the pathobiology of cancer (e.g. TNFα, IFN, IL6/STAT, NF-κB) that are enriched in cisplatin-resistant ALDH high CD44 high cells, when compared to control cells. FGF2 was also enriched in cisplatin-resistant ALDH high CD44 high , which was confirmed by ELISA analysis. Inhibition of FGF signaling using BGJ398, a pan-FGF receptor (FGFR) small-molecule inhibitor, decreased ALDH high CD44 high alone in UM-SCC-1 and preferentially targeted cisplatin-resistant ALDH high CD44 high cells in UM-SCC-22B. These findings suggest that FGFR signaling might play an important role in the resistance of head and neck CSC to cisplatin. Collectively, this work suggests that some head and neck cancer patients might benefit from the combination of cisplatin and a FGFR inhibitor.

A Ku band 5 bit MEMS phase shifter for active electronically steerable phased array applications

NASA Astrophysics Data System (ADS)

Sharma, Anesh K.; Gautam, Ashu K.; Farinelli, Paola; Dutta, Asudeb; Singh, S. G.

2015-03-01

The design, fabrication and measurement of a 5 bit Ku band MEMS phase shifter in different configurations, i.e. a coplanar waveguide and microstrip, are presented in this work. The development architecture is based on the hybrid approach of switched and loaded line topologies. All the switches are monolithically manufactured on a 200 µm high resistivity silicon substrate using 4 inch diameter wafers. The first three bits (180°, 90° and 45°) are realized using switched microstrip lines and series ohmic MEMS switches whereas the fourth and fifth bits (22.5° and 11.25°) consist of microstrip line sections loaded by shunt ohmic MEMS devices. Individual bits are fabricated and evaluated for performance and the monolithic device is a 5 bit Ku band (16-18 GHz) phase shifter with very low average insertion loss of the order of 3.3 dB and a return loss better than 15 dB over the 32 states with a chip area of 44 mm2. A total phase shift of 348.75° with phase accuracy within 3° is achieved over all of the states. The performance of individual bits has been optimized in order to achieve an integrated performance so that they can be implemented into active electronically steerable antennas for phased array applications.

THE DIFFERENCES IN THE TORUS GEOMETRY BETWEEN HIDDEN AND NON-HIDDEN BROAD LINE ACTIVE GALACTIC NUCLEI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ichikawa, Kohei; Ueda, Yoshihiro; Packham, Christopher

2015-04-20

We present results from the fitting of infrared (IR) spectral energy distributions of 21 active galactic nuclei (AGNs) with clumpy torus models. We compiled high spatial resolution (∼0.3–0.7 arcsec) mid-IR (MIR) N-band spectroscopy, Q-band imaging, and nuclear near- and MIR photometry from the literature. Combining these nuclear near- and MIR observations, far-IR photometry, and clumpy torus models enables us to put constraints on the torus properties and geometry. We divide the sample into three types according to the broad line region (BLR) properties: type-1s, type-2s with scattered or hidden broad line region (HBLR) previously observed, and type-2s without any publishedmore » HBLR signature (NHBLR). Comparing the torus model parameters gives us the first quantitative torus geometrical view for each subgroup. We find that NHBLR AGNs have smaller torus opening angles and larger covering factors than HBLR AGNs. This suggests that the chance to observe scattered (polarized) flux from the BLR in NHBLR could be reduced by the dual effects of (a) less scattering medium due to the reduced scattering volume given the small torus opening angle and (b) the increased torus obscuration between the observer and the scattering region. These effects give a reasonable explanation for the lack of observed HBLR in some type-2 AGNs.« less

National Pork Producers Council Maternal Line National Genetic Evaluation Program: a comparison of sow longevity and trait associations with sow longevity.

PubMed

Serenius, T; Stalder, K J; Baas, T J; Mabry, J W; Goodwin, R N; Johnson, R K; Robison, O W; Tokach, M; Miller, R K

2006-09-01

Data from the National Pork Producers Council Maternal Line National Genetic Evaluation Program were used to compare longevity of sows from 6 commercial genetic lines and to estimate the phenotypic associations of sow longevity with gilt backfat thickness, ADG, age at first farrowing, litter size at first farrowing, litter weight at first farrowing, average feed intake during lactation, and average backfat loss during lactation. The lines evaluated were American Diamond Genetics, Danbred North America, Dekalb-Monsanto DK44, Dekalb-Monsanto GPK347, Newsham Hybrids, and National Swine Registry. The data set contained information from 3,251 gilts, of which 17% had censored longevity records (sows lived longer than 6 parities). The line comparison was carried out by analyzing all lines simultaneously. Because the survival distribution functions differed among genetic lines, later analyses were carried out separately for each genetic line. All analyses were based on the non-parametric proportional hazard (Cox model). Dekalb-Monsanto GPK347 sows had a lower risk of being culled than sows from the other lines. Moreover, the shape of the survival distribution function of the Delkab-Monsanto GPK347 line was different from the other 5 lines. The Dekalb-Monsanto 347 line had lower culling rates because they had lower gilt reproductive failure before the first parity than gilts from the other lines. Within line, sows with lower feed intake and greater backfat loss during lactation had a shorter productive lifetime. Thus, producers should implement management practices having positive effects on sow lactation feed intake. Additionally, the swine genetics industry is challenged to simultaneously improve efficiency of gain of their terminal market pigs and to obtain high feed intake during lactation of their maternal lines for future improvement of sow longevity. Recording sow feed intake and backfat loss during lactation in nucleus and multiplication breeding herds should be considered. Between-line differences in this study indicate that it is possible to select for sow longevity, but more research is needed to determine the most efficient selection methods to improve sow longevity.

A Survey of Metal Lines at High-redshift. I. SDSS Absorption Line Studies—the Methodology and First Search Results for O VI

NASA Astrophysics Data System (ADS)

Frank, S.; Mathur, S.; Pieri, M.; York, D. G.

2010-09-01

We report the results of a systematic search for signatures of metal lines in quasar spectra of the Sloan Digital Sky Survey (SDSS) data release 3 (DR3), focusing on finding intervening absorbers via detection of their O VI doublet. Here, we present the search algorithm and criteria for distinguishing candidates from spurious Lyα forest lines. In addition, we compare our findings with simulations of the Lyα forest in order to estimate the detectability of O VI doublets over various redshift intervals. We have obtained a sample of 1756 O VI doublet candidates with rest-frame equivalent width (EW) >=0.05 Å in 855 active galactic nuclei spectra (out of 3702 objects with redshifts in the accessible range for O VI detection). This sample is further subdivided into three groups according to the likelihood of being real and the potential for follow-up observation of the candidate. The group with the cleanest and most secure candidates is comprised of 145 candidates. Sixty-nine of these reside at a velocity separation >=5000 km s-1 from the QSO and can therefore be classified tentatively as intervening absorbers. Most of these absorbers have not been picked up by earlier, automated QSO absorption line detection algorithms. This sample increases the number of known O VI absorbers at redshifts beyond z abs>= 2.7 substantially.

First-line treatment of advanced ALK-positive non-small-cell lung cancer

PubMed Central

Gandhi, Shipra; Chen, Hongbin; Zhao, Yujie; Dy, Grace K

2015-01-01

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%–7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule–associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood–brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC. PMID:28210152

New Transition in the Vortex Liquid State: intrinsic limit of the irreversibility line

NASA Astrophysics Data System (ADS)

Kwok, Wai-Kwong; Paulius, Lisa; Figueras, Jordi

2005-03-01

We have carried out angular dependent magneto-transport measurements on optimally doped, untwinned YBCO crystals irradiated with high energy heavy ions to determine the onset of vortex line tension in the vortex liquid state. The matching field was controlled and kept at a low level to partially preserve the first order vortex lattice melting transition. A Bose glass transition is observed below the lower critical point which then transforms into a first order phase transition near 5 Tesla. The locus of points which indicate the onset of vortex line tension overlaps with the Bose glass transition line at low fields and then deviates at higher fields, indicating a new transition line in the vortex liquid state. This new line in the vortex liquid phase extends beyond the upper critical point.This work was supported by the U.S. Department of Energy, BES, Materials Science under Contract No. W-31-109-ENG-38 at Argonne National Laboratory.

Antagonizing Bcl-2 Family Members Sensitizes Neuroblastoma and Ewing’s Sarcoma to an Inhibitor of Glutamine Metabolism

PubMed Central

Olsen, Rachelle R.; Mary-Sinclair, Michelle N.; Yin, Zhirong; Freeman, Kevin W.

2015-01-01

Neuroblastomas (NBL) and Ewing’s sarcomas (EWS) together cause 18% of all pediatric cancer deaths. Though there is growing interest in targeting the dysregulated metabolism of cancer as a therapeutic strategy, this approach has not been fully examined in NBL and EWS. In this study, we first tested a panel of metabolic inhibitors and identified the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) as the most potent chemotherapeutic across all NBL and EWS cell lines tested. Myc, a master regulator of metabolism, is commonly overexpressed in both of these pediatric malignancies and recent studies have established that Myc causes cancer cells to become “addicted” to glutamine. We found DON strongly inhibited tumor growth of multiple tumor lines in mouse xenograft models. In vitro, inhibition of caspases partially reversed the effects of DON in high Myc expressing cell lines, but not in low Myc expressing lines. We further showed that induction of apoptosis by DON in Myc-overexpressing cancers is via the pro-apoptotic factor Bax. To relieve inhibition of Bax, we tested DON in combination with the Bcl-2 family antagonist navitoclax (ABT-263). In vitro, this combination caused an increase in DON activity across the entire panel of cell lines tested, with synergistic effects in two of the N-Myc amplified neuroblastoma cell lines. Our study supports targeting glutamine metabolism to treat Myc overexpressing cancers, such as NBL and EWS, particularly in combination with Bcl-2 family antagonists. PMID:25615615

Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study.

PubMed

Fink, Anna Maria; Bahlo, Jasmin; Robrecht, Sandra; Al-Sawaf, Othman; Aldaoud, Ali; Hebart, Holger; Jentsch-Ullrich, Kathleen; Dörfel, Steffen; Fischer, Kirsten; Wendtner, Clemens-Martin; Nösslinger, Thomas; Ghia, Paolo; Bosch, Francesc; Kater, Arnon P; Döhner, Hartmut; Kneba, Michael; Kreuzer, Karl-Anton; Tausch, Eugen; Stilgenbauer, Stephan; Ritgen, Matthias; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

2017-10-01

The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing. Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free survival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group). Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment. Celgene Corporation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modelling prehistoric terrain Models using LiDAR-data: a geomorphological approach

NASA Astrophysics Data System (ADS)

Höfler, Veit; Wessollek, Christine; Karrasch, Pierre

2015-10-01

Terrain surfaces conserve human activities in terms of textures and structures. With reference to archaeological questions, the geological archive is investigated by means of models regarding anthropogenic traces. In doing so, the high-resolution digital terrain model is of inestimable value for the decoding of the archive. The evaluation of these terrain models and the reconstruction of historical surfaces is still a challenging issue. Due to the data collection by means of LiDAR systems (light detection and ranging) and despite their subsequent pre-processing and filtering, recently anthropogenic artefacts are still present in the digital terrain model. Analysis have shown that elements, such as contour lines and channels, can well be extracted from a high-resolution digital terrain model. This way, channels in settlement areas show a clear anthropogenic character. This fact can also be observed for contour lines. Some contour lines representing a possibly natural ground surface and avoid anthropogenic artefacts. Comparable to channels, noticeable patterns of contour lines become visible in areas with anthropogenic artefacts. The presented workflow uses functionalities of ArcGIS and the programming language R.1 The method starts with the extraction of contour lines from the digital terrain model. Through macroscopic analyses based on geomorphological expert knowledge, contour lines are selected representing the natural geomorphological character of the surface. In a first step, points are determined along each contour line in regular intervals. This points and the corresponding height information which is taken from an original digital terrain model is saved as a point cloud. Using the programme library gstat, a variographic analysis and the use of a Kriging-procedure based on this follow.2-4 The result is a digital terrain model filtered considering geomorphological expert knowledge showing no human degradation in terms of artefacts, preserving the landscape-genetic character and can be called a prehistoric terrain model.

A clumpy stellar wind and luminosity-dependent cyclotron line revealed by the first Suzaku observation of the high-mass X-ray binary 4U 1538–522

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hemphill, Paul B.; Rothschild, Richard E.; Markowitz, Alex

2014-09-01

We present results from the first Suzaku observation of the high-mass X-ray binary 4U 1538–522. The broadband spectral coverage of Suzaku allows for a detailed spectral analysis, characterizing the cyclotron resonance scattering feature at 23.0 ± 0.4 keV and the iron Kα line at 6.426 ± 0.008 keV, as well as placing limits on the strengths of the iron Kβ line and the iron K edge. We track the evolution of the spectral parameters both in time and in luminosity, notably finding a significant positive correlation between cyclotron line energy and luminosity. A dip and spike in the light curvemore » is shown to be associated with an order-of-magnitude increase in column density along the line of sight, as well as significant variation in the underlying continuum, implying the accretion of a overdense region of a clumpy stellar wind. We also present a phase-resolved analysis, with most spectral parameters of interest showing significant variation with phase. Notably, both the cyclotron line energy and the iron Kα line intensity vary significantly with phase, with the iron line intensity significantly out of phase with the pulse profile. We discuss the implications of these findings in the context of recent work in the areas of accretion column physics and cyclotron resonance scattering feature formation.« less

33 CFR 110.125 - Morro Bay Harbor, Calif.

Code of Federal Regulations, 2013 CFR

2013-07-01

... beginning. (b) Area A-2. Beginning at a point 322° and 150 feet from the high water line on the most westerly part of Fairbanks Point; thence continuing on this bearing for a distance of 1,346 feet; thence 52... high water line to the point of beginning. Note: Moorings and boating activities will be allowed in...

Antibacterial and cytotoxic activity of isoprenylated coumarin mammea A/AA isolated from Mammea africana.

PubMed

Canning, Corene; Sun, Shi; Ji, Xiangming; Gupta, Smiti; Zhou, Kequan

2013-05-02

The stem bark of Mammea africana is widely distributed in tropical Africa and commonly used in traditional medicine. This study aims to identify the active compound in Mammea africana and to evaluate its antimicrobial and antiproliferative activity. Methanol extract from the bark of the Mammea africana was separated by liquid-liquid extraction, followed by open column chromatography. A principal antimicrobial compound was purified by high performance liquid chromatography (HPLC) and its structure was elucidated by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The antibacterial activity of the purified compound was determined using the broth microdilution method against 7 common pathogenic bacteria. The compound was also evaluated for cytotoxicity by cell proliferation assay (MTS) using the mouse embryonic fibroblast cell line NIH 3T3 and the non-small cell lung cancer cell line A549. The purified active compound was determined to be mammea A/AA and was found to be highly active against Campylobacter jejuni (MIC=0.5 μg/ml), Streptococcus pneumoniae (MIC=0.25 μg/ml), and Clostridium difficile (MIC=0.25 μg/ml). The compound exhibited significant antiproliferative activities against both NIH 3T3 and A549 cell lines. Mammea A/AA isolated from Mammea africana exerts specific inhibitory activity against Campylobacter jejuni, Streptococcus pneumoniae, and Campylobacter difficile. Mammea A/AA was also found to exhibit significant cytotoxicity against both cancer and normal cell lines. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Going from "paper and pen" to ICT systems: Perspectives on managing the change process.

PubMed

Andersson Marchesoni, Maria; Axelsson, Karin; Fältholm, Ylva; Lindberg, Inger

2017-03-01

Lack of participation from staff when developing information and communication technologies (ICT) has been shown to lead to negative consequences and might be one explanation for failure. Management during development processes has rarely been empirically studied, especially when introducing ICT systems in a municipality context. To describe and interpret experiences of the management during change processes where ICT was introduced among staff and managers in elderly care. A qualitative interpretive method was chosen for this study and content analysis for analyzing the interviews. "Clear focus-unclear process" demonstrated that focus on ICT solutions was clear but the process of introducing the ICT was not. "First-line managers receiving a system of support" gave a picture of the first-line manager as not playing an active part in the projects. First-line managers and staff described "Low power to influence" when realizing that for some reasons, they had not contributed in the change projects. "Low confirmation" represented the previous and present feelings of staff not being listened to. Lastly, "Reciprocal understanding" pictures how first-line managers and staff, although having some expectations on each other, understood each other's positions. Empowerment could be useful in creating an organization where critical awareness and reflection over daily practice becomes a routine.

