AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human ...cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours.
This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model.
AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Virgo detector is a kilometer-length interferometer for gravitational wave detection located near Pisa (Italy). During its second science run (VSR2) in 2009, 6 months of data were accumulated ...with a sensitivity close to its design. In this paper, the methods used to determine the parameters for sensitivity estimation and gravitational wave reconstruction are described. The main quantities to be calibrated are the frequency response of the mirror actuation and the sensing of the output power. Focus is also put on their absolute timing. The monitoring of the calibration data and the parameter estimation with independent techniques are discussed to provide an estimation of the calibration uncertainties. Finally, the estimation of the Virgo sensitivity in the frequency domain is described and typical sensitivities measured during VSR2 are shown.
Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 ...metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We report on an all-sky search for periodic gravitational waves in the frequency range 50-1000 Hz with the first derivative of frequency in the range −8.9 × 10−10 Hz s−1 to zero in two years of data ...collected during LIGO's fifth science run. Our results employ a Hough transform technique, introducing a χ2 test and analysis of coincidences between the signal levels in years 1 and 2 of observations that offers a significant improvement in the product of strain sensitivity with compute cycles per data sample compared to previously published searches. Since our search yields no surviving candidates, we present results taking the form of frequency dependent, 95% confidence upper limits on the strain amplitude h0. The most stringent upper limit from year 1 is 1.0 × 10−24 in the 158.00-158.25 Hz band. In year 2, the most stringent upper limit is 8.9 × 10−25 in the 146.50-146.75 Hz band. This improved detection pipeline, which is computationally efficient by at least two orders of magnitude better than our flagship Einstein@Home search, will be important for 'quick-look' searches in the Advanced LIGO and Virgo detector era.
The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, ...and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In the Advanced Virgo+ interferometric gravitational-wave detector, the length control of the Fabry-Pérot cavities in the arms and of the detuned filter cavity, used for generating ...frequency-dependent squeezing, uses an auxiliary green beam at half of the operation laser wavelength (1064 nm). While operating the filter cavity with such a bichromatic control scheme for tens of hours, we observed that the mirror reflection phase shift of the fields at the two wavelengths responds differently to temperature changes in the mirrors, causing a change in the relative resonance condition of the two beams. In this paper we show that this thermal detuning effect can be explained by considering the thermomechanical properties of the mirror coating. Our experimental measurements are in good agreement with the theoretical predictions and allow us to drive requirements on the bicolor coating design and mirror temperature stability for long-term stable cavity control.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 ...administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m(-2) day(-1) (n=7), 2.8 mg m(-2) day(-1) (n=5) and 4.2 mg m(-2) day(-1) (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C(ss)) of SN-38 were between 1 and 3.3 ng ml(-1). From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4+/-30.1 and 130.4+/-9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m(-2) day(-1) dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The monotonous increasing with temperature behavior of the neutralization of Ga+ scattered by a gold surface plus the nonmagnetic character of the ion induced to disregard the important electronic ...correlation effects. In this work, we show that contrary to this assumption, the electron-electron interaction in the Ga site is crucial for describing the experimental results. We extend the formalism previously used in the Sr+/Au system to include more than one valence orbital in the projectile, which is the case of Ga+, where the neutralization occurs to a p-type shell. We consider the six possible orbital-spin neutral configurations in a correlated way within the Anderson model. The comparison with the results obtained from a noninteracting electron model allows one to infer how important the many-body effects in the charge exchange between Ga+ and the gold surface are. We also found that the proximity of the projectile one-electron energy levels to the substrate Fermi level determines the influence of electronic correlation effects on the neutral fraction and its temperature and velocity dependences.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
The anthracycline glycoside antibiotics represent a group of potent anticancer agents with a wide spectrum of activity against solid tumours and haematological malignancies, and are the mainstay of a ...large number of clinical protocols for the treatment of adult and childhood neoplastic diseases. Their clinical activity is limited, however, by acute and chronic adverse effects. Myelosuppression, predominantly neutropenia and leucopenia, is the dose-limiting toxicity; in addition to this, mucositis, nausea, vomiting and alopecia are frequent, whereas hepatopathy, characterised by elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and can be acute or chronic; in the acute setting, electrocardiographic abnormalities may be seen, including ST-T elevations and arrhythmias, but chronic cardiotoxicity represents a serious adverse effect that may be lethal due to the development of irreversible, cumulative dose-dependent, congestive cardiomyopathy. The occurrence of toxicity displays a marked interindividual variation, and for this reason the pharmacokinetics and pharmacodynamics of anthracyclines have been extensively investigated in order to identify integrated models that can be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximise tumour exposure. Pharmacokinetics has been recognised to influence both the toxicity and the activity of anthracyclines; in particular, there is increasing evidence that the mode of administration plays an important role for cumulative cardiotoxicity and data indicate that bolus administration, rather than continuous infusion, appears to be an important risk factor for anthracycline-induced cardiomyopathy, thus implying that this type of toxicity is maximum concentration-dependent. On the contrary, exposure to the drug, as measured by area under the curve, seems best related to the occurrence of leucopenia. Finally, the development of pharmacokinetic-pharmacodynamic models allows the simulation of drug effects and ultimately dose optimisation in order to anticipate important toxicities and prevent their occurrence by the administration of prophylactic treatments.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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