26 research outputs found
Causes of hOCT1-dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor-selective gene therapy
Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent up-regulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib
Independent susceptibility markers for atrial fibrillation on chromosome 4q25
Background-: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and results-: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2Ă10) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF
Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.
BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
AGILE detection of a rapid Îł-ray flare from the blazar PKS 1510-089 during the GASP-WEBT monitoring
We report the detection by the AGILE satellite of a rapid gamma-ray flare
from the powerful gamma-ray quasar PKS 1510-089, during a pointing centered on
the Galactic Center region from 1 March to 30 March 2008. This source has been
continuosly monitored in the radio-to-optical bands by the GLAST-AGILE Support
Program (GASP) of the Whole Earth Blazar Telescope (WEBT). Moreover, the
gamma-ray flaring episode triggered three ToO observations by the Swift
satellite in three consecutive days, starting from 20 March 2008. In the period
1-16 March 2008, AGILE detected gamma-ray emission from PKS 1510-089 at a
significance level of 6.2-sigma with an average flux over the entire period of
(84 +/- 17) x 10^{-8} photons cm^{-2} s^{-1} for photon energies above 100 MeV.
After a predefined satellite re-pointing, between 17 and 21 March 2008, AGILE
detected the source at a significance level of 7.3-sigma, with an average flux
(E > 100 MeV) of (134 +/- 29) x 10^{-8} photons cm^{-2} s^{-1} and a peak level
of (281 +/- 68) x 10^{-8} photons cm^{-2} s^{-1} with daily integration. During
the observing period January-April 2008, the source also showed an intense and
variable optical activity, with several flaring episodes and a significant
increase of the flux was observed at millimetric frequencies. Moreover, in the
X-ray band the Swift/XRT observations seem to show an harder-when-brighter
behaviour of the source spectrum. The spectral energy distribution of mid-March
2008 is modelled with a homogeneous one-zone synchrotron self Compton emission
plus contributions from inverse Compton scattering of external photons from
both the accretion disc and the broad line region. Indeed, some features in the
optical-UV spectrum seem to indicate the presence of Seyfert-like components,
such as the little blue bump and the big blue bump
AGILE detection of extreme Îł -ray activity from the blazar PKS 1510-089 during March 2009: Multifrequency analysis
We report on the extreme gamma-ray activity from the FSRQ PKS 1510-089
observed by AGILE in March 2009. In the same period a radio-to-optical
monitoring of the source was provided by the GASP-WEBT and REM. Moreover,
several Swift ToO observations were triggered, adding important information on
the source behaviour from optical/UV to hard X-rays. We paid particular
attention to the calibration of the Swift/UVOT data to make it suitable to the
blazars spectra. Simultaneous observations from radio to gamma rays allowed us
to study in detail the correlation among the emission variability at different
frequencies and to investigate the mechanisms at work. In the period 9-30 March
2009, AGILE detected an average gamma-ray flux of (311+/-21)x10^-8 ph cm^-2
s^-1 for E>100 MeV, and a peak level of (702+/-131)x10^-8 ph cm^-2 s^-1 on
daily integration. The gamma-ray activity occurred during a period of
increasing activity from near-IR to UV, with a flaring episode detected on
26-27 March 2009, suggesting that a single mechanism is responsible for the
flux enhancement observed from near-IR to UV. By contrast, Swift/XRT
observations seem to show no clear correlation of the X-ray fluxes with the
optical and gamma-ray ones. However, the X-ray observations show a harder
photon index (1.3-1.6) with respect to most FSRQs and a hint of
harder-when-brighter behaviour, indicating the possible presence of a second
emission component at soft X-ray energies. Moreover, the broad band spectrum
from radio-to-UV confirmed the evidence of thermal features in the optical/UV
spectrum of PKS 1510-089 also during high gamma-ray state. On the other hand,
during 25-26 March 2009 a flat spectrum in the optical/UV energy band was
observed, suggesting an important contribution of the synchrotron emission in
this part of the spectrum during the brightest gamma-ray flare, therefore a
significant shift of the synchrotron peak
Multiwavelength observations of 3C 454.3. III. Eighteen months of agile monitoring of the "crazy diamond"
We report on 18 months of multiwavelength observations of the blazar 3C 454.3 (Crazy Diamond) carried out in the period 2007 July-2009 January. In particular, we show the results of the AGILE campaigns which took place on 2008 May-June, 2008 July-August, and 2008 October-2009 January. During the 2008 May-2009 January period, the source average flux was highly variable, with a clear fading trend toward the end of the period, from an average Îł-ray flux F E>100 MeV âł 200 Ă 10-8photonscm -2s-1 in 2008 May-June, to F E>100 MeV 80 Ă 10-8photonscm-2s-1 in 2008 October-2009 January. The average Îł-ray spectrum between 100 MeV and 1 GeV can be fit by a simple power law, showing a moderate softening (from ÎGRID ⌠2.0 to ÎGRID ⌠2.2) toward the end of the observing campaign. Only 3Ï upper limits can be derived in the 20-60 keV energy band with Super-AGILE, because the source was considerably off-axis during the whole time period. In 2007 July-August and 2008 May-June, 3C 454.3 was monitored by Rossi X-ray Timing Explorer (RXTE). The RXTE/Proportional Counter Array (PCA) light curve in the 3-20 keV energy band shows variability correlated with the Îł-ray one. The RXTE/PCA average flux during the two time periods is F 3-20 keV = 8.4 Ă 10-11ergcm-2s -1, and F 3-20 keV = 4.5 Ă 10 -11ergcm-2s-1, respectively, while the spectrum (a power law with photon index ÎPCA = 1.65 0.02) does not show any significant variability. Consistent results are obtained with the analysis of the RXTE/High-Energy X-Ray Timing Experiment quasi-simultaneous data. We also carried out simultaneous Swift observations during all AGILE campaigns. Swift/XRT detected 3C 454.3 with an observed flux in the 2-10 keV energy band in the range (0.9-7.5) Ă 10-11ergcm-2s-1 and a photon index in the range ÎXRT = 1.33-2.04. In the 15-150 keV energy band, when detected, the source has an average flux of about 5mCrab. GASP-WEBT monitored 3C 454.3 during the whole 2007-2008 period in the radio, millimeter, near-IR, and optical bands. The observations show an extremely variable behavior at all frequencies, with flux peaks almost simultaneous with those at higher energies. A correlation analysis between the optical and the Îł-ray fluxes shows that the Îł-optical correlation occurs with a time lag of Ï = -0.4+0.6-0.8 days, consistent with previous findings for this source. An analysis of 15 GHz and 43 GHz VLBI core radio flux observations in the period 2007 July-2009 February shows an increasing trend of the core radio flux, anti-correlated with the higher frequency data, allowing us to derive the value of the source magnetic field. Finally, the modeling of the broadband spectral energy distributions for the still unpublished data, and the behavior of the long-term light curves in different energy bands, allow us to compare the jet properties during different emission states, and to study the geometrical properties of the jet on a time-span longer than one year. © 2010. The American Astronomical Society. All rights reserved
Insights into the high-energy Îł-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era
We report on the Îł-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) Îł-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size âČ0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (â1044 erg s-1) constitutes only a small fraction (âŒ10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society