OUTFLOW AND METALLICITY IN THE BROAD-LINE REGION OF LOW-REDSHIFT ACTIVE GALACTIC NUCLEI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, Jaejin; Woo, Jong-Hak; Nagao, Tohru

2017-01-20

Outflows in active galactic nuclei (AGNs) are crucial to understand in investigating the co-evolution of supermassive black holes (SMBHs) and their host galaxies since outflows may play an important role as an AGN feedback mechanism. Based on archival UV spectra obtained with the Hubble Space Telescope and IUE , we investigate outflows in the broad-line region (BLR) in low-redshift AGNs ( z < 0.4) through detailed analysis of the velocity profile of the C iv emission line. We find a dependence of the outflow strength on the Eddington ratio and the BLR metallicity in our low-redshift AGN sample, which ismore » consistent with earlier results obtained for high-redshift quasars. These results suggest that BLR outflows, gas accretion onto SMBHs, and past star formation activity in host galaxies are physically related in low-redshift AGNs as in powerful high-redshift quasars.« less

Who knows not where an anemone does wear his sting? Could polypeptides released from the columnar vesicles of Bunodosoma cangicum induce apoptosis in the ZF-L cell line?

PubMed

Bastos, Claudio L Q; Varela, Antonio Sergio; Ferreira, Shana Pires; Nornberg, Bruna Felix; Boyle, Robert Tew

2016-12-15

We provide ultrastructural and cytological evidence that the tentacles of the sea anemone Bunodosoma cangicum does not contain cytotoxic venom. However, we show that the stimulated secretion of an apparent mixture of biomolecules containing polypeptides from the columnar vesicles of Bunodosoma cangicum is apparently a potent inducer of apoptosis in the zebrafish cell line, ZF-L. Microscopic fluorescence, cell morphology and flow cytometric assays confirm the apoptotic activity. Crude vesicle venom was partially purified by size exclusion chromatography. PAGE analysis shows that this venom contains low weight polypeptides but no measurable protein. The apoptotic activity is heat labile, and the observed peptides concurrent with this activity have a molecular weight of approximately 2000 Da. This manuscript is the first report of biologically active molecules and peptides associated with columnar vesicles of anemones, and the first to confirm that the tentacles of B. cangicum do not contain cytotoxic venom, and express spirocytes exclusively. Copyright © 2016 Elsevier Ltd. All rights reserved.

SBS 0846+513: a New Gamma-ray Emitting Narrow-line Seyfert 1 Galaxy

NASA Technical Reports Server (NTRS)

D'Ammando, F.; Orienti, M.; Finke, J.; Raiteri, C. M.; Angelakis, E.; Fuhrmann, L.; Giroletti, M.; Hovatta, T.; Max-Moerbeck, W.; Perkins, J. S.;

Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koukourakis, Michael I., E-mail: targ@her.forthnet.gr; Kalamida, Dimitra; Mitrakas, Achilleas

2015-05-29

Introduction: Radiotherapy is an equivalent alternative or complement to radical prostatectomy, with high therapeutic efficacy. High risk patients, however, experience high relapse rates, so that research on radio-sensitization is the most evident route to improve curability of this common disease. Materials and methods: In the current study we investigated the autophagic activity in a series of patients with localized prostate tumors treated with radical radiotherapy, using the LC3A and the LAMP2a proteins as markers of autophagosome and lysosome cellular content, respectively. The role of autophagy on prostate cancer cell line resistance to radiation was also examined. Results: Using confocal microscopymore » on tissue biopsies, we showed that prostate cancer cells have, overall, high levels of LC3A and low levels of LAMP2a compared to normal prostate glands. Tumors with a ‘highLC3A/lowLAMP2a’ phenotype, suggestive of intensified lysosomal consumption, had a significantly poorer biochemical relapse free survival. The PC3 radioresistant cell line sustained remarkably its autophagic flux ability after radiation, while the DU145 radiosensitive one experiences a prolonged blockage of the autophagic process. This was assessed with aggresome accumulation detection and LC3A/LAMP2a double immunofluorescence, as well as with sequestrosome/p62 protein detection. By silencing the LC3A or LAMP2a expression, both cell lines became more sensitive to escalated doses of radiation. Conclusions: High base line autophagy activity and cell ability to sustain functional autophagy define resistance of prostate cancer cells to radiotherapy. This can be reversed by blocking up-regulated components of the autophagy pathway, which may prove of importance in the field of clinical radiotherapy. - Highlights: • High LC3A and low LAMP2a levels is a frequent expression pattern of prostate carcinoma. • This pattern of intensified autophagic flux relates with high relapse rates after radiotherapy. • The PC3 radio-resistant cell line sustains remarkably its autophagic flux ability after radiation. • Irradiation of the DU145 radio-sensitive cell line blocks the autophagic flux. • Intense autophagy activity defines prostate cancer radio-resistance, in vivo and in vitro.« less

Selecting Cells for Bioartificial Liver Devices and the Importance of a 3D Culture Environment: A Functional Comparison between the HepaRG and C3A Cell Lines.

PubMed

van Wenum, Martien; Adam, Aziza A A; Hakvoort, Theodorus B M; Hendriks, Erik J; Shevchenko, Valery; van Gulik, Thomas M; Chamuleau, Robert A F M; Hoekstra, Ruurdtje

2016-01-01

Recently, the first clinical trials on Bioartificial Livers (BALs) loaded with a proliferative human hepatocyte cell source have started. There are two cell lines that are currently in an advanced state of BAL development; HepaRG and HepG2/C3A. In this study we aimed to compare both cell lines on applicability in BALs and to identify possible strategies for further improvement. We tested both cell lines in monolayer- and BAL cultures on growth characteristics, hepatic differentiation, nitrogen-, carbohydrate-, amino acid- and xenobiotic metabolism. Interestingly, both cell lines adapted the hepatocyte phenotype more closely when cultured in BALs; e.g. monolayer cultures produced lactate, while BAL cultures showed diminished lactate production (C3A) or conversion to elimination (HepaRG), and urea cycle activity increased upon BAL culturing in both cell lines. HepaRG-BALs outperformed C3A-BALs on xenobiotic metabolism, ammonia elimination and lactate elimination, while protein synthesis was comparable. In BAL cultures of both cell lines ammonia elimination correlated positively with glutamine production and glutamate consumption, suggesting ammonia elimination was mainly driven by the balance between glutaminase and glutamine synthetase activity. Both cell lines lacked significant urea cycle activity and both required multiple culture weeks before reaching optimal differentiation in BALs. In conclusion, culturing in BALs enhanced hepatic functionality of both cell lines and from these, the HepaRG cells are the most promising proliferative cell source for BAL application.

Assessing chemical constituents of Mimosa caesalpiniifolia stem bark: possible bioactive components accountable for the cytotoxic effect of M. caesalpiniifolia on human tumour cell lines.

PubMed

Monção, Nayana Bruna Nery; Araújo, Bruno Quirino; Silva, Jurandy do Nascimento; Lima, Daisy Jereissati Barbosa; Ferreira, Paulo Michel Pinheiro; Airoldi, Flavia Pereira da Silva; Pessoa, Cláudia; Citó, Antonia Maria das Graças Lopes

2015-03-05

Mimosa caesalpiniifolia is a native plant of the Brazilian northeast, and few studies have investigated its chemical composition and biological significance. This work describes the identification of the first chemical constituents in the ethanolic extract and fractions of M. caesalpiniifolia stem bark based on NMR, GC-qMS and HRMS analyses, as well as an assessment of their cytotoxic activity. GC-qMS analysis showed fatty acid derivatives, triterpenes and steroid substances and confirmed the identity of the chemical compounds isolated from the hexane fraction. Metabolite biodiversity in M. caesalpiniifolia stem bark revealed the differentiated accumulation of pentacyclic triterpenic acids, with a high content of betulinic acid and minor amounts of 3-oxo and 3β-acetoxy derivatives. Bioactive analysis based on total phenolic and flavonoid content showed a high amount of these compounds in the ethanolic extract, and ESI-(-)-LTQ-Orbitrap-MS identified caffeoyl hexose at high intensity, as well as the presence of phenolic acids and flavonoids. Furthermore, the evaluation of the ethanolic extract and fractions, including betulinic acid, against colon (HCT-116), ovarian (OVCAR-8) and glioblastoma (SF-295) tumour cell lines showed that the crude extract, hexane and dichloromethane fractions possessed moderate to high inhibitory activity, which may be related to the abundance of betulinic acid. The phytochemical and biological study of M. caesalpiniifolia stem bark thus revealed a new alternative source of antitumour compounds, possibly made effective by the presence of betulinic acid and by chemical co-synergism with other compounds.

Design of noise barrier inspection system for high-speed railway

NASA Astrophysics Data System (ADS)

Liu, Bingqian; Shao, Shuangyun; Feng, Qibo; Ma, Le; Cholryong, Kim

2016-10-01

The damage of noise barriers will highly reduce the transportation safety of the high-speed railway. In this paper, an online inspection system of noise barrier based on laser vision for the safety of high-speed railway is proposed. The inspection system, mainly consisted of a fast camera and a line laser, installed in the first carriage of the high-speed CIT(Composited Inspection Train).A Laser line was projected on the surface of the noise barriers and the images of the light line were received by the camera while the train is running at high speed. The distance between the inspection system and the noise barrier can be obtained based on laser triangulation principle. The results of field tests show that the proposed system can meet the need of high speed and high accuracy to get the contour distortion of the noise barriers.

Hematopoietic Cancer Cell Lines Can Support Replication of Sabin Poliovirus Type 1

PubMed Central

van Eikenhorst, Gerco; de Gruijl, Tanja D.; van der Pol, Leo A.; Bakker, Wilfried A. M.

2015-01-01

Viral vaccines can be produced in adherent or in suspension cells. The objective of this work was to screen human suspension cell lines for the capacity to support viral replication. As the first step, it was investigated whether poliovirus can replicate in such cell lines. Sabin poliovirus type 1 was serially passaged on five human cell lines, HL60, K562, KG1, THP-1, and U937. Sabin type 1 was capable of efficiently replicating in three cell lines (K562, KG1, and U937), yielding high viral titers after replication. Expression of CD155, the poliovirus receptor, did not explain susceptibility to replication, since all cell lines expressed CD155. Furthermore, we showed that passaged virus replicated more efficiently than parental virus in KG1 cells, yielding higher virus titers in the supernatant early after infection. Infection of cell lines at an MOI of 0.01 resulted in high viral titers in the supernatant at day 4. Infection of K562 with passaged Sabin type 1 in a bioreactor system yielded high viral titers in the supernatant. Altogether, these data suggest that K562, KG1, and U937 cell lines are useful for propagation of poliovirus. PMID:25815312

Human a-L-fucosidase-1 attenuates the invasive properties of thyroid cancer.

PubMed

Vecchio, Giancarlo; Parascandolo, Alessia; Allocca, Chiara; Ugolini, Clara; Basolo, Fulvio; Moracci, Marco; Strazzulli, Andrea; Cobucci-Ponzano, Beatrice; Laukkanen, Mikko O; Castellone, Maria Domenica; Tsuchida, Nobuo

2017-04-18

Glycans containing α-L-fucose participate in diverse interactions between cells and extracellular matrix. High glycan expression on cell surface is often associated with neoplastic progression. The lysosomal exoenzyme, α-L-fucosidase-1 (FUCA-1) removes fucose residues from glycans. The FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors. However, the role of FUCA-1 in tumor progression remains unclear. It is speculated that its inactivation perturbs glycosylation of proteins involved in cell adhesion and promotes cancer. FUCA-1 expression of various thyroid normal and cancer tissues assayed by immunohistochemical (IHC) staining was high in normal thyroids and papillary thyroid carcinomas (PTC), whereas it progressively decreased in poorly differentiated, metastatic and anaplastic thyroid carcinomas (ATC). FUCA-1 mRNA expression from tissue samples and cell lines and protein expression levels and enzyme activity in thyroid cancer cell lines paralleled those of IHC staining. Furthermore, ATC-derived 8505C cells adhesion to human E-selectin and HUVEC cells was inhibited by bovine α-L-fucosidase or Lewis antigens, thus pointing to an essential role of fucose residues in the adhesive phenotype of this cancer cell line. Finally, 8505C cells transfected with a FUCA-1 containing plasmid displayed a less invasive phenotype versus the parental 8505C. These results demonstrate that FUCA-1 is down-regulated in ATC compared to PTC and normal thyroid tissues and cell lines. As shown for other human cancers, the down-regulation of FUCA-1 correlates with increased aggressiveness of the cancer type. This is the first report indicating that the down-regulation of FUCA-1 is related to the increased aggressiveness of thyroid cancer.

Characterization of lunar ferromagnetic phases by the effective linewidth method

NASA Technical Reports Server (NTRS)

Patton, C. E.; Schmidt, H.

1978-01-01

The effective line-width technique, first developed to study the physics of microwave relaxation in ferrites, has been successfully applied to lunar matter. Effective line-width measurements have been made on two selected samples containing disperse spherical metallic iron particles below 40 microns in diam. The data were obtained for fields from 7 to 12 kOe and a temperature range 125 - 300 K. The effective line width was field-independent and temperature-independent at 650 - 750 Oe. The high-field tails of the ferromagnetic resonance absorption were highly Lorentzian. From the relatively large and temperature-independent high-field effective line widths, it appears that (1) the metallic iron phases in lunar soil are rather impure; (2) the impurities are passive, in that there is no evidence for a temperature peak process; and (3) these samples contain no appreciable magnetite.

Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

PubMed Central

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

2014-01-01

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

Cost-effectiveness analysis of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer.

PubMed

Graham, Christopher N; Hechmati, Guy; Hjelmgren, Jonas; de Liège, Frédérique; Lanier, Julie; Knox, Hediyyih; Barber, Beth

2014-11-01

To investigate the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) compared with bevacizumab plus mFOLFOX6 in first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC). A semi-Markov model was constructed from a French health collective perspective, with health states related to first-line treatment (progression-free), disease progression with and without subsequent active treatment, resection of metastases, disease-free after successful resection and death. Parametric survival analyses of patient-level progression-free and overall survival data from the only head-to-head clinical trial of panitumumab and bevacizumab (PEAK) were performed to estimate transitions to disease progression and death. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and French public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second- and third-line settings. A life-time perspective was applied. Scenario, one-way, and probabilistic sensitivity analyses were performed. Based on a head-to-head clinical trial that demonstrates better efficacy outcomes for patients with wild-type RAS mCRC who receive panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6, the incremental cost per life-year gained was estimated to be €26,918, and the incremental cost per quality-adjusted life year (QALY) gained was estimated to be €36,577. Sensitivity analyses indicate the model is robust to alternative parameters and assumptions. The incremental cost per QALY gained indicates that panitumumab plus mFOLFOX6 represents good value for money in comparison to bevacizumab plus mFOLFOX6 and, with a willingness-to-pay ranging from €40,000 to €60,000, can be considered cost-effective in first-line treatment of patients with wild-type RAS mCRC. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Physiological and genetic correlates of boldness: characterising the mechanisms of behavioural variation in rainbow trout, Oncorhynchus mykiss.

