939 research outputs found
Preclinical antitumour activity of F 11782, a novel dual catalytic inhibitor of topoisomerases
F 11782 is a novel inhibitor of topoisomerases I and II, with an original mechanism of action (Perrin et al, 2000). This study, aimed to define its anticancer efficacy against a series of murine and human tumour models, has provided evidence of major antitumour activity for F 11782. This was demonstrated as a high level of activity against the P388 leukaemia, as reflected by increased survival of 143–457%, when administered i.p., p.o. or i.v. as single or multiple doses, and proved consistently superior to etoposide or camptothecin tested concurrently. Single or multiple i.p. doses of F 11782 also proved highly active against the s.c. grafted B16 melanoma, significantly increasing survival (P < 0.001) and inhibiting tumour growth (T/C of 0.3%), again superior to etoposide tested concurrently. Furthermore, F 11782 inhibited the number of pulmonary metastatic foci of the B16F10 melanoma by 99%. In human tumour xenograft studies, multiple i.p. doses of F 11782 resulted in major inhibitory activity against MX-1 (breast) tumours (T/C of 0.1%), as well as causing definite tumour regressions, whereas none resulted from similar experimental treatments with etoposide. Significant activity was also recorded with F 11782 against the relatively refractory LX-1 (lung) xenografts, with an optimal T/C value of 19%. It was notable that the antitumour activity of F 11782 was consistently demonstrated over a wide range of 2–6 dose levels, providing evidence of its good overall tolerance. In conclusion, these results emphasize the preclinical interest of this novel molecule and support its further preclinical development. © 2000 Cancer Research Campaign http://www.bjcancer.co
The Search for Stellar Companions to Exoplanet Host Stars Using the CHARA Array
Most exoplanets have been discovered via radial velocity studies, which are
inherently insensitive to orbital inclination. Interferometric observations
will show evidence of a stellar companion if it sufficiently bright, regardless
of the inclination. Using the CHARA Array, we observed 22 exoplanet host stars
to search for stellar companions in low-inclination orbits that may be
masquerading as planetary systems. While no definitive stellar companions were
discovered, it was possible to rule out certain secondary spectral types for
each exoplanet system observed by studying the errors in the diameter fit to
calibrated visibilities and by searching for separated fringe packets.Comment: 26 pages, 5 tables, 8 figure
Applicability and precautions of use of liver injury biomarker FibroTest. A reappraisal at 7 years of age
<p>Abstract</p> <p>Background</p> <p>FibroTest (FT) is a validated biomarker of fibrosis. To assess the applicability rate and to reduce the risk of false positives/negatives (RFPN), security algorithms were developed. The aims were to estimate the prevalence of RFPN and of proven failures, and to identify factors associated with their occurrences.</p> <p>Methods</p> <p>Four populations were studied: 954 blood donors (P1), 7,494 healthy volunteers (P2), 345,695 consecutive worldwide sera (P3), including 24,872 sera analyzed in a tertiary care centre (GHPS) (P4). Analytical procedures of laboratories with RFPN > 5% and charts of P4 patients in with RFPN were reviewed.</p> <p>Results</p> <p>The prevalence of RFPN was 0.52% (5/954; 95%CI 0.17-1.22) in P1, 0.51% (38/7494; 0.36-0.70) in P2, and 0.97% (3349/345695; 0.94-1.00) in P3. Three a priori high-risk populations were confirmed: 1.97% in P4, 1.77% in HIV centre and 2.61% in Sub-Saharan origin subjects. RFPN was mostly associated with low haptoglobin (0.46%), and high apolipoproteinA1 (0.21%). A traceability study of a P3 laboratory with RFPFN > 5% permitted to correct analytical procedures.</p> <p>Conclusion</p> <p>The mean applicability rate of Fibrotest was 99.03%. Independent factors associated with the high risk of false positives/negatives were HIV center, subSaharan origin, and a tertiary care reference centre, although the applicability rate remained above 97%.</p
Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia
This is the final version. Available on open access from Elsevier via the DOI in this recordThe delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine5-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.The UK Engineering and Physical Sciences Research Council(EP/K502340/1), Nanomerics Ltd.(NM12TSB-NPP) and Innovate UK(16939-124181) are acknowledged for funding
Calibrating the Cepheid Period-Luminosity relation from the infrared surface brightness technique I. The p-factor, the Milky Way relations, and a universal K-band relation
We determine Period-Luminosity relations for Milky Way Cepheids in the
optical and near-IR bands. These relations can be used directly as reference
for extra-galactic distance determination to Cepheid populations with solar
metallicity, and they form the basis for a direct comparison with relations
obtained in exactly the same manner for stars in the Magellanic Clouds,
presented in an accompanying paper. In that paper we show that the metallicity
effect is very small and consistent with a null effect, particularly in the
near-IR bands, and we combine here all 111 Cepheids from the Milky Way, the LMC
and SMC to form a best relation. We employ the near-IR surface brightness
(IRSB) method to determine direct distances to the individual Cepheids after we
have recalibrated the projection factor using the recent parallax measurements
to ten Galactic Cepheids and the constraint that Cepheid distances to the LMC
should be independent of pulsation period. We confirm our earlier finding that
the projection factor for converting radial velocity to pulsational velocity
depends quite steeply on pulsation period, p=1.550-0.186*log(P) in disagrement
with recent theoretical predictions. We delineate the Cepheid PL relation using
111 Cepheids with direct distances from the IRSB analysis. The relations are by
construction in agreement with the recent HST parallax distances to Cepheids
and slopes are in excellent agreement with the slopes of apparent magnitudes
versus period observed in the LMC.Comment: Accepted for publication by Astronomy and Astrophysics. 15 pages, 11
figure
Ruling Out Possible Secondary Stars to Exoplanet Host Stars Using the CHARA Array
Of the over 450 exoplanets known to date, more than 420 of them have been
discovered using radial velocity studies, a method that tells nothing about the
inclination of the planet's orbit. Because it is more likely that the companion
is a planetary-mass object in a moderate- to high-inclination orbit than a
low-mass stellar object in a nearly face-on orbit, the secondary bodies are
presumed to be planets. Interferometric observations allow us to inspect the
angular diameter fit residuals to calibrated visibilities in order to rule out
the possibility of a low-mass stellar companion in a very low-inclination
orbit. We used the Center for High Angular Resolution Astronomy (CHARA) Array
interferometer to observe 20 exoplanet host stars and considered five potential
secondary spectral types: G5 V, K0 V, K5 V, M0 V, and M5 V. If a secondary star
is present and is sufficiently bright, the effects of the added light will
appear in interferometric observations where the planet will not. All secondary
types could be eliminated from consideration for 7 host stars and no secondary
stars of any spectral type could be ruled out for 7 more. The remaining 6 host
stars showed a range of possible secondary types.Comment: Accepted for publication in the Astronomical Journa
Magnetic Interactions and Transport in (Ga,Cr)As
The magnetic, transport, and structural properties of (Ga,Cr)As are reported.
