Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.     

DNA-binding preferences of bisantrene analogues: relevance to the sequence specificity of drug-mediated topoisomerase II poisoning

To elucidate structure-activity relationships for drugs that are able to poison or inhibit topoisomerase II, we investigated the thermodynamics and stereochemistry of the DNA binding of a number of anthracene derivatives bearing one or two 4, 5-dihydro-1H-imidazol-2-yl-hydrazone side chains (characteristic of bisantrene) at different positions of the planar aromatic system. An aza-bioisostere, which can be considered a bisantrene-amsacrine hybrid, was also tested. The affinity for nucleic acids in different sequence contexts was evaluated by spectroscopic techniques, using various experimental conditions. DNA-melting and DNase I footprinting experiments were also performed. The location and number of the otherwise identical side chains dramatically affected the affinity of the test compounds for the nucleic acid. In addition, the new compounds exhibited different DNA sequence preferences, depending on the locations of the dihydroimidazolyl-hydrazone groups, which indicates a major role for the side-chain position in generating specific contacts with the nucleic acid. Molecular modeling studies of the intercalative binding of the 1- or 9-substituted isomers to DNA fully supported the experimental data, because a substantially more favorable recognition of A-T steps, compared with G-C steps, was found for the 9-substituted derivative, whereas a much closer energy balance was found for the 1-substituted isomer. These results compare well with the alteration of base specificity found for the topoisomerase II-mediated DNA cleavage stimulated by the isomeric drugs. Therefore, DNA-binding specificity appears to represent an important determinant for the recognition of the topoisomerase-DNA cleavable complex by the drug, at least for poisons belonging to the amsacrine-bisantrene family.     

Exploiting the high-frequency performance of low-voltage low-power SC filters

This paper investigates the design of low-voltage low-power switched-capacitor (SC) filters for high-frequency applications by using the clock-booster approach. In particular, our proposed SC filter architecture uses single-ended double-sampling integrator cells based on low-voltage operational transconductance amplifiers which take advantage of dynamic biasing and the clock-booster technique to drive the switch transistors. To validate its high-frequency capability, two low-pass elliptic SC filters respectively with a corner frequency of 6 and 8-MHz, were designed in a 0.35-/spl mu/m CMOS process. Both are suitable for telecom applications and can operate with a power supply as low as 1.5 V, while dissipating 11 mW. Measurements showed that for an output amplitude of 1 V/sub pp/, their total harmonic distortions were maintained well below -40 dB in their bandwidths. Comparisons with other SC filter implementations in the literature, which highlight the quality of our implementation are also provided.     

Macrophage-derived cytokines in the follicular fluids of women with infertility due to immunological causes. Elevated levels of interleukin 6 and low levels of granulocyte-macrophage colony-stimulating factor

Myoclonus of the middle ear is a rare condition characterized by abnormal repetitive muscle contractions of the tympanic cavity. In this paper we describe what we believe is the first reported case of continuous high-frequency objective tinnitus caused by middle ear myoclonus. During exploratory tympanomastoidectomy it was hypothesized that a small dural arteriovenous malformation not identified on previous tests was the cause of the tinnitus. However, complete disappearance of the tinnitus during administration of curare for anesthesia led us to believe that the tinnitus might have been caused by myoclonus of the middle ear. Sectioning of the stapedius and tensor tympani tendons rendered the patient asymptomatic and confirmed the diagnosis of middle ear myoclonus. At follow-up of one year, the patient's quality of life had improved substantially; the tinnitus did not recur and she no longer had vertigo.     

Thermodynamic analysis and assessment of the Ce–Ni system

An optimised set of thermodynamic parameters for the Ce–Ni system has been obtained using the CALPHAD approach. A thorough thermodynamic analysis of the system has been carried out using different calorimetric techniques and the data have been used in the assessment. The free energy of the liquid phase has been described as a function of temperature and composition using a Redlich–Kister polynomial. Solid compounds have been considered as stoichiometric with the exception of the Laves phases. The phase diagram and thermodynamic quantities calculated from assessed parameters agree well with experimental data.     

The effect of surfaces on the tunneling density of states of an anisotropically paired superconductor

We present calculations of the tunneling density of states in an anisotropically paired superconductor for two different sample geometries: a semi-infinite system with a single specular wall, and a slab of finite thickness and infinite lateral extent. In both cases we are interested in the effects of surface pair breaking on the tunneling spectrum. We take the stable bulk phase to be of d_x ²–y² symmetry. Our calculations are performed within two different band structure environments: an isotropic cylindrical Fermi surface with a bulk order parameter of the form k _x ² –k _y ² , and a nontrivial tight-binding Fermi surface with the order parameter structure coming from an antiferromagnetic spin-fluctuation model. In each case we find additional structures in the energy spectrum coming from the surface layer. These structures are sensitive to the orientation of the surface with respect to the crystal lattice, and have their origins in the detailed form of the momentum and spatial dependence of the order parameter. By means of tunneling spectroscopy, one can obtain information on both the anisotropy of the energy gap, ¦(p)¦, as well as on the phase of the order parameter, (p) = ¦(p)¦ e^i(p).     

A comparison between wet and cryogenic drilling of CFRP/Ti stacks

This paper compares conventional and cryogenic cooling in the deep hole drilling of carbon fiber reinforced polymer (CFRP)/Ti stacks. Various parameters are taken into account to find if the use of cryogenic coolant is justified by the improvement of the final results. Both the thrust and the torque were acquired continuously during the machining operations and compared both in average and distribution. The use of a cryogenic coolant brings a reduction in thrust force and torque without any sensible drawback. Overall the results prove that cryogenic drilling is a suitable technology for CFRP/Ti stack drill.     

Evaluating the impact of smart technologies on harbor’s logistics via BPMN modeling and simulation

A smart Information and Communication Technology (ICT) enables a synchronized interplay of different key factors, aligning infrastructures, consumers, and governmental policy-making needs. In the harbor’s logistics context, smart ICT has been driving a multi-year wave of growth. Although there is a standalone value in the technological innovation of a task, the impact of a new smart technology is unknown without quantitative analysis methods on the end-to-end process. In this paper, we first present a review of the smart ICT for marine container terminals, and then we propose to evaluate the impact of such smart ICT via business process model and notation (BPMN) modeling and simulation. The proposed approach is discussed in a real-world modeling and simulation analysis, made on a pilot terminal of the Port of Leghorn (Italy).