PubMed

Thomson, Jack S; Watts, Phillip C; Pottinger, Tom G; Sneddon, Lynne U

2011-01-01

Bold, risk-taking animals have previously been putatively linked with a proactive stress coping style whereas it is suggested shyer, risk-averse animals exhibit a reactive coping style. The aim of this study was to investigate whether differences in the expression of bold-type behaviour were evident within and between two lines of rainbow trout, Oncorhynchus mykiss, selectively bred for a low (LR) or high (HR) endocrine response to stress, and to link boldness and stress responsiveness with the expression of related candidate genes. Boldness was determined in individual fish over two trials by measuring the latency to approach a novel object. Differences in plasma cortisol concentrations and the expression of eight novel candidate genes previously identified as being linked with divergent behaviours or stress were determined. Bold and shy individuals, approaching the object within 180 s or not approaching within 300 s respectively, were evident within each line, and this was linked with activity levels in the HR line. Post-stress plasma cortisol concentrations were significantly greater in the HR line compared with the LR line, and six of the eight tested genes were upregulated in the brains of LR fish compared with HR fish. However, no direct relationship between boldness and either stress responsiveness or gene expression was found, although clear differences in stress physiology and, for the first time, gene expression could be identified between the lines. This lack of correlation between physiological and molecular responses and behavioural variation within both lines highlights the complexity of the behavioural-physiological complex. Copyright © 2010 Elsevier Inc. All rights reserved.

Human renal cell carcinoma: establishment and characterization of two new cell lines.

PubMed

Naito, S; Kanamori, T; Hisano, S; Tanaka, K; Momose, S; Kamata, N

1982-11-01

Characterization studies have been carried out on 2 cell lines (KPK 1 and KPK 13) established from human renal adenocarcinoma. KPK 1 and KPK 13 have been passaged 178 times in vitro for about 6 years and 7 months and 78 times for about 3 years an 2 months, respectively. Although morphologic differences exist between the 2 lines, each has an epithelial morphology and exhibits multilayering. Doubling time of KPK 1 and KPK 13 cells was 29 hours and 51 hours, respectively. Both KPK 1 and KPK 13 induced tumors at the site of subcutaneous injection, closely resembling the original tumor from which they were derived. Chromosome number of both cell lines was 100 per cent aneuploid and the presence of Y chromosomes was confirmed by G banding in KPK 13 cells. KPK 1 was found to have high thromboplastic and high fibrinolytic activities, whereas KPK 13 was shown to have comparatively low thromboplastic and no detectable fibrinolytic activities. These activities were detected in the serum free supernatant fraction from KPK 1 cells but were not detected in that from KPK 13 cells.

Neutrino-heated stars and broad-line emission from active galactic nuclei

NASA Technical Reports Server (NTRS)

Macdonald, James; Stanev, Todor; Biermann, Peter L.

1991-01-01

Nonthermal radiation from active galactic nuclei indicates the presence of highly relativistic particles. The interaction of these high-energy particles with matter and photons gives rise to a flux of high-energy neutrinos. In this paper, the influence of the expected high neutrino fluxes on the structure and evolution of single, main-sequence stars is investigated. Sequences of models of neutrino-heated stars in thermal equilibrium are presented for masses 0.25, 0.5, 0.8, and 1.0 solar mass. In addition, a set of evolutionary sequences for mass 0.5 solar mass have been computed for different assumed values for the incident neutrino energy flux. It is found that winds driven by the heating due to high-energy particles and hard electromagnetic radiation of the outer layers of neutrino-bloated stars may satisfy the requirements of the model of Kazanas (1989) for the broad-line emission clouds in active galactic nuclei.

Managing vulvovaginal hematoma by arterial embolization as first-line hemostatic therapy.

PubMed

Takagi, Kenjiro; Akashi, Keiko; Horiuchi, Isao; Nakamura, Eishin; Samejima, Koki; Ushijima, Junko; Okochi, Tomohisa; Hamamoto, Kohei; Tanno, Keisuke

2017-04-01

A puerperal vulvovaginal hematoma may continue to grow after a surgical procedure and may require blood transfusion. Thus, we selected arterial embolization for hemostasis as the first-line management in two cases of large vulvovaginal hematoma. Case 1 was a 32-year-old pregnant woman. After delivery, a 10-cm vulvar hematoma developed. An enhanced computed tomography (CT) scan revealed active bleeding. Arterial embolization was performed and complete hemostasis was obtained. Case 2 was a 34-year-old woman with a recurring hematoma after delivery. An enhanced CT scan revealed extravasation in the hematoma. Gelatin sponges were applied and complete hemostasis was obtained. In both cases, arterial embolization was successful without requiring blood transfusions. We successfully managed two cases of puerperal vulvovaginal hematoma by arterial embolization based on the evaluation of an enhanced CT scan. In conclusion, we suggest arterial embolization to be a viable option for first-line treatment in the management of vulvovaginal hematomas. Copyright © 2017. Published by Elsevier B.V.

OT2_smalhotr_3: Herschel Extreme Lensing Line Observations (HELLO)

NASA Astrophysics Data System (ADS)

Malhotra, S.

2011-09-01

We request 59.8 hours of Herschel time to observe 20 normal star-forming galaxies in the [CII] 158 micron and [OI] 63 micron lines. These galaxies lie at high redshift (1

Solar cells and methods of fabrication thereof

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shumate, Seth Daniel; Hutchings, Douglas Arthur; Mohammed, Hafeezuddin

A passivation layer is deposited on a first portion of a region of the solar cell. A grid line is deposited on a second portion of the region. The passivation layer is annealed to drive chemical species from the passivation layer to deactivate an electrical activity of a dopant in the first portion of the region of the solar cell.

Synthesis and cytotoxic analysis of some disodium 3beta,6beta-dihydroxysterol disulfates.

PubMed

Cui, Jianguo; Wang, Hui; Huang, Yanmin; Xin, Yi; Zhou, Aimin

2009-01-01

Disodium 3beta,6beta-dihydroxy-5alpha-cholestane disulfate (1) was synthesized in 4 steps with a high overall yield from cholesterol. First, cholesterol (4a) was converted to cholest-4-en-3,6-dione (5a) via oxidation with pyridinium chlorochromate (PCC) and then 5a was reduced by NaBH(4) in the presence of NiCl(2) to produce cholest-3beta,6beta-diol (6a). The reaction of 6a with the triethylamine-sulfur trioxide complex generated diammonium 3beta,6beta-dihydroxy-5alpha-cholestane disulfate (7a) and the treatment of 7a by cation exchange resin 732 (sodium form)(Na(+)) yielded the target steroid 1. Disodium 24-ethyl-3beta,6beta-dihydroxycholest-22-ene disulfate (2) and disodium 24-ethyl-3beta,6beta-dihydroxycholestane disulfate (3) were synthesized using a similar method. The cytotoxicity of these compounds against Sk-Hep-1 (human liver carcinoma cell line), H-292 (human lung carcinoma cell line), PC-3 (human prostate carcinoma cell line) and Hey-1B (human ovarian carcinoma cell line) cells was investigated. Our results indicate that presence of a cholesterol-type side chain at position 17 is necessary for their biological activity.

A facile and efficient synthesis of some (6E)-hydroximino-4-en-3-one steroids, steroidal oximes from Cinachyrella spp. sponges.

PubMed

Cui, Jianguo; Huang, Liliang; Fan, Lei; Zhou, Aimin

2008-03-01

Using beta-sitosterol as a starting material, (6E)-hydroximino-24-ethylcholest-4-en-3-one (1), a natural steroidal oxime from Cinachyrella alloclada and C. apion, was synthesized in four steps with a high overall yield. First, beta-sitosterol (5a) is transformed into the corresponding 24-ethylcholest-4-en-3,6-dione (6a) via oxidation with pyridinium chlorochromate (PCC). Selective reduction of 6a by NaBH(4) in the presence of CoCl(2) gives 24-ethylcholest- 4-en-3beta-ol-6-one (7a). The reaction of 7a with hydroxylamine hydrochloride offers the oxime 8a and the oxidation of 8a by Jones reagent gives the target steroid 1. (6E)-Hydroximinocholest-4-en-3-one (2) and (6E)-hydroximino-24-ethylcholest-4,22-dien-3-one (4) were synthesized by a similar method. The cytotoxicity of the synthesized compounds against sk-Hep-1 (human liver carcinoma cell line), H-292 (human lung carcinoma cell line), PC-3 (human prostate carcinoma cell line) and Hey-1B (human ovarian carcinoma cell line) cells were investigated. The presence of a cholesterol-type side chain appears to be necessary for the biological activity.

High-resolution H -band Spectroscopy of Be Stars with SDSS-III/APOGEE. II. Line Profile and Radial Velocity Variability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chojnowski, S. Drew; Holtzman, Jon A.; Wisniewski, John P.

2017-04-01

We report on the H -band spectral variability of classical Be stars observed over the course of the Apache Point Galactic Evolution Experiment (APOGEE), one of four subsurveys comprising SDSS-III. As described in the first paper of this series, the APOGEE B-type emission-line (ABE) star sample was culled from the large number of blue stars observed as telluric standards during APOGEE observations. In this paper, we explore the multi-epoch ABE sample, consisting of 1100 spectra for 213 stars. These “snapshots” of the circumstellar disk activity have revealed a wealth of temporal variability including, but not limited to, gradual disappearance ofmore » the line emission and vice versa over both short and long timescales. Other forms of variability include variation in emission strength, emission peak intensity ratios, and emission peak separations. We also analyze radial velocities (RVs) of the emission lines for a subsample of 162 stars with sufficiently strong features, and we discuss on a case-by-case basis whether the RV variability exhibited by some stars is caused by binary motion versus dynamical processes in the circumstellar disks. Ten systems are identified as convincing candidates for binary Be stars with as of yet undetected companions.« less

The joint NASA/Goddard-University of Maryland research program in charged particle and high energy photon detector technology

NASA Technical Reports Server (NTRS)

1987-01-01

The first measurements of Fe charge states in two coronal hole-association high speed streams, using the sensor on ISEE-3, are presented. Eight event intervals from the January to June 1983 timeframe were chosen for the study of magnetotail dynamics and its relationship to substorm activity and the possible formation of plasmoids. Techniques are being explored for measurement of secondary electrons which are characteristically emitted when ions hit a target material. Efforts are continuing to understand kilometer wavelength shock associated radio events. An all-sky survey of fast X-ray transients of duration of 5 to 10,000 s was completed. Research using high resolution gamma-ray spectroscopy of celestial sources in the 20 keV to 20 MeV range to search for and study narrow lines in low-energy gamma-ray spectrum continues. Research in high energy radiation from pulsars is being conducted.

The copper intrauterine device for emergency contraception: an opportunity to provide the optimal emergency contraception method and transition to highly effective contraception.

PubMed

Dermish, Amna I; Turok, David K

2013-07-01

Worldwide, 40% of all pregnancies are unintended. Widespread, over-the-counter availability of oral emergency contraception (EC) has not reduced unintended pregnancy rates. The EC visit presents an opportunity to initiate a highly effective method of contraception in a population at high risk of unintended pregnancy who are actively seeking to avoid pregnancy. The copper intrauterine device (IUD), the most effective method of EC, continues to provide contraception as effective as sterilization for up to 12 years, and it should be offered as the first-line method of EC wherever possible. Increased demand for and supply of the copper IUD for EC may have an important role in reducing rates of unintended pregnancy. The EC visit should include access to the copper IUD as optimal care but should ideally include access to all highly effective methods of contraception.

The redox state of the apoplast influences the acclimation of photosynthesis and leaf metabolism to changing irradiance

PubMed Central

Karpinska, Barbara; Zhang, Kaiming; Rasool, Brwa; Pastok, Daria; Morris, Jenny; Verrall, Susan R.; Hedley, Pete E.

2017-01-01

Abstract The redox state of the apoplast is largely determined by ascorbate oxidase (AO) activity. The influence of AO activity on leaf acclimation to changing irradiance was explored in wild‐type (WT) and transgenic tobacco (Nicotiana tobaccum) lines containing either high [pumpkin AO (PAO)] or low [tobacco AO (TAO)] AO activity at low [low light (LL); 250 μmol m−2 s−1] and high [high light (HL); 1600 μmol m−2 s−1] irradiance and following the transition from HL to LL. AO activities changed over the photoperiod, particularly in the PAO plants. AO activity had little effect on leaf ascorbate, which was significantly higher under HL than under LL. Apoplastic ascorbate/dehydroascorbate (DHA) ratios and threonate levels were modified by AO activity. Despite decreased levels of transcripts encoding ascorbate synthesis enzymes, leaf ascorbate increased over the first photoperiod following the transition from HL to LL, to much higher levels than LL‐grown plants. Photosynthesis rates were significantly higher in the TAO leaves than in WT or PAO plants grown under HL but not under LL. Sub‐sets of amino acids and fatty acids were lower in TAO and WT leaves than in the PAO plants under HL, and following the transition to LL. Light acclimation processes are therefore influenced by the apoplastic as well as chloroplastic redox state. PMID:28369975

Cost effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B from a Canadian public payer perspective.

PubMed

Dakin, Helen; Sherman, Morris; Fung, Scott; Fidler, Carrie; Bentley, Anthony

2011-12-01

Previous research has demonstrated that tenofovir disoproxil fumarate (DF) is the most cost-effective nucleos(t)ide treatment for chronic hepatitis B (CHB) in the UK, Spain, Italy and France. However, to our knowledge, no published studies have yet evaluated the cost effectiveness of any treatments for CHB in a Canadian setting, where relative prices and management of CHB differ from those in Europe. Our objective was to determine the cost effectiveness of tenofovir DF compared with other nucleos(t)ide therapies licensed for CHB in Canada from the perspective of publicly funded healthcare payers. A Markov model was used to calculate the costs and benefits of nucleos(t)ide therapy in three groups of patients with hepatitis B e antigen (HBeAg)-positive and -negative CHB: nucleos(t)ide-naive patients without cirrhosis; nucleos(t)ide-naive patients with compensated cirrhosis; and lamivudine-resistant patients. Disease progression was modelled as annual transitions between 18 disease states. Transition probabilities, quality of life and costs were based on published studies. Health benefits were measured in QALYs. The reference year for costs was 2007 and costs and outcomes were discounted at 5% per annum. First-line tenofovir DF was the most effective nucleos(t)ide strategy for managing CHB, generating 6.85-9.39 QALYs per patient. First-line tenofovir DF was also the most cost-effective strategy in all patient subgroups investigated, costing between $Can43,758 and $Can48,015 per QALY gained compared with lamivudine then tenofovir. First-line tenofovir DF strongly dominated first-line entecavir. Giving tenofovir DF monotherapy immediately after lamivudine resistance developed was less costly and more effective than any other active treatment strategy investigated for lamivudine-resistant CHB, including second-line use of adefovir or adefovir + lamivudine. Probabilistic sensitivity analysis demonstrated 50% confidence that first-line tenofovir DF is the most cost-effective nucleos(t)ide strategy for treatment-naive patients with CHB, at a $Can50,000 per QALY threshold, and confirmed that first-line tenofovir DF has the highest expected net benefits. First-line tenofovir DF appears to be the most cost-effective nucleos(t)ide treatment for both cirrhotic and non-cirrhotic CHB patients in Canada, providing that society is willing to pay at least $Can48,015 per QALY gained, although sensitivity analyses highlighted uncertainty around the results.

New Cytochalasin from Rosellinia sanctae-cruciana, an Endophytic Fungus of Albizia lebbeck.