Zincblende GaCrAs was grown by low-temperature molecular beam
epitaxy (MBE). At low concentrations, x0.1, the materials exhibit unusual
magnetic properties associated with the random magnetism of the alloy. At low
temperatures the magnetization M(B) increases rapidly with increasing field due
to the alignment of ferromagnetic units (polarons or clusters) having large
dipole moments of order 10-10. A standard model of
superparamagnetism is inadequate for describing both the field and temperature
dependence of the magnetization M(B,T). In order to explain M(B) at low
temperatures we employ a distributed magnetic moment (DMM) model in which
polarons or clusters of ions have a distribution of moments. It is also found
that the magnetic susceptibility increases for decreasing temperature but
saturates below T=4 K. The inverse susceptibility follows a linear-T
Curie-Weiss law and extrapolates to a magnetic transition temperature
=10 K. In magnetotransport measurements, a room temperature resistivity
of =0.1 cm and a hole concentration of cm
are found, indicating that Cr can also act as a acceptor similar to Mn. The
resistivity increases rapidly for decreasing temperature below room
temperature, and becomes strongly insulating at low temperatures. The
conductivity follows exp[-(T/T)] over a large range of
conductivity, possible evidence of tunneling between polarons or clusters.Comment: To appear in PRB 15 Mar 200
Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease
BACKGROUND: Liver biopsy is considered as the gold standard for assessing non-alcoholic fatty liver disease (NAFLD) histologic lesions. The aim of this study was to determine the diagnostic utility of non-invasive markers of fibrosis, validated in chronic viral hepatitis and alcoholic liver disease (FibroTest, FT), in patients with NAFLD. METHODS: 170 patients with suspected NAFLD were prospectively included in a reference center (Group 1), 97 in a multicenter study (Group 2) and 954 blood donors as controls. Fibrosis was assessed on a 5 stage histological scale validated by Kleiner et al from F0 = none, F1 = perisinusoidal or periportal, F2 = perisinusoidal and portal/periportal, F3 = bridging and F4 = cirrhosis. Histology and the biochemical measurements were blinded to any other characteristics. The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV, NPV) were assessed. RESULTS: In both groups FT has elevated and not different AUROCs for the diagnosis of advanced fibrosis (F2F3F4): 0.86 (95%CI 0.77–0.91) versus 0.75 (95%CI 0.61–0.83; P = 0.10), and for F3F4: 0.92 (95%CI 0.83–0.96) versus 0.81 (95%CI 0.64–0.91; P = 0.12) in Group1 and Group 2 respectively. When the 2 groups were pooled together a FT cutoff of 0.30 had a 90% NPV for advanced fibrosis (Se 77%); a FT cutoff of 0.70 had a 73% PPV for advanced fibrosis (Sp 98%). CONCLUSION: In patients with NAFLD, FibroTest, a simple and non-invasive quantitative estimate of liver fibrosis reliably predicts advanced fibrosis
An Accurate Definition of the Status of Inactive Hepatitis B Virus Carrier by a Combination of Biomarkers (FibroTest-ActiTest) and Viral Load
BACKGROUND: The combination of transaminases (ALT), biopsy, HBeAg and viral load have classically defined the inactive status of carriers of chronic hepatitis B. The use of FibroTest (FT) and ActiTest (AT), biomarkers of fibrosis and necroinflammatory activity, has been previously validated as alternatives to biopsy. We compared the 4-year prognostic value of combining FT-AT and viral load for a better definition of the inactive carrier status. METHODS AND FINDINGS: 1,300 consecutive CHB patients who had been prospectively followed since 2001 were pre-included. The main endpoint was the absence of liver-related complications, transplantation or death. We used the manufacturers' definitions of normal FT (< = 0.27), normal AT (< = 0.29) and 3 standard classes for viral load. The adjustment factors were age, sex, HBeAg, ethnic origin, alcohol consumption, HIV-Delta-HCV co-infections and treatment. RESULTS: 1,074 patients with baseline FT-AT and viral load were included: 41 years old, 47% African, 27% Asian, 26% Caucasian. At 4 years follow-up, 50 complications occurred (survival without complications 93.4%), 36 deaths occurred (survival 95.0%), including 27 related to HBV (survival 96.1%). The prognostic value of FT was higher than those of viral load or ALT when compared using area under the ROC curves [0.89 (95%CI 0.84-0.93) vs 0.64 (0.55-0.71) vs 0.53 (0.46-0.60) all P<0.001], survival curves and multivariate Cox model [regression coefficient 5.2 (3.5-6.9; P<0.001) vs 0.53 (0.15-0.92; P = 0.007) vs -0.001 (-0.003-0.000;P = 0.052)] respectively. A new definition of inactive carriers was proposed with an algorithm combining "zero" scores for FT-AT (F0 and A0) and viral load classes. This new algorithm provides a 100% negative predictive value for the prediction of liver related complications or death. Among the 275 patients with the classic definition of inactive carrier, 62 (23%) had fibrosis presumed with FT, and 3 died or had complications at 4 year. CONCLUSION: In patients with chronic hepatitis B, a combination of FibroTest-ActiTest and viral load testing accurately defined the prognosis and the inactive carrier status
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