PubMed

Sharma, Nisha; Kushwaha, Manoj; Arora, Divya; Jain, Shreyans; Singamaneni, Venugopal; Sharma, Sonia; Shankar, Ravi; Bhushan, Shashi; Gupta, Prasoon; Jaglan, Sundeep

2018-03-24

To explore the potential of Rosellinia sanctae-cruciana an endophytic fungus associated with Albizia lebbeck for pharmaceutically important cytotoxic compounds. One novel cytochalasin, named Jammosporin A (1) and four known analogues (2-5) were isolated from the culture of the endophytic fungus Rosellinia sanctae-cruciana, harbored from the leaves of medicinal plant Albizia lebbeck. Their structures were elucidated by extensive spectroscopic analyses including 1D and 2D NMR data along with MS data and by comparison with literature reports. In preliminary screening the ethyl acetate extract of the fungal culture was tested for the cytotoxic activity against a panel of four cancer cell lines (MOLT-4, A549, MIA PaCa -2 and MDA-MB-231), was found to be active against MOLT-4 with IC 50 value of 10 μg/mL. Owing to the remarkable cytotoxic activity of the extract the isolated compounds (1-5) were evaluated for their cytototoxicity against MOLT-4 cell line by MTT assay. Interestingly, compounds 1-2, 4 and 5 showed considerable cytotoxic potential against the human leukemia cancer cell line (MOLT-4) with IC 50 values of 20.0, 10.0, 8.0 and 6.0 μM, respectively, while compound 3 showed IC 50 value of 25 μM. This is the first report of existence of this class of secondary metabolites in Rosellinia sanctae-cruciana fungus. This study discovered a novel compound, named Jammosporin A, isolated for the first time from Rosellinia sanctae-cruciana, an endophytic fungus of Albizia lebbeck with anticancer activity against MOLT-4 cell line. Rosellinia sanctae-cruciana represents an interesting source of a new compound with bioactive potential as a therapeutic agent against human leukemia cancer cell line (MOLT-4). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Ligand activation of peroxisome proliferator-activated receptor-β/δ (PPAR β/δ) inhibits cell growth in a mouse mammary gland cancer cell line

PubMed Central

Foreman, Jennifer E.; Sharma, Arun K.; Amin, Shantu; Gonzalez, Frank J.; Peters, Jeffrey M.

2009-01-01

The effects of ligand activation of PPARβ/δ were examined in the mouse mammary tumor cell line (C20). Expression of PPARβ/δ was markedly lower in C20 cells as compared to the human non-tumorigenic mammary gland derived cell line (MCF10A) and mouse keratinocytes. Ligand activation of PPARβ/δ in C20 cells caused upregulation of the PPARβ/δ target gene angiopoietin-like 4 (Angptl4). Inhibition of C20 cell proliferation and clonogenicity was observed following treatment with GW0742 or GW501516, two highly specific PPARβ/δ ligands. In addition, an increase in apoptosis was observed in C20 cells cultured with 10 µM GW501516 that preceded the observed inhibition of cell proliferation. Results from this study show that proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPARβ/δ due in part to increased apoptosis. PMID:19660859

Laser-induced selective copper plating of polypropylene surface

NASA Astrophysics Data System (ADS)

Ratautas, K.; Gedvilas, M.; Stankevičiene, I.; JagminienÄ--, A.; Norkus, E.; Li Pira, N.; Sinopoli, S.; Emanuele, U.; Račiukaitis, G.

2016-03-01

Laser writing for selective plating of electro-conductive lines for electronics has several significant advantages, compared to conventional printed circuit board technology. Firstly, this method is faster and cheaper at the prototyping stage. Secondly, material consumption is reduced, because it works selectively. However, the biggest merit of this method is potentiality to produce moulded interconnect device, enabling to create electronics on complex 3D surfaces, thus saving space, materials and cost of production. There are two basic techniques of laser writing for selective plating on plastics: the laser-induced selective activation (LISA) and laser direct structuring (LDS). In the LISA method, pure plastics without any dopant (filler) can be used. In the LDS method, special fillers are mixed in the polymer matrix. These fillers are activated during laser writing process, and, in the next processing step, the laser modified area can be selectively plated with metals. In this work, both methods of the laser writing for the selective plating of polymers were investigated and compared. For LDS approach, new material: polypropylene with carbon-based additives was tested using picosecond and nanosecond laser pulses. Different laser processing parameters (laser pulse energy, scanning speed, the number of scans, pulse durations, wavelength and overlapping of scanned lines) were applied in order to find out the optimal regime of activation. Areal selectivity tests showed a high plating resolution. The narrowest width of a copper-plated line was less than 23 μm. Finally, our material was applied to the prototype of the electronic circuit board on a 2D surface.

Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.

PubMed

Chesney, Jason; Clark, Jennifer; Lanceta, Lilibeth; Trent, John O; Telang, Sucheta

2015-07-20

Human tumors exhibit increased glucose uptake and metabolism as a result of high demand for ATP and anabolic substrates and this metabolotype is a negative prognostic indicator for survival. Recent studies have demonstrated that cancer cells from several tissue origins and genetic backgrounds require the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), a regulatory enzyme that synthesizes an allosteric activator of glycolysis, fructose-2,6-bisphosphate. We report the discovery of a first-in-class PFKFB4 inhibitor, 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate (5MPN), using structure-based virtual computational screening. We find that 5MPN is a selective inhibitor of PFKFB4 that suppresses the glycolysis and proliferation of multiple human cancer cell lines but not non-transformed epithelial cells in vitro. Importantly, 5MPN has high oral bioavailability and per os administration of a non-toxic dose of 5MPN suppresses the glucose metabolism and growth of tumors in mice.

Alpha: A real-time decentralized operating system for mission-oriented system integration and operation

NASA Technical Reports Server (NTRS)

Jensen, E. Douglas

1988-01-01

Alpha is a new kind of operating system that is unique in two highly significant ways. First, it is decentralized transparently providing reliable resource management across physically dispersed nodes, so that distributed applications programming can be done largely as though it were centralized. And second, it provides comprehensive, high technology support for real-time system integration and operation, an application area which consists predominately of aperiodic activities having critical time constraints such as deadlines. Alpha is extremely adaptable so that it can be easily optimized for a wide range of problem-specific functionality, performance, and cost. Alpha is the first systems effort of the Archons Project, and the prototype was created at Carnegie-Mellon University directly on modified Sun multiprocessor workstation hardware. It has been demonstrated with a real-time C(sup 2) application. Continuing research is leading to a series of enhanced follow-ons to Alpha; these are portable but initially hosted on Concurrent's MASSCOMP line of multiprocessor products.

H-alpha synoptic charts of solar activity during the first year of solar cycle 20, October 1964 - August 1965. [Skylab program

NASA Technical Reports Server (NTRS)

Mcintosh, P. S.

1975-01-01

Solar activity during the period October 28, 1964 through August 27, 1965 is presented in the form of charts for each solar rotation constructed from observations made with the chromospheric H-alpha spectra line. These H-alpha synoptic charts are identical in format and method of construction to those published for the period of Skylab observations. The sunspot minimum marking the start of Solar Cycle 20 occurred in October, 1964; therefore, charts represent solar activity during the first year of this solar cycle.

27 CFR 9.189 - High Valley.

Code of Federal Regulations, 2014 CFR

2014-04-01

...; then (4) Proceed easterly 2.7 miles along the meandering 2,000-foot elevation line to its first... mile along the north branch of the Salt Canyon Creek to its intersection with the 1,600-foot elevation...) Proceed westerly 15.2 miles along the meandering 1,600-foot elevation line, crossing the Clearlake Oaks...

27 CFR 9.189 - High Valley.

Code of Federal Regulations, 2010 CFR

2010-04-01

...; then (4) Proceed easterly 2.7 miles along the meandering 2,000-foot elevation line to its first... mile along the north branch of the Salt Canyon Creek to its intersection with the 1,600-foot elevation...) Proceed westerly 15.2 miles along the meandering 1,600-foot elevation line, crossing the Clearlake Oaks...

27 CFR 9.189 - High Valley.

Code of Federal Regulations, 2011 CFR

2011-04-01

...; then (4) Proceed easterly 2.7 miles along the meandering 2,000-foot elevation line to its first... mile along the north branch of the Salt Canyon Creek to its intersection with the 1,600-foot elevation...) Proceed westerly 15.2 miles along the meandering 1,600-foot elevation line, crossing the Clearlake Oaks...

27 CFR 9.189 - High Valley.

Code of Federal Regulations, 2013 CFR

2013-04-01

...; then (4) Proceed easterly 2.7 miles along the meandering 2,000-foot elevation line to its first... mile along the north branch of the Salt Canyon Creek to its intersection with the 1,600-foot elevation...) Proceed westerly 15.2 miles along the meandering 1,600-foot elevation line, crossing the Clearlake Oaks...

27 CFR 9.189 - High Valley.

Code of Federal Regulations, 2012 CFR

2012-04-01

...; then (4) Proceed easterly 2.7 miles along the meandering 2,000-foot elevation line to its first... mile along the north branch of the Salt Canyon Creek to its intersection with the 1,600-foot elevation...) Proceed westerly 15.2 miles along the meandering 1,600-foot elevation line, crossing the Clearlake Oaks...

HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

PubMed Central

Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick CK; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher KC; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

2014-01-01

Introduction First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line. Results A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥2 TAMs; and 32 with M184V+≥1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤200 cells/µL at genotyping (OR=4.43, 95% CI [1.59–12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39–16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ≥95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43–35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome. Conclusions Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy. PMID:25141905

HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia.

PubMed

Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick C K; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher K C; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

2014-01-01

First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance - Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥ 2 TAMs; or M184V+≥ 1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line. A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥ 1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥ 2 TAMs; and 32 with M184V+≥ 1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤ 200 cells/µL at genotyping (OR=4.43, 95% CI [1.59-12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39-16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ≥ 95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43-35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome. Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

Clinical features and response to systemic therapy in a historical cohort of advanced or unresectable mucosal melanoma.

PubMed

Shoushtari, Alexander N; Bluth, Mark J; Goldman, Debra A; Bitas, Christiana; Lefkowitz, Robert A; Postow, Michael A; Munhoz, Rodrigo R; Buchar, Gauri; Hester, Robert H; Romero, Jacqueline A; Fitzpatrick, Laura J; Weiser, Martin R; Panageas, Katherine S; Wolchok, Jedd D; Chapman, Paul B; Carvajal, Richard D

2017-02-01

There are very few data available regarding the pattern of first metastases in resected mucosal melanomas (MMs) as well as the response of advanced MM to cytotoxic therapy. A retrospective, single-institution cohort was assembled of all patients with advanced/unresectable MM between 1995 and 2012 who had received systemic therapy with available imaging (N=81). Responses to first-line and second-line systemic therapy were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The relationship between response, overall survival, and clinical covariates was investigated using Cox proportional hazards regression. Primary sites included anorectal (N=31, 38%), vulvovaginal (N=28, 35%), head and neck (N=21, 26%), and gallbladder (N=1, 1%) mucosa. Seven percent of patients had their first relapse in the brain. Cytotoxic therapy represented 82 and 51% of first-line and second-line regimens. The best response achieved in the first-line setting was similar for single-agent [10%; 95% confidence interval (CI): 1-32%] and combination alkylator therapy (8%; 95% CI: 2-21%). Median overall survival from first-line treatment was 10.3 months (95% CI: 8.7-13.9 months). Patients with elevated lactic dehydrogenase [hazard ratio (HR): 1.87, 95% CI: 1.10-3.19, P=0.020] and Eastern Cooperative Oncology Group performance status 1-2 (HR: 1.69, 95% CI: 1.05-2.72, P=0.030) had a higher risk of death, whereas patients with 12-week objective responses had a lower risk of death (HR: 0.12, 95% CI: 0.04-0.41, P<0.001). Cytotoxic systemic therapy has modest activity in advanced/unresectable MM, belying its adjuvant benefit. Patients whose tumors have an objective response to therapy have a lower probability of death. Brain imaging should be considered in routine surveillance.

Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen.

PubMed

Michaelis, Martin; Agha, Bishr; Rothweiler, Florian; Löschmann, Nadine; Voges, Yvonne; Mittelbronn, Michel; Starzetz, Tatjana; Harter, Patrick N; Abhari, Behnaz A; Fulda, Simone; Westermann, Frank; Riecken, Kristoffer; Spek, Silvia; Langer, Klaus; Wiese, Michael; Dirks, Wilhelm G; Zehner, Richard; Cinatl, Jaroslav; Wass, Mark N; Cinatl, Jindrich

2015-02-03

Flubendazole was shown to exert anti-leukaemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was tested for its effects on the viability of in total 461 cancer cell lines. Neuroblastoma was identified as highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities. Flubendazole also reduced the viability of five primary neuroblastoma samples in nanomolar concentrations thought to be achievable in humans and inhibited vessel formation and neuroblastoma tumour growth in the chick chorioallantoic membrane assay. Resistance acquisition is a major problem in high-risk neuroblastoma. 119 cell lines from a panel of 140 neuroblastoma cell lines with acquired resistance to various anti-cancer drugs were sensitive to flubendazole in nanomolar concentrations. Tubulin-binding agent-resistant cell lines displayed the highest flubendazole IC50 and IC90 values but differences between drug classes did not reach statistical significance. Flubendazole induced p53-mediated apoptosis. The siRNA-mediated depletion of the p53 targets p21, BAX, or PUMA reduced the neuroblastoma cell sensitivity to flubendazole with PUMA depletion resulting in the most pronounced effects. The MDM2 inhibitor and p53 activator nutlin-3 increased flubendazole efficacy while RNAi-mediated p53-depletion reduced its activity. In conclusion, flubendazole represents a potential treatment option for neuroblastoma including therapy-refractory cells.

Identification of flubendazole as potential anti-neuroblastoma compound in a large cell line screen

PubMed Central

Michaelis, Martin; Agha, Bishr; Rothweiler, Florian; Löschmann, Nadine; Voges, Yvonne; Mittelbronn, Michel; Starzetz, Tatjana; Harter, Patrick N.; Abhari, Behnaz A.; Fulda, Simone; Westermann, Frank; Riecken, Kristoffer; Spek, Silvia; Langer, Klaus; Wiese, Michael; Dirks, Wilhelm G.; Zehner, Richard; Cinatl, Jaroslav; Wass, Mark N.; Cinatl, Jindrich

2015-01-01

Flubendazole was shown to exert anti-leukaemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was tested for its effects on the viability of in total 461 cancer cell lines. Neuroblastoma was identified as highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities. Flubendazole also reduced the viability of five primary neuroblastoma samples in nanomolar concentrations thought to be achievable in humans and inhibited vessel formation and neuroblastoma tumour growth in the chick chorioallantoic membrane assay. Resistance acquisition is a major problem in high-risk neuroblastoma. 119 cell lines from a panel of 140 neuroblastoma cell lines with acquired resistance to various anti-cancer drugs were sensitive to flubendazole in nanomolar concentrations. Tubulin-binding agent-resistant cell lines displayed the highest flubendazole IC50 and IC90 values but differences between drug classes did not reach statistical significance. Flubendazole induced p53-mediated apoptosis. The siRNA-mediated depletion of the p53 targets p21, BAX, or PUMA reduced the neuroblastoma cell sensitivity to flubendazole with PUMA depletion resulting in the most pronounced effects. The MDM2 inhibitor and p53 activator nutlin-3 increased flubendazole efficacy while RNAi-mediated p53-depletion reduced its activity. In conclusion, flubendazole represents a potential treatment option for neuroblastoma including therapy-refractory cells. PMID:25644037

The use of alectinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancer.

PubMed

Gadgeel, Shirish M

2018-03-14

Anaplastic lymphoma kinase (ALK) gene rearrangements as driver genetic alterations occur in approximately 2-4% of non-small-cell lung cancer (NSCLC) patients. Alectinib, a next generation ALK inhibitor, recently demonstrated, in two separate Phase III trials, superior efficacy to crizotinib, the first ALK inhibitor to demonstrate clinical efficacy in ALK-positive NSCLC patients. Alectinib also demonstrated superior efficacy in the CNS. The data from these two Phase III studies suggest that the efficacy of starting with alectinib is superior to the overall clinical efficacy of starting with crizotinib followed by switching to alectinib at the time of disease progression. These results have changed the standard of care to alectinib as front-line therapy for advanced ALK-positive NSCLC patients. Areas covered: this paper reviews the available data on alectinib as front-line therapy in patients with ALK-positive NSCLC patients including its activity against brain metastases. In addition, the paper will review the data with other ALK inhibitors as front-line therapy.

Examining the Influence of a New Light Rail Line on the Health of a Demographically Diverse and Understudied Population within the Washington, D.C. Metropolitan Area: A Protocol for a Natural Experiment Study

PubMed Central

Saksvig, Brit Irene; Brachman, Micah L.; Durand, Casey P.

2018-01-01

Approximately two-thirds of adults and youth in Prince George’s County, Maryland, a suburb of Washington, D.C. are overweight or obese and less than half are achieving daily physical activity recommendations. Active transportation (AT), such as walking, biking or using public transportation (PT), is a strategic pathway to improving physical activity levels and thus reducing excess weight. Utilizing an expansion of the Washington, D.C. area transportation system with a new light rail line, the Purple Line Outcomes on Transportation (PLOT) Study will exam pre- and post-Purple Line PT use, AT behaviors and attitudes and physical activity among Prince George’s County adults and youth. The PLOT Study will take advantage of this natural experiment in an area enduring significant racial/ethnic and gender-based overweight or obesity and physical inactivity disparities. While similar natural experiments on AT have been conducted in other U.S. cities, those studies lacked diverse and representative samples. To effectively evaluate these physical activity outcomes among this population, efforts will be used to recruit African American and Latino populations, the first and second most common racial/ethnic groups in Prince George’s County. Finally, the PLOT Study will also examine how contextual effects (e.g., neighborhood built environment) impact PT, AT and physical activity.

Formation of Relativistic Jets : Magnetohydrodynamics and Synchrotron Radiation

NASA Astrophysics Data System (ADS)

Porth, Oliver J. G.

2011-11-01

In this thesis, the formation of relativistic jets is investigated by means of special relativistic magnetohydrodynamic simulations and synchrotron radiative transfer. Our results show that the magnetohydrodynamic jet self-collimation paradigm can also be applied to the relativistic case. In the first part, jets launched from rotating hot accretion disk coronae are explored, leading to well collimated, but only mildly relativistic flows. Beyond the light-cylinder, the electric charge separation force balances the classical trans-field Lorentz force almost entirely, resulting in a decreased efficiency of acceleration and collimation in comparison to non-relativistic disk winds. In the second part, we examine Poynting dominated flows of various electric current distributions. By following the outflow for over 3000 Schwarzschild radii, highly relativistic jets of Lorentz factor 8 and half-opening angles below 1 degree are obtained, providing dynamical models for the parsec scale jets of active galactic nuclei. Applying the magnetohydrodynamic structure of the quasi-stationary simulation models, we solve the relativistically beamed synchrotron radiation transport. This yields synthetic radiation maps and polarization patterns that can be used to confront high resolution radio and (sub-) mm observations of nearby active galactic nuclei. Relativistic motion together with the helical magnetic fields of the jet formation site imprint a clear signature on the observed polarization and Faraday rotation. In particular, asymmetries in the polarization direction across the jet can disclose the handedness of the magnetic helix and thus the spin direction of the central engine. Finally, we show first results from fully three-dimensional, high resolution adaptive mesh refinement simulations of jet formation from a rotating magnetosphere and examine the jet stability. Relativistic field-line rotation leads to an electric charge separation force that opposes the magnetic Lorentz force, such that we obtain an increased stability of relativistic flows. Accordingly, the non-axisymmetric modes applied to the field-line foot-points saturate quickly, with no signs of enhanced dissipation or disruption near the jet launching site.

Anti-leishmanial and toxicity activities of some selected Iranian medicinal plants.

PubMed

Kheiri Manjili, Hamidreza; Jafari, Hamidreza; Ramazani, Ali; Davoudi, Noushin

2012-11-01

Leishmaniasis is caused by protozoan parasites belonging to the genus Leishmania. Cutaneous leishmaniasis is the most common form of leishmaniasis in Iran. As there is not any vaccine for leishmaniasis, treatment is important to prevent the spreading of parasites. There is, therefore, a need to develop newer drugs from different sources. The aim of this study was to assess anti-leishmanial activity of the ethanolic extracts of 17 different medicinal plants against Leishmania major promastigotes and macrophage cell line J774. The selection of the hereby studied 17 plants was based on the existing information on their local ethnobotanic history. Plants were dried, powdered, and macerated in a hydroalcoholic solution. Resulting extracts have been assessed for in vitro anti-leishmanial and brine shrimp toxicity activities. Four plants, Caesalpinia gilliesii, Satureia hortensis, Carum copticum heirm, and Thymus migricus, displayed high anti-leishmanial activity (IC50, 9.76 ± 1.27, 15.625 ± 3.76, 15.625 ± 5.46, and 31.25 ± 15.44 μM, respectively) and were toxic against the J774 macrophage cell line at higher concentrations than those needed to inhibit the parasite cell growth (IC50, 45.13 ± 3.17, 100.44 ± 17.48, 43.76 ± 0.78, and 39.67 ± 3.29 μM, respectively). Glucantime as positive control inhibited the growth of L. major promastigotes with IC50 = 254 μg/ml on promastigotes (1 × 10(6)/100 μ/well) of a log phase culture, without affecting the growth of J774 macrophages. These data revealed that C. gilliesii, S. hortensis, C. copticum heirm, and T. migricus extracts contain active compounds, which could serve as alternative agents in the control of cutaneous leishmaniasis. The activity of these herbs against L. major promastigotes and macrophage cell line J774 was reported for the first time in our study.

DNA methylation and hydroxymethylation analyses of the active LINE-1 subfamilies in mice.

PubMed

Murata, Yui; Bundo, Miki; Ueda, Junko; Kubota-Sakashita, Mie; Kasai, Kiyoto; Kato, Tadafumi; Iwamoto, Kazuya

2017-10-19

Retrotransposon long interspersed nuclear element-1 (LINE-1) occupies a large proportion of the mammalian genome, comprising approximately 100,000 genomic copies in mice. Epigenetic status of the 5' untranslated region (5'-UTR) of LINE-1 is critical for its promoter activity. DNA methylation levels in the 5'-UTR of human active LINE-1 subfamily can be measured by well-established methods, such as a pyrosequencing-based assay. However, because of the considerable sequence and structural diversity in LINE-1 among species, methods for such assays should be adapted for the species of interest. Here we developed pyrosequencing-based assays to examine methylcytosine (mC) and hydroxymethylcytosine (hmC) levels of the three active LINE-1 subfamilies in mice (TfI, A, and GfII). Using these assays, we quantified mC and hmC levels in four brain regions and four nonbrain tissues including tail, heart, testis, and ovary. We observed tissue- and subfamily-specific mC and hmC differences. We also found that mC levels were strongly correlated among different brain regions, but mC levels of the testis showed a poor correlation with those of other tissues. Interestingly, mC levels in the A and GfII subfamilies were highly correlated, possibly reflecting their close evolutionary relationship. Our assays will be useful for exploring the epigenetic regulation of the active LINE-1 subfamilies in mice.

The development and clinical use of a beam ON-LINE PET system mounted on a rotating gantry port in proton therapy.

PubMed

Nishio, Teiji; Miyatake, Aya; Ogino, Takashi; Nakagawa, Keiichi; Saijo, Nagahiro; Esumi, Hiroyasu

2010-01-01

To verify the usefulness of our developed beam ON-LINE positron emission tomography (PET) system mounted on a rotating gantry port (BOLPs-RGp) for dose-volume delivery-guided proton therapy (DGPT). In the proton treatment room at our facility, a BOLPs-RGp was constructed so that a planar PET apparatus could be mounted with its field of view covering the iso-center of the beam irradiation system. Activity measurements were performed in 48 patients with tumors of the head and neck, liver, lungs, prostate, and brain. The position and intensity of the activity were measured using the BOLPs-RGp during the 200 s immediately after the proton irradiation. The daily measured activity images acquired by the BOLPs-RGp showed the proton irradiation volume in each patient. Changes in the proton-irradiated volume were indicated by differences between a reference activity image (taken at the first treatment) and the daily activity-images. In the case of head-and-neck treatment, the activity distribution changed in the areas where partial tumor reduction was observed. In the case of liver treatment, it was observed that the washout effect in necrotic tumor cells was slower than in non-necrotic tumor cells. The BOLPs-RGp was developed for the DGPT. The accuracy of proton treatment was evaluated by measuring changes of daily measured activity. Information about the positron-emitting nuclei generated during proton irradiation can be used as a basis for ensuring the high accuracy of irradiation in proton treatment.

Novel urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation.

PubMed

Perković, I; Antunović, M; Marijanović, I; Pavić, K; Ester, K; Kralj, M; Vlainić, J; Kosalec, I; Schols, D; Hadjipavlou-Litina, D; Pontiki, E; Zorc, B

2016-11-29

A series of novel compounds 3a-j and 6a-j with primaquine and hydroxyl or halogen substituted benzene moieties bridged by urea or bis-urea functionalities were designed, synthesized and evaluated for biological activity. The title compounds were prepared using benzotriazole as the synthon, through several synthetic steps. 3-[3,5-Bis(trifluoromethyl)phenyl]-1-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}urea (3j) was the most active urea and 1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-3-[3-(trifluoromethyl)phenyl]urea (6h) the most active bis-urea derivative in antiproliferative screening in vitro against eight tested cancer cell lines. Urea derivatives 3a-g with hydroxy group or one halogen atom showed moderate antiproliferative effects against all the tested cell lines, but stronger activity against breast carcinoma MCF-7 cell line, while trifluoromethyl derivatives 3h-j showed antiproliferative effects against all the tested cell lines in low micromolar range. Finally, bis-ureas with hydroxy and fluoro substituents 6a-d showed extreme selectivity and chloro or bromo derivatives 6e-g high selectivity against MCF-7 cells (IC 50 0.1-2.6 μM). p-Fluoro derivative 6d, namely 3-(4-fluorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea, is the most promising compound. Further biological experiments showed that 6d affected cell cycle and induced cell death of MCF-7 cell line. Due to its high activity against MCF-7 cell line (IC 50 0.31 μM), extreme selectivity and full agreement with the Lipinski's and Gelovani's rules for prospective small molecular drugs, 6d may be considered as a lead compound in development of breast carcinoma drugs. Urea 3b and almost all bis-ureas showed high antioxidant activity in DPPH assay, but urea derivatives were more active in lipid peroxidation test. Only few compounds exhibited weak inhibition of soybean lipoxygenase. Compound 3j exhibited the strongest antimicrobial activity in susceptibility assay in vitro (MIC = 1.6-12.5 μg ml -1 ). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Mechanisms of cellular uptake, intracellular transportation, and degradation of CIGB-300, a Tat-conjugated peptide, in tumor cell lines.

PubMed

Benavent Acero, Fernando R; Perera Negrin, Yasser; Alonso, Daniel F; Perea, Silvio E; Gomez, Daniel E; Farina, Hernán G

2014-06-02

CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate's phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB-300 is internalized and transported into cells preferentially by caveolae-mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells.

Impact of clinical parameters and systemic inflammatory status on epidermal growth factor receptor-mutant non-small cell lung cancer patients readministration with epidermal growth factor receptor tyrosine kinase inhibitors.

PubMed

Chen, Yu-Mu; Lai, Chien-Hao; Rau, Kun-Ming; Huang, Cheng-Hua; Chang, Huang-Chih; Chao, Tung-Ying; Tseng, Chia-Cheng; Fang, Wen-Feng; Chung, Yu-Hsiu; Wang, Yi-Hsi; Su, Mao-Chang; Huang, Kuo-Tung; Liu, Shih-Feng; Chen, Hung-Chen; Chang, Ya-Chun; Chang, Yu-Ping; Wang, Chin-Chou; Lin, Meng-Chih

2016-11-08

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration to lung cancer patients is common owing to the few options available. Impact of clinical factors on prognosis of EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKI readministration after first-line EGFR-TKI failure and a period of TKI holiday remains unclear. Through this retrospective study, we aimed to understand the impact of clinical factors in such patients. Of 1386 cases diagnosed between December 2010 and December 2013, 80 EGFR-mutant NSCLC patients who were readministered TKIs after failure of first-line TKIs and intercalated with at least one cycle of cytotoxic agent were included. We evaluated clinical factors that may influence prognosis of TKI readministration as well as systemic inflammatory status in terms of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Baseline NLR and LMR were estimated at the beginning of TKI readministration and trends of NLR and LMR were change amount from patients receiving first-Line TKIs to TKIs readministration. Median survival time since TKI readministration was 7.0 months. In the univariable analysis, progression free survival (PFS) of first-line TKIs, baseline NLR and LMR, and trend of LMR were prognostic factors in patients receiving TKIs readministration. In the multivariate analysis, only PFS of first-line TKIs (p < 0.001), baseline NLR (p = 0.037), and trend of LMR (p = 0.004) were prognostic factors. Longer PFS of first-line TKIs, low baseline NLR, and high trend of LMR were good prognostic factors in EGFR-mutant NSCLC patients receiving TKI readministration.

The Nano-Patch-Clamp Array: Microfabricated Glass Chips for High-Throughput Electrophysiology

NASA Astrophysics Data System (ADS)

Fertig, Niels

2003-03-01

Electrophysiology (i.e. patch clamping) remains the gold standard for pharmacological testing of putative ion channel active drugs (ICADs), but suffers from low throughput. A new ion channel screening technology based on microfabricated glass chip devices will be presented. The glass chips contain very fine apertures, which are used for whole-cell voltage clamp recordings as well as single channel recordings from mammalian cell lines. Chips containing multiple patch clamp wells will be used in a first bench-top device, which will allow perfusion and electrical readout of each well. This scalable technology will allow for automated, rapid and parallel screening on ion channel drug targets.

A multi-epoch spectroscopic study of the BAL quasar APM 08279+5255. II. Emission- and absorption-line variability time lags

NASA Astrophysics Data System (ADS)

Saturni, F. G.; Trevese, D.; Vagnetti, F.; Perna, M.; Dadina, M.

2016-03-01

Context. The study of high-redshift bright quasars is crucial to gather information about the history of galaxy assembly and evolution. Variability analyses can provide useful data on the physics of quasar processes and their relation with the host galaxy. Aims: In this study, we aim to measure the black hole mass of the bright lensed BAL QSO APM 08279+5255 at z = 3.911 through reverberation mapping, and to update and extend the monitoring of its C IV absorption line variability. Methods: We perform the first reverberation mapping of the Si IV and C IV emission lines for a high-luminosity quasar at high redshift with the use of 138 R-band photometric data and 30 spectra available over 16 years of observations. We also cross-correlate the C IV absorption equivalent width variations with the continuum light curve to estimate the recombination time lags of the various absorbers and infer the physical conditions of the ionised gas. Results: We find a reverberation-mapping time lag of ~900 rest-frame days for both Si IV and C IV emission lines. This is consistent with an extension of the BLR size-to-luminosity relation for active galactic nuclei up to a luminosity of ~1048 erg s-1, and implies a black hole mass of 1010 M⊙. Additionally, we measure a recombination time lag of ~160 days in the rest frame for the C IV narrow absorption system, which implies an electron density of the absorbing gas of ~2.5 × 104 cm-3. Conclusions: The measured black hole mass of APM 08279+5255 indicates that the quasar resides in an under-massive host-galaxy bulge with Mbulge ~ 7.5MBH, and that the lens magnification is lower than ~8. Finally, the inferred electron density of the narrow-line absorber implies a distance of the order of 10 kpc of the absorbing gas from the quasar, placing it within the host galaxy.

Solution In-Line Alpha Counter (SILAC) Instruction Manual-Version 4.00

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steven M. Alferink; Joel E. Farnham; Malcolm M. Fowler

2002-06-01

The Solution In-Line Alpha Counter (SILAC) provides near real-time alpha activity measurements of aqueous solutions in gloveboxes located in the Plutonium Facility (TA-55) at Los Alamos National Laboratory (LANL). The SILAC detector and its interface software were first developed by Joel Farnham at LANL [1]. This instruction manual describes the features of the SILAC interface software and contains the schematic and fabrication instructions for the detector.

Brentuximab vedotin exerts profound antiproliferative and pro-apoptotic efficacy in CD30-positive as well as cocultured CD30-negative germ cell tumour cell lines.

PubMed

Schönberger, Stefan; van Beekum, Cornelius; Götz, Barbara; Nettersheim, Daniel; Schorle, Hubert; Schneider, Dominik T; Casati, Anna; Craveiro, Rogerio B; Calaminus, Gabriele; Dilloo, Dagmar

2018-01-01

Prognosis in patients suffering from high-risk, refractory and relapsed germ cell tumours (GCT) often comprising of CD30-positive embryonal carcinoma (EC) components remains poor. Thus, novel treatment strategies are warranted. The antibody-drug conjugate (ADC) brentuximab vedotin delivers the potent antimitotic drug monomethyl auristatin E (MMAE) to CD30-expressing tumour cells. After CD30 binding, internalization and intracellular linker cleavage cytotoxic MMAE can efflux and eradicate neighbouring CD30-negative cells. To analyse cytotoxicity and a potential bystander effect of brentuximab vedotin in GCT, we established an in vitro coculture model mimicking GCT of heterogeneous CD30 positivity and measured cell viability, proliferation and apoptosis after exposure to brentuximab vedotin and unbound MMAE by MTS- and flow cytometry-based CFSE/Hoechst assay. CD30 expression being assessed by quantitative RT-PCR and immunohistochemistry was apparent in all EC cell lines with different intensity. Brentuximab vedotin abrogates cell viability of CD30-positive GCT27 EC line exerting marked time-dependent antiproliferative and pro-apoptotic activity. CD30-negative JAR cultured alone barely responds to brentuximab vedotin, while in coculture with GCT27 brentuximab vedotin induces clear dose-dependent cytotoxicity. Cellular proliferation and cell death are significantly enhanced in CD30-negative JAR cocultured with CD30-positive GCT27 compared to JAR cultured alone in proof of substantial bystander activity of brentuximab vedotin in CD30-negative GCT. We present first evidence that in an in vitro model mimicking GCT of heterogeneous histology, brentuximab vedotin exerts potent antiproliferative and pro-apoptotic activity against both CD30-positive as well as CD30-negative GCT subsets. Our results strongly support translational efforts to evaluate clinical efficacy of brentuximab vedotin in high-risk GCT of heterogeneous CD30 positivity. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Low concentrations of alendronate increase the local invasive potential of osteoblastic sarcoma cell lines via connexin 43 activation.

PubMed

Yoshitani, Kazuhiro; Kido, Akira; Honoki, Kanya; Akahane, Manabu; Fujii, Hiromasa; Tanaka, Yasuhito

2011-07-15

Bisphosphonates (BPs) are agents used for treating disorders of excessive bone resorption. In addition, due to their cell-killing activity, BPs were potent candidates for adjuvant cancer therapy. On the other hand, low-concentrations of BPs have been reported to increase cellular viability in several types of tumor cells. Therefore, we focused on the effect of BPs on cellular aggressiveness of malignant bone tumors at low concentrations. MTS assay was performed using osteosarcoma cell lines MG63 and HOS, fibrosarcoma cell line HT1080, and prostate cancer cell line PC3. All the cell lines showed toxicity at high concentrations. On the other hand, at lower concentrations, the cellular viabilities of HOS and MG63 were rather higher than those of untreated controls. Since this tendency was most evident, HOS was used for further assays, including cellular motility, bone resorption activity, and cathepsin K activity. The low-concentration of alendronate enhanced cellular viability and motility, which correlated with the expression of connexin 43 at the mRNA and protein levels. Interestingly, oleamide, a potent connexin 43 inhibitor, had an inhibitory effect on the enhanced proliferation. Our data suggest that alendronate may enhance the proliferation of osteoblastic cell line through connexin 43 activation. Copyright © 2011 Elsevier GmbH. All rights reserved.

Quality of life and sexuality issues in aging women.

PubMed

Birkhäuser, M H

2009-01-01

Quality of life may decrease after menopause. Hormone replacement therapy remains the first-line and most effective treatment for menopausal symptoms and improvement of low quality of life due to estrogen deficiency. The decrease of health-related quality of life in women suffering from cardiovascular disease may be superimposed on the decrease of quality of life induced by menopause itself. Postmenopausal women with acute cardiovascular disease have a significantly higher probability of death than men of the same age. Quality of life predicts long-term mortality. A myocardial infarction does not automatically interdict sexual activity. The Princeton guidelines classify patients suffering from cardiovascular diseases in three categories. Most patients belong to the low-risk category. In general, these patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. Patients at intermediate (or indeterminate) levels of risk should further receive cardiologic evaluation to be classified into either the low- or high-risk group. Patients in the high-risk category have to be stabilized by specific treatment for their cardiac condition before resumption of sexual activity, or initiation of treatment for sexual dysfunction.

Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system.

PubMed

Lemaire, Géraldine; Mnif, Wissem; Pascussi, Jean-Marc; Pillon, Arnaud; Rabenoelina, Fanja; Fenet, Hélène; Gomez, Elena; Casellas, Claude; Nicolas, Jean-Claude; Cavaillès, Vincent; Duchesne, Marie-Josèphe; Balaguer, Patrick

2006-06-01

Pregnane X receptor (PXR, NR1I2) is activated by various chemically unrelated compounds, including environmental pollutants and drugs. We proceeded here to in vitro screening of 28 pesticides with a new reporter system that detects human pregnane X receptor (hPXR) activators. The cell line was obtained by a two-step stable transfection of cervical cancer HeLa cells. The first transfected cell line, HG5LN, contained an integrated luciferase reporter gene under the control of a GAL4 yeast transcription factor-binding site. The second cell line HGPXR was derived from HG5LN and stably expressed hPXR ligand-binding domain fused to GAL4 DNA-binding domain (DBD). The HG5LN cells were used as a control to detect nonspecific activities. Pesticides from various chemical classes were demonstrated, for the first time, to be hPXR activators: (1) herbicides: pretilachlor, metolachlor, and alachlor chloracetanilides, oxadiazon oxiconazole, and isoproturon urea; (2) fungicides: bupirimate and fenarimol pyrimidines, propiconazole, fenbuconazole, prochloraz conazoles, and imazalil triazole; and (3) insecticides: toxaphene organochlorine, permethrin pyrethroid, fipronil pyrazole, and diflubenzuron urea. Pretilachlor, metolachlor, bupirimate, and oxadiazon had an affinity for hPXR equal to or greater than the positive control rifampicin. Some of the newly identified hPXR activators were also checked for their ability to induce cytochrome P450 3A4 expression in a primary culture of human hepatocytes. HGPXR, with HG5LN as a reference, was grafted onto nude mice to assess compound bioavailability through in vivo quantification of hPXR activation. Altogether, our data indicate that HGPXR cells are an efficient tool for identifying hPXR ligands and establishing pesticides as hPXR activators.

Characterization of free radical defense system in high glucose cultured HeLa-tat cells: consequences for glucose-induced cytotoxicity.

PubMed

Bouvard, Sophie; Faure, Patrice; Roucard, Corinne; Favier, Alain; Halimi, Serge

2002-09-01

HeLa cell line stably transfected with the tat gene from human immunodeficiency virus type 1 has a decreased antioxidant potential. In this work, we used this model to investigate the effect of a high glucose level (20 mM) on the glucose induced cytotoxicity and on the antioxidant system. In comparison to cell culture under control medium, HeLa-wild cell cultured under 20 mM glucose did not exhibit necrosis or apoptosis, contrary to HeLa-tat cell presenting a significant increase in necrotic or apoptotic state. Moreover after 48 h culture under high glucose level the HeLa-tat proliferation rate was not higher than the one of HeLa-wild cells. In HeLa-wild cell high glucose level resulted in an induction of glutathione reductase activity in opposition to HeLa-tat cells where no change was observed. High glucose level resulted in 20% increase in GSSG/GSH ratio in HeLa-wild cells and 38% increase in HeLa-tat cells. Moreover, high glucose level resulted in a dramatic cytosolic thiol decrease and an important lipid peroxidation in HeLa-tat cells. No significant change of these two parameters was observed in HeLa-wild cells. In both cell lines, high glucose resulted in an increase of total SOD activity, as a consequence of the increase in Cu,Zn-SOD activity. High glucose did not result in an increase of Mn-SOD activity in both cell lines. As a consequence of tat tranfection Mn-SOD activity was 50% lower in HeLa-tat cells in comparison to HeLa-wild cells. This work emphasizes the importance of the antioxidant system in the glucose induced cytotoxicity.

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand.

PubMed

Gourdeau, Henriette; McAlpine, James B; Ranger, Maxime; Simard, Bryan; Berger, Francois; Beaudry, Francis; Farnet, Chris M; Falardeau, Pierre

2008-05-01

ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER technology, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed. Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) bolus administrations. ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus s.c. and i.p. administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, i.v. dosing was followed by rapid elimination of the drug and was ineffective. Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained drug levels rather than C (max). These in vivo data constitute a rationale for clinical studies testing prolonged continuous administration of ECO-4601.

tRNA modification profiles of the fast-proliferating cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Chao; Niu, Leilei; Song, Wei

Despite the recent progress in RNA modification study, a comprehensive modification profile is still lacking for mammalian cells. Using a quantitative HPLC/MS/MS assay, we present here a study where RNA modifications are examined in term of the major RNA species. With paired slow- and fast-proliferating cell lines, distinct RNA modification profiles are first revealed for diverse RNA species. Compared to mRNAs, increased ribose and nucleobase modifications are shown for the highly-structured tRNAs and rRNAs, lending support to their contribution to the formation of high-order structures. This study also reveals a dynamic tRNA modification profile in the fast-proliferating cells. In additionmore » to cultured cells, this unique tRNA profile has been further confirmed with endometrial cancers and their adjacent normal tissues. Taken together, the results indicate that tRNA is a actively regulated RNA species in the fast-proliferating cancer cells, and suggest that they may play a more active role in biological process than expected. -- Highlights: •RNA modifications were first examined in term of the major RNA species. •A dynamic tRNA modifications was characterized for the fast-proliferating cells. •The unique tRNA profile was confirmed with endometrial cancers and their adjacent normal tissues. •tRNA was predicted as an actively regulated RNA species in the fast-proliferating cancer cells.« less

Insulin Exhibits an Antiproliferative and Hypertrophic Effect in First Trimester Human Extravillous Trophoblasts.

PubMed

Silva, Cláudia; Nunes, Catarina; Correia-Branco, Ana; Araújo, João R; Martel, Fátima

2017-04-01

Our aim was to investigate the effect of high levels of glucose, insulin, leptin, and tumor necrosis factor alpha, biomarkers of diabetes in pregnancy, in the process of placentation, using as a cell model a first trimester extravillous human trophoblast cell line (HTR8/SVneo cells). Exposure of HTR8/SVneo cells for 24 hours to either glucose (20 mmol/L) or leptin (25-100 ng/mL) did not cause significant changes in cell proliferation and viability. Tumor necrosis factor alpha (24 hours; 10-100 ng/L) caused a small decrease (10%) in cell proliferation and an increase (9%) in cell viability; however, both effects disappeared when exposure time was increased. Insulin (24 hours; 1-10 nmol/L) caused a concentration- and time-dependent decrease (10%-20%) in cell proliferation; the effect of insulin (10 nmol/L) was more pronounced after a 48 hours exposure (35%). In contrast, exposure to insulin (10 nmol/L; 48 hours) showed no significant effect on cell viability, apoptosis, and migration capacity. Insulin appears to cause hypertrophy of HTR8/SVneo cells as it reduces the cell mitotic index while increasing the culture protein content. The antiproliferative effect of insulin seems to involve activation of mammalian target of rapamycin, phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase. Finally, simvastatin and the polyphenol quercetin potentiated the antiproliferative effect of insulin; on the contrary, the polyphenol resveratrol, the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids, and folic acid were not able to change it. In conclusion, we show that insulin has an antiproliferative and hypertrophic effect on a first trimester extravillous human trophoblast cell line. So insulin might affect the process of placentation.

GRB 980425 host: [C II], [O I], and CO lines reveal recent enhancement of star formation due to atomic gas inflow

NASA Astrophysics Data System (ADS)

Michałowski, M. J.; Castro Cerón, J. M.; Wardlow, J. L.; Karska, A.; Messias, H.; van der Werf, P.; Hunt, L. K.; Baes, M.; Castro-Tirado, A. J.; Gentile, G.; Hjorth, J.; Le Floc'h, E.; Pérez-Martínez, R.; Nicuesa Guelbenzu, A.; Rasmussen, J.; Rizzo, J. R.; Rossi, A.; Sánchez-Portal, M.; Schady, P.; Sollerman, J.; Xu, D.

2016-11-01

Context. Accretion of gas from the intergalactic medium is required to fuel star formation in galaxies. We have recently suggested that this process can be studied using host galaxies of gamma-ray bursts (GRBs). Aims: Our aim is to test this possibility by studying in detail the properties of gas in the closest galaxy hosting a GRB (980425). Methods: We obtained the first ever far-infrared (FIR) line observations of a GRB host, namely Herschel/PACS resolved [C II] 158 μm and [O I] 63 μm spectroscopy, and an APEX/SHeFI CO(2-1) line detection and ALMA CO(1-0) observations of the GRB 980425 host. Results: The GRB 980425 host has elevated [C II]/FIR and [O I]/FIR ratios and higher values of star formation rates (SFR) derived from line ([C II], [O I], Hα) than from continuum (UV, IR, radio) indicators. [C II] emission exhibits a normal morphology, peaking at the galaxy centre, whereas [O I] is concentrated close to the GRB position and the nearby Wolf-Rayet region. The high [O I] flux indicates that there is high radiation field and high gas density at these positions, as derived from modelling of photo-dissociation regions. The [C II]/CO luminosity ratio of the GRB 980425 host is close to the highest values found for local star-forming galaxies. Indeed, its CO-derived molecular gas mass is low given its SFR and metallicity, but the [C II]-derived molecular gas mass is close to the expected value. Conclusions: The [O I] and H I concentrations and the high radiation field and density close to the GRB position are consistent with the hypothesis of a very recent (at most a few tens of Myr ago) inflow of atomic gas triggering star formation. In this scenario dust has not had time to build up (explaining high line-to-continuum ratios). Such a recent enhancement of star formation activity would indeed manifest itself in high SFRline/SFRcontinuum ratios because the line indicators are sensitive only to recent (≲10 Myr) activity, whereas the continuum indicators measure the SFR averaged over much longer periods ( 100 Myr). Within a sample of 32 other GRB hosts, 20 exhibit SFRline/SFRcontinuum> 1 with a mean ratio of 1.74 ± 0.32. This is consistent with a very recent enhancement of star formation that is common among GRB hosts, so galaxies that have recently experienced inflow of gas may preferentially host stars exploding as GRBs. Therefore GRBs may be used to select a unique sample of galaxies that is suitable for the investigation of recent gas accretion. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.

8-Methly-4-(3-diethylaminopropylamino) pyrimido [4',5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivate that causes ROS-mediated apoptosis in leukemia cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shenoy, Sudheer; Vasania, Viraf S.; Gopal, M.

2007-07-01

The present study reports the biological activity of 8-methly-4-(3-diethylamino-propylamino) pyrimido [4';5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivative structurally related to ellipticine and suggests a possible mechanism through which the compound induces apoptosis in carcinoma cell lines. Out of the 8 cell lines used in the study as representatives of different types of cancer, MDPTQ was found to be effective only against leukemia cell lines (HL-60 and K-562) whereas it had no effect on normal human bone marrow cells (BMC) which were used as controls. Fall mitochondrial membrane potential and increased reactive oxygen species (ROS) were mainly responsible for inducingmore » apoptosis in the two cell lines. Cell death was demonstrated by increase in caspase 3 activity as well as phosphatidyl serine exposure. Pre-incubation with N-acetylcysteine (NAC) reduced the increased ROS and caspase 3 activity as well as phosphatidyl serine exposure. MDPTQ also caused cell cycle arrest in these cell lines. The above study for the first time reports the mode of action of a quinoline derivative, which could be a possible future candidate for leukemia therapy. However, there are lot of questions that need to be answered in terms of signalling pathways and its effects on animal models.« less

Antiproliferative activity of synthetic fatty acid amides from renewable resources.

PubMed

dos Santos, Daiane S; Piovesan, Luciana A; D'Oca, Caroline R Montes; Hack, Carolina R Lopes; Treptow, Tamara G M; Rodrigues, Marieli O; Vendramini-Costa, Débora B; Ruiz, Ana Lucia T G; de Carvalho, João Ernesto; D'Oca, Marcelo G Montes

2015-01-15

In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line-the most aggressive CNS cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Investigation of a stripline transmission line structure for gyromagnetic nonlinear transmission line high power microwave sources.

PubMed

Reale, D V; Parson, J M; Neuber, A A; Dickens, J C; Mankowski, J J

2016-03-01

A stripline gyromagnetic nonlinear transmission line (NLTL) was constructed out of yttrium iron garnet ferrite and tested at charge voltages of 35 kV-55 kV with bias fields ranging from 10 kA/m to 20 kA/m. Typically, high power gyromagnetic NLTLs are constructed in a coaxial geometry. While this approach has many advantages, including a uniform transverse electromagnetic (TEM) mode, simple interconnection between components, and the ability to use oil or pressurized gas as an insulator, the coaxial implementation suffers from complexity of construction, especially when using a solid insulator. By moving to a simpler transmission line geometry, NLTLs can be constructed more easily and arrayed on a single substrate. This work represents a first step in exploring the suitability of various transmission line structures, such as microstrips and coplanar waveguides. The resulting high power microwave (HPM) source operates in ultra high frequency (UHF) band with an average bandwidth of 40.1% and peak rf power from 2 MW to 12.7 MW.

Investigation of a stripline transmission line structure for gyromagnetic nonlinear transmission line high power microwave sources

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reale, D. V., E-mail: david.reale@ttu.edu; Parson, J. M.; Neuber, A. A.

2016-03-15

A stripline gyromagnetic nonlinear transmission line (NLTL) was constructed out of yttrium iron garnet ferrite and tested at charge voltages of 35 kV–55 kV with bias fields ranging from 10 kA/m to 20 kA/m. Typically, high power gyromagnetic NLTLs are constructed in a coaxial geometry. While this approach has many advantages, including a uniform transverse electromagnetic (TEM) mode, simple interconnection between components, and the ability to use oil or pressurized gas as an insulator, the coaxial implementation suffers from complexity of construction, especially when using a solid insulator. By moving to a simpler transmission line geometry, NLTLs can be constructedmore » more easily and arrayed on a single substrate. This work represents a first step in exploring the suitability of various transmission line structures, such as microstrips and coplanar waveguides. The resulting high power microwave (HPM) source operates in ultra high frequency (UHF) band with an average bandwidth of 40.1% and peak rf power from 2 MW to 12.7 MW.« less

SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor.

PubMed

Rinaldi-Carmona, M; Barth, F; Millan, J; Derocq, J M; Casellas, P; Congy, C; Oustric, D; Sarran, M; Bouaboula, M; Calandra, B; Portier, M; Shire, D; Brelière, J C; Le Fur, G L

1998-02-01

Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.

Immortal, telomerase-negative cell lines derived from a Li-Fraumeni syndrome patient exhibit telomere length variability and chromosomal and minisatellite instabilities.

PubMed

Tsutsui, Takeki; Kumakura, Shin-Ichi; Tamura, Yukiko; Tsutsui, Takeo W; Sekiguchi, Mizuki; Higuchi, Tokihiro; Barrett, J Carl

2003-05-01

Five immortal cell lines derived from a Li-Fraumeni syndrome patient (MDAH 087) with a germline mutant p53 allele were characterized with respect to telomere length and genomic instability. The remaining wild-type p53 allele is lost in the cell lines. Telomerase activity was undetectable in all immortal cell lines. Five subclones of each cell line and five re-subclones of each of the subclones also showed undetectable telomerase activity. All five immortal cell lines exhibited variability in the mean length of terminal restriction fragments (TRFs). Subclones of each cell line, and re-subclones of the subclones also showed TRF variability, indicating that the variability is owing to clonal heterogeneity. Chromosome aberrations were observed at high frequencies in these cell lines including the subclones and re-subclones, and the principal types of aberrations were breaks, double minute chromosomes and dicentric chromosomes. In addition, minisatellite instability detected by DNA fingerprints was observed in the immortal cell lines. However, all of the cell lines were negative for microsatellite instability. As minisatellite sequences are considered recombinogenic in mammalian cells, these results suggest that recombination rates can be increased in these cell lines. Tumor-derived human cell lines, HT1080 cells and HeLa cells that also lack p53 function, exhibited little genomic instability involving chromosomal and minisatellite instabilities, indicating that chromosomal and minisatellite instabilities observed in the immortal cell lines lacking telomerase activity could not result from loss of p53 function.

A new pregnane glycoside from Rubus phoenicolasius and its antiproliferative activity.

PubMed

Liu, Chao; Liao, Zhi-Xin; Liu, Shi-Jun; Sun, Jin-Yue; Yao, Gui-Yang; Wang, Heng-Shan

2014-01-01

Chemical investigations of the whole plant ethanol extract of Rubus phoenicolasius led to the isolation and identification of a new pregnane glycoside, 3-O-β-glucopyranosyl-3β,15β-dihydroxypregn-5-en-20-one (1), along with other nine known compounds (2-10). All the isolates were reported from this plant for the first time. The structure of compound 1 was determined by detailed analysis of its spectral data including 1D and 2D NMR. In vitro anti-proliferative activities of compounds 1-3 on MCF-7 and NCI-H460 tumour cell lines were evaluated, and compound 1 was active against the two cell lines with IC50 values of 15.6 and 13.5 μM, respectively.

Biflorin: an o-naphthoquinone of clinical significance.

PubMed

Wisintainer, Gabrielle G N S; Simões, Evelyne R B; Lemos, Telma L G; Moura, Sidnei; Souza, Luciana G S; Fonseca, Aluisio M; Moraes, Manoel Odorico; Pessoa, Claudia; Roesch-Ely, Mariana; Henriques, João A P

2014-12-01

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule.

Biflorin: an o-naphthoquinone of clinical significance.

PubMed

Wisintainer, Gabrielle G N S; Simões, Evelyne R B; Lemos, Telma L G; Moura, Sidnei; Souza, Luciana G S; Fonseca, Aluisio M; Moraes, Manoel Odorico; Pessoa, Claudia; Roesch-Ely, Mariana; Henriques, João A P

2014-10-14

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule.

Rapid screening and identification of antioxidants in the leaves of Malus hupehensis using off-line two-dimensional HPLC-UV-MS/MS coupled with a 1,1'-diphenyl-2-picrylhydrazyl assay.

PubMed

Liu, Minzhuo; Huang, Xueqian; Liu, Qi; Chen, Miao; Liao, Sen; Zhu, Fawei; Shi, Shuyun; Yang, Hua; Chen, Xiaoqing

2018-04-17

The leaves of Malus hupehensis have a strong antioxidant activity and are commonly consumed as a healthy tea. However, detailed information about its antioxidants is incomplete. Herein, we developed an effective strategy based on combining off-line two-dimensional high-performance liquid chromatography with ultraviolet and tandem mass spectrometry detection with a 1,1'-diphenyl-2-picrylhydrazyl assay to rapidly screen and identify the antioxidants from the leaves of M. hupehensis. In the orthogonal two-dimensional liquid chromatography system, a Venusil HILIC column was used for the first dimension, while a Universil XB-C 18 column was installed in the second dimension. As a result, 32 antioxidants, including ten dihydrochalcones, two flavanones, nine flavonols, four flavones, and seven phenolic acids were tentatively identified, out of which 23 compounds, as far as we know, were isolated and characterized from the leaves of M. hupehensis for the first time. To the best of our knowledge, this is the first systematic investigation of the antioxidants from the leaves of M. hupehensis. The results indicated that the proposed method is an efficient technique to rapidly investigate antioxidants, especially for coeluted and minor compounds in a complex system. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Prioritizing molecular markers to test for in the initial workup of advanced non-small cell lung cancer: wants versus needs.

PubMed

West, Howard

2017-09-01

The current standard of care for molecular marker testing in patients with advanced non-small cell lung cancer (NSCLC) has been evolving over several years and is a product of the quality of the evidence supporting a targeted therapy for a specific molecular marker, the pre-test probability of that marker in the population, and the magnitude of benefit seen with that treatment. Among the markers that have one or more matched targeted therapies, only a few are in the subset for which they should be considered as most clearly worthy of prioritizing to detect in the first line setting in order to have them supplant other first line alternatives, and in only a subset of patients, as defined currently by NSCLC histology. Specifically, this currently includes testing for an activating epidermal growth factor receptor ( EGFR ) mutation or an anaplastic lymphoma kinase ( ALK ) or ROS1 rearrangement. This article reviews the history and data supporting the prioritization of these markers in patients with non-squamous NSCLC, a histologically selected population in whom the probability of these markers combined with the anticipated efficacy of targeted therapies against them is high enough to favor these treatments in the first line setting. In reviewing the evidence supporting this very limited core subset of most valuable molecular markers to detect in the initial workup of such patients, we can also see the criteria by which other actionable markers need to reach in order to be widely recognized as reliably valuable enough to warrant prioritization to detect in the initial workup of advanced NSCLC as well.

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

PubMed

Moiseyenko, Vladimir M; Moiseyenko, Fedor V; Yanus, Grigoriy A; Kuligina, Ekatherina Sh; Sokolenko, Anna P; Bizin, Ilya V; Kudriavtsev, Alexey A; Aleksakhina, Svetlana N; Volkov, Nikita M; Chubenko, Vyacheslav A; Kozyreva, Kseniya S; Kramchaninov, Mikhail M; Zhuravlev, Alexandr S; Shelekhova, Kseniya V; Pashkov, Denis V; Ivantsov, Alexandr O; Venina, Aigul R; Sokolova, Tatyana N; Preobrazhenskaya, Elena V; Mitiushkina, Natalia V; Togo, Alexandr V; Iyevleva, Aglaya G; Imyanitov, Evgeny N

2018-06-01

Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. Nineteen patients were prospectively included in the study. Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

Power line identification of millimeter wave radar based on PCA-GS-SVM

NASA Astrophysics Data System (ADS)

Fang, Fang; Zhang, Guifeng; Cheng, Yansheng

2017-12-01

Aiming at the problem that the existing detection method can not effectively solve the security of UAV's ultra low altitude flight caused by power line, a power line recognition method based on grid search (GS) and the principal component analysis and support vector machine (PCA-SVM) is proposed. Firstly, the candidate line of Hough transform is reduced by PCA, and the main feature of candidate line is extracted. Then, upport vector machine (SVM is) optimized by grid search method (GS). Finally, using support vector machine classifier optimized parameters to classify the candidate line. MATLAB simulation results show that this method can effectively identify the power line and noise, and has high recognition accuracy and algorithm efficiency.

Serious play: A comparative study of engagement and learning in hobby practices

NASA Astrophysics Data System (ADS)

Azevedo, Flavio Saraiva

This dissertation is concerned with human behavior usually attributed to individual interests. As conceptualized in experimental and educational psychology, an individual interest refers to a particular relationship (called an interest relationship) between a person and a set of topically related activities. Interest relationships are self-motivated, long-term, and relatively stable, though they might change over time. As an example, a teenager's enduring and self-motivated involvement with model rocketry reflects her individual interest in the topic or domain of rocketry. As an alternative to this formulation, I develop a practice-centered theory of persistent engagement---or, simply, a theory of persistence---in free-choice, self-motivated practices. Taken together, self-motivated, long-term persistence in a free-choice practice refers exactly to the same set of phenomena that is the purview of psychological theories of individual interests. Hobbies are prototypic of free-choice, self-motivated, extended pursuit practices and therefore are the focal object of study of this dissertation. The centerpiece of the theory I put forward is the grounded theoretical concept of lines of practice. A line of practice is a distinctive, recurrent pattern of engagement in a person's continued pursuit of a hobby. To return to the example above, our rocketry buff might have three lines of practice in her hobby---one related to designing and flying unusual rockets, the other related to designing and flying high-powered rockets, and yet a third line concerned with designing and flying low-powered models. Any particular line of practice entails a set of closely interrelated activities. For instance, designing and flying high-powered rockets might entail visiting particular hobby stores, becoming a member of particular rocketry clubs, and engaging in construction work. Designing and flying unusual rockets, on the other hand, might entail some very different activities (e.g., continuously searching for unusual materials that can be transformed into rockets), as well as activities that cross line boundaries (e.g., construction work). The "essence" that runs through a set of closely related activities is what defines a line of practice. Such an "essence" is determined by two structural elements. The first element is the preferences that a hobbyist brings to bear on her practice. Preferences refer to psychological constructs such as goals, beliefs, values, and so forth. Our hypothetical subject's line of unusual rockets might reflect her need to fashion an identity as a competent practitioner and her love of design and construction. The second structural element refers to the conditions of practice impinging on the persons hobby. Conditions of practice include such things as the material infrastructure available to the practitioner (e.g., tools for working rocket parts), the immediate circumstances of the hobbyist's life (e.g., the person's socio-economic status and whether or not the person has easy access to practice sites), the rules of practice adopted by a hobby community (e.g., the maximum ceiling for rocket flights), the larger socio-cultural space in which the hobby exists (e.g., the availability of hobby stores), and so on. Each of these factors, and the many sub-factors included therein, may be seen to provide constraints and affordances for practice. I illustrate the theory with a comparative study of two hobby practices with techno-scientific underpinnings---model rocketry and amateur astronomy. The empirical base of the work is a series of ethnographic video records of two focal subjects, one for each hobby practice. (Abstract shortened by UMI.)

Probing Pre-Galactic Metal Enrichment with High-Redshift Gamma-Ray Bursts

NASA Technical Reports Server (NTRS)

Wang, F. Y.; Bromm, Volker; Greif, Thomas H.; Stacy, Athena; Dai, Z. G.; Loeb, Abraham; Cheng, K. S.

2012-01-01

We explore high-redshift gamma-ray bursts (GRBs) as promising tools to probe pre-galactic metal enrichment. We utilize the bright afterglow of a Population III (Pop III) GRB exploding in a primordial dwarf galaxy as a luminous background source, and calculate the strength of metal absorption lines that are imprinted by the first heavy elements in the intergalactic medium (IGM). To derive the GRB absorption line diagnostics, we use an existing highly resolved simulation of the formation of a first galaxy which is characterized by the onset of atomic hydrogen cooling in a halo with virial temperature approximately greater than10(exp 4) K.We explore the unusual circumburst environment inside the systems that hosted Pop III stars, modeling the density evolution with the self-similar solution for a champagne flow. For minihalos close to the cooling threshold, the circumburst density is roughly proportional to (1 + z) with values of about a few cm(exp -3). In more massive halos, corresponding to the first galaxies, the density may be larger, n approximately greater than100 cm(exp -3). The resulting afterglow fluxes are weakly dependent on redshift at a fixed observed time, and may be detectable with the James Webb Space Telescope and Very Large Array in the near-IR and radio wavebands, respectively, out to redshift z approximately greater than 20. We predict that the maximum of the afterglow emission shifts from near-IR to millimeter bands with peak fluxes from mJy to Jy at different observed times. The metal absorption line signature is expected to be detectable in the near future. GRBs are ideal tools for probing the metal enrichment in the early IGM, due to their high luminosities and featureless power-law spectra. The metals in the first galaxies produced by the first supernova (SN) explosions are likely to reside in low-ionization stages (C II, O I, Si II and Fe II). We show that, if the afterglow can be observed sufficiently early, analysis of the metal lines may distinguish whether the first heavy elements were produced in a pair-instability supernova or a core-collapse (Type II) SN, thus constraining the initial mass function of the first stars.

[Diagnostic and Therapeutic Approach of Chronic Spontaneous Urticaria: Recommendations in Portugal].

PubMed

Costa, Célia; Gonçalo, Margarida

2016-11-01

Chronic spontaneous urticaria is a complex disorder, of unclear etiology, easily diagnosed although often difficult to treat. It has a significant impact on the patients' quality of life and results in high direct and indirect costs. The diagnosis of chronic spontaneous urticaria is mainly clinical and a limited number of tests is recommended for differential diagnosis and/or for the investigation/exclusion of possible causes. In addition to the complete blood count and C-reactive protein, and/or erythrocyte sedimentation rate, additional tests must be selected according to clinical criteria. The aim of therapy is the complete clinical control of chronic spontaneous urticaria. Evolution should be documented by weekly symptom scoring - Weekly Urticaria Activity Score (UAS7) -, as well as the assessment of quality of life. The therapeutic approach is based on second-generation H1 antihistamines (anti-H1) administered continuously in the approved doses (first line), and, in the absence of a clinical response, up to four times the daily-approved dose (second line). First generation H1 antihistamines are not recommended. Approximately 30% of patients are not controlled with second line therapy, and it is recommended to add a third line therapy. Of the two options, omalizumab and cyclosporine, only omalizumab is approved for chronic spontaneous urticaria and has a better safety profile, thus being preferably recommended. In Portugal there are no national-based recommendations applicable to clinical practice. The elaboration of these recommendations is justified by the need to standardize both the diagnosis and the treatment approach of patients with chronic spontaneous urticaria in Portugal, and for the referral of patients to specialized centers, in the most severe cases.

Radio-Loud Narrow-Line Seyfert 1 as a New Class of Gamma-Ray Active Galactic Nuclei

DOE PAGES

Abdo, A. A.; Ackermann, M.; Ajello, M.; ...

2009-12-04

In this work, we report the discovery with Fermi/LAT of γ-ray emission from three radio-loud narrow-line Seyfert 1 galaxies: PKS 1502+036 (z = 0.409), 1H 0323+342 (z = 0.061), and PKS 2004 – 447 (z = 0.24). In addition to PMN J0948+0022 (z = 0.585), the first source of this type to be detected in γ rays, they may form an emerging new class of γ-ray active galactic nuclei (AGNs). Lastly, these findings can have strong implications on our knowledge about relativistic jets and the unified model of the AGN.

Monitoring proton radiation therapy with in-room PET imaging

NASA Astrophysics Data System (ADS)

Zhu, Xuping; España, Samuel; Daartz, Juliane; Liebsch, Norbert; Ouyang, Jinsong; Paganetti, Harald; Bortfeld, Thomas R.; El Fakhri, Georges

2011-07-01

We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of 15O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary.

In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

PubMed Central

Plouffe, David; Brinker, Achim; McNamara, Case; Henson, Kerstin; Kato, Nobutaka; Kuhen, Kelli; Nagle, Advait; Adrián, Francisco; Matzen, Jason T.; Anderson, Paul; Nam, Tae-gyu; Gray, Nathanael S.; Chatterjee, Arnab; Janes, Jeff; Yan, S. Frank; Trager, Richard; Caldwell, Jeremy S.; Schultz, Peter G.; Zhou, Yingyao; Winzeler, Elizabeth A.

2008-01-01

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈1.7 million compounds, we identified a diverse collection of ≈6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 μM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities. PMID:18579783

Geotail Measurements Compared with the Motions of High-Latitude Auroral Boundaries during Two Substorms

NASA Technical Reports Server (NTRS)

Maynard, N. C.; Burke, W. J.; Erickson, G. M.; Nakamura, M.; Mukai, T.; Kokubun, S.; Yamamoto, T.; Jacobsen, B.; Egeland, A.; Samson, J. C.;

ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure

PubMed Central

Marum, Justine E.; Yeung, David T.; Purins, Leanne; Reynolds, John; Parker, Wendy T.; Stangl, Doris; Wang, Paul P. S.; Price, David J.; Tuke, Jonathan; Schreiber, Andreas W.; Scott, Hamish S.; Hughes, Timothy P.

2017-01-01

Scoring systems used at diagnosis of chronic myeloid leukemia (CML), such as Sokal risk, provide important response prediction for patients treated with imatinib. However, the sensitivity and specificity of scoring systems could be enhanced for improved identification of patients with the highest risk. We aimed to identify genomic predictive biomarkers of imatinib response at diagnosis to aid selection of first-line therapy. Targeted amplicon sequencing was performed to determine the germ line variant profile in 517 and 79 patients treated with first-line imatinib and nilotinib, respectively. The Sokal score and ASXL1 rs4911231 and BIM rs686952 variants were independent predictors of early molecular response (MR), major MR, deep MRs (MR4 and MR4.5), and failure-free survival (FFS) with imatinib treatment. In contrast, the ASXL1 and BIM variants did not consistently predict MR or FFS with nilotinib treatment. In the imatinib-treated cohort, neither Sokal or the ASXL1 and BIM variants predicted overall survival (OS) or progression to accelerated phase or blast crisis (AP/BC). The Sokal risk score was combined with the ASXL1 and BIM variants in a classification tree model to predict imatinib response. The model distinguished an ultra-high-risk group, representing 10% of patients, that predicted inferior OS (88% vs 97%; P = .041), progression to AP/BC (12% vs 1%; P = .034), FFS (P < .001), and MRs (P < .001). The ultra-high-risk patients may be candidates for more potent or combination first-line therapy. These data suggest that germ line genetic variation contributes to the heterogeneity of response to imatinib and may contribute to a prognostic risk score that allows early optimization of therapy. PMID:29296778

Empowerment and performance of managers and subordinates in elderly care: A longitudinal and multilevel study.

PubMed

Hagerman, Heidi; Högberg, Hans; Skytt, Bernice; Wadensten, Barbro; Engström, Maria

2017-11-01

To investigate relationships between first-line managers' ratings of structural and psychological empowerment, and the subordinates' ratings of structural empowerment, as well as their ratings of the managers' leadership-management performance. Work situations in elderly care are complex. To date, few studies have used a longitudinal, correlational and multilevel design to study the working life of subordinates and managers. In five Swedish municipalities, questionnaires were answered twice during 2010-12 by 56 first-line managers and 769 subordinates working in nursing homes or home-help services. First-line managers' empowerment at Time 1 partially predicted subordinate's structural empowerment and ratings of their managers' leadership-management performance at Time 2. Changes over time partially revealed that the more access managers had to structural empowerment, i.e. increase over time, the higher the ratings were for structural empowerment and managerial leadership-management performance among subordinates. Findings strengthen research and theoretical suggestions linking first-line managers' structural empowerment to their subordinates' structural empowerment and ratings of their manager's leadership-management performance. Managers with high access to structural empowerment are more likely to provide subordinates access to structural empowerment. © 2017 The Authors. Journal of Nursing Management Published by John Wiley & Sons Ltd.

Delta-configurations - Flare activity and magnetic-field structure

NASA Technical Reports Server (NTRS)

Patty, S. R.; Hagyard, M. J.

1986-01-01

Complex sunspots in four active regions of April and May 1980, all exhibiting regions of magnetic classification delta, were studied using data from the NASA Marshall Space Flight Center vector magnetograph. The vector magnetic field structure in the vicinity of each delta was determined, and the location of the deltas in each active region was correlated with the locations and types of flare activity for the regions. Two types of delta-configuration were found to exist, active and inactive, as defined by the relationships between magnetic field structure and activity. The active delta exhibited high flare activity, strong horizontal gradients of the longitudinal (line-of-sight) magnetic field component, a strong transverse (perpendicular to line-of-sight) component, and a highly nonpotential orientation of the photospheric magnetic field, all indications of a highly sheared magnetic field. The inactive delta, on the other hand, exhibited little or no flare production, weaker horizontal gradients of the longitudinal component, weaker transverse components, and a nearly potential, nonsheared orientation of the magnetic field. It is concluded that the presence of such sheared fields is the primary signature by which the active delta may be distinguished, and that it is this shear which produces the flare activity of the active delta.

Low temperature delays timing and enhances the cost of nitrogen fixation in the unicellular cyanobacterium Cyanothece

PubMed Central

Brauer, Verena S; Stomp, Maayke; Rosso, Camillo; van Beusekom, Sebastiaan AM; Emmerich, Barbara; Stal, Lucas J; Huisman, Jef

2013-01-01

Marine nitrogen-fixing cyanobacteria are largely confined to the tropical and subtropical ocean. It has been argued that their global biogeographical distribution reflects the physiologically feasible temperature range at which they can perform nitrogen fixation. In this study we refine this line of argumentation for the globally important group of unicellular diazotrophic cyanobacteria, and pose the following two hypotheses: (i) nitrogen fixation is limited by nitrogenase activity at low temperature and by oxygen diffusion at high temperature, which is manifested by a shift from strong to weak temperature dependence of nitrogenase activity, and (ii) high respiration rates are required to maintain very low levels of oxygen for nitrogenase, which results in enhanced respiratory cost per molecule of fixed nitrogen at low temperature. We tested these hypotheses in laboratory experiments with the unicellular cyanobacterium Cyanothece sp. BG043511. In line with the first hypothesis, the specific growth rate increased strongly with temperature from 18 to 30 °C, but leveled off at higher temperature under nitrogen-fixing conditions. As predicted by the second hypothesis, the respiratory cost of nitrogen fixation and also the cellular C:N ratio rose sharply at temperatures below 21 °C. In addition, we found that low temperature caused a strong delay in the onset of the nocturnal nitrogenase activity, which shortened the remaining nighttime available for nitrogen fixation. Together, these results point at a lower temperature limit for unicellular nitrogen-fixing cyanobacteria, which offers an explanation for their (sub)tropical distribution and suggests expansion of their biogeographical range by global warming. PMID:23823493

Chromospherically Active Stars in the RAdial Velocity Experiment (RAVE) Survey. I. The Catalog

NASA Astrophysics Data System (ADS)

Žerjal, M.; Zwitter, T.; Matijevič, G.; Strassmeier, K. G.; Bienaymé, O.; Bland-Hawthorn, J.; Boeche, C.; Freeman, K. C.; Grebel, E. K.; Kordopatis, G.; Munari, U.; Navarro, J. F.; Parker, Q. A.; Reid, W.; Seabroke, G.; Siviero, A.; Steinmetz, M.; Wyse, R. F. G.

2013-10-01

RAVE, the unbiased magnitude limited survey of southern sky stars, contained 456,676 medium-resolution spectra at the time of our analysis. Spectra cover the Ca II infrared triplet (IRT) range, which is a known indicator of chromospheric activity. Our previous work classified all spectra using locally linear embedding. It identified 53,347 cases with a suggested emission component in calcium lines. Here, we use a spectral subtraction technique to measure the properties of this emission. Synthetic templates are replaced by the observed spectra of non-active stars to bypass the difficult computations of non-local thermal equilibrium profiles of the line cores and stellar parameter dependence. We derive both the equivalent width of the excess emission for each calcium line on a 5 Å wide interval and their sum EWIRT for ~44,000 candidate active dwarf stars with signal-to-noise ratio >20, with no cuts on the basis of the source of their emission flux. From these, ~14,000 show a detectable chromospheric flux with at least a 2σ confidence level. Our set of active stars vastly enlarges previously known samples. Atmospheric parameters and, in some cases, radial velocities of active stars derived from automatic pipelines suffer from systematic shifts due to their shallower calcium lines. We re-estimate the effective temperature, metallicity, and radial velocities for candidate active stars. The overall distribution of activity levels shows a bimodal shape, with the first peak coinciding with non-active stars and the second with the pre-main-sequence cases. The catalog will be made publicly available with the next RAVE public data releases.

Evidence on anti-malarial and diagnostic markets in Cambodia to guide malaria elimination strategies and policies.

PubMed

Phok, Sochea; Lek, Dysoley

2017-04-25

Understanding Cambodia's anti-malarial and diagnostic landscape in 2015 is critical for informing and monitoring strategies and policies as Cambodia moves forward with national efforts to eliminate malaria. The aim of this paper is to present timely and key findings on the public and private sector anti-malarial and diagnostic landscape in Cambodia. This evidence can serve as a baseline benchmark for guiding implementation of national strategies as well as other regional initiatives to address malaria elimination activities. From August 17th to October 1st, 2015, a cross sectional, nationally-representative malaria outlet survey was conducted in Cambodia. A census of all public and private outlets with potential to distribute malaria testing and/or treatment was conducted among 180 communes. An audit was completed for all anti-malarials, malaria rapid diagnostic tests (RDT) and microscopy. A total of 26,664 outlets were screened, and 1303 outlets were eligible and interviewed. Among all screened outlets in the public sector, 75.9% of public health facilities and 67.7% of community health workers stocked both malaria diagnostic testing and a first-line artemisinin-based combination therapy (ACT). Among anti-malarial-stocking private sector outlets, 64.7% had malaria blood testing available, and 70.9% were stocking a first-line ACT. Market share data illustrate that most of the anti-malarials were sold or distributed through the private sector (58.4%), including itinerant drug vendors (23.4%). First-line ACT accounted for the majority of the market share across the public and private sectors (90.3%). Among private sector outlets stocking any anti-malarial, the proportion of outlets with a first-line ACT or RDT was higher among outlets that had reportedly received one or more forms of 'support' (e.g. reportedly received training in the previous year on malaria diagnosis [RDT and/or microscopy] and/or the national treatment guidelines for malaria) compared to outlets that did not report receiving any support (ACT: 82.1 and 60.6%, respectively; RDT: 78.2 and 64.0%, respectively). The results point to high availability and distribution of first-line ACT and widespread availability of malaria diagnosis, especially in the public sector. This suggests that there is a strong foundation for achieving elimination goals in Cambodia. However, key gaps in terms of availability of malaria commodities for case management must be addressed, particularly in the private sector where most people seek treatment. Continued engagement with the private sector will be important to ensure accelerated progress towards malaria elimination.

Focus on Alectinib and Competitor Compounds for Second-Line Therapy in ALK-Rearranged NSCLC

PubMed Central

Tran, Phu N.; Klempner, Samuel J.

2016-01-01

The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK kinase domain. Alectinib is a second-generation ALK inhibitor capable of overcoming multiple crizotinib-resistant ALK mutations and has demonstrated improved outcomes after crizotinib failure. Favorable toxicity profile and improved intracranial activity have spurred ongoing front-line trials and comparisons to other ALK inhibitors. However, important questions regarding comparability to competitor compounds, acquired alectinib resistance, and ALK inhibitor sequencing remain. Here, we review the key clinical data supporting alectinib in the second-line therapy of ALK+ NSCLC and provide context in comparison to other ALK inhibitors in development. PMID:27965961

Focus on Alectinib and Competitor Compounds for Second-Line Therapy in ALK-Rearranged NSCLC.

PubMed

Tran, Phu N; Klempner, Samuel J

2016-01-01

The management of anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) exemplifies the potential of a precision medicine approach to cancer care. The ALK inhibitor crizotinib has led to improved outcomes in the first- and second-line setting; however, toxicities, intracranial activity, and acquired resistance necessitated the advent of later generation ALK inhibitors. A large portion of acquired resistance to ALK inhibitors is caused by secondary mutations in the ALK kinase domain. Alectinib is a second-generation ALK inhibitor capable of overcoming multiple crizotinib-resistant ALK mutations and has demonstrated improved outcomes after crizotinib failure. Favorable toxicity profile and improved intracranial activity have spurred ongoing front-line trials and comparisons to other ALK inhibitors. However, important questions regarding comparability to competitor compounds, acquired alectinib resistance, and ALK inhibitor sequencing remain. Here, we review the key clinical data supporting alectinib in the second-line therapy of ALK+ NSCLC and provide context in comparison to other ALK inhibitors in development.

A Resource Guide for the Maryland Plan's Group Project and Line Production.

ERIC Educational Resources Information Center

Day, Gerald F.

This guide was developed for teachers who are using the Maryland Plan's group processes--the group project and line production methods. The guide is divided into four sections. The first section is an overview of the entire Maryland Plan. It describes the program which provides high school industrial arts students, from seventh grade through ninth…