Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications

Properties of Intercalated 2H-NbSe2, 4Hb-TaS2 and 1T-TaS2

The layered compounds 2H-NbSe, 24Hb-TaS, 2and 1T-TaS2 have been intercalated with organic molecules; and the resulting crystal structure, heat capacity, conductivity, and superconductivity have been studied. The coordination in the disulfide layers was found to be unchanged in the product phase. Resistance minima appear and the superconducting transition temperature is reduced in the NbSe2 complex. Conversely, superconductivity is induced in the 4Hb-TaS2 complex. Corresponding evidence of a large change of the density of states, negative for 2H-NbSe2 and positive for 4Hb-TaS2, was also observed upon intercalation. The transport properties of all the intercalation complexes show a pronounced dependence upon the coordination of the transition metal

Interventions for treating oral mucositis for patients with cancer receiving treatment

Background Treatment of cancer is increasingly effective but is associated with short and long term side effects. Oral and gastrointestinal side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them. Objectives To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both. Search strategy Computerised searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 1 June 2010), CENTRAL via the Cochrane Library (Issue 2, 2010, 1 June 2010), MEDLINE via OVID (1 June 2010), EMBASE via OVID (1 June 2010), CINAHL via EBSCO (1 June 2010), CANCERLIT via PubMed (1 June 2010), OpenSIGLE (1 June 2010) and LILACS via Virtual Health Library (1 June 2010) were undertaken. Reference lists fromrelevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Selection criteria All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life. Data collection and analysis Data were independently extracted, in duplicate, by two review authors. Trial authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. Risk ratios (RR) were calculated using fixed-effect models. Main results Ten trials involving 940 patients, satisfied the inclusion criteria and are included in this review. Drugs absorbed from the gastrointestinal (GI) tract were beneficial in eradication of oral candidiasis compared with drugs not absorbed from the GI tract (three trials: RR = 1.29, 95% confidence interval (CI) 1.09 to 1.52), however there was significant heterogeneity. A drug absorbed from the GI tract, ketoconazole, wasmore beneficial than placebo in eradicating oral candidiasis (one trial: RR = 3.61, 95% CI 1.47 to 8.88). Clotrimazole, at a higher dose of 50 mg was more effective than a lower 10 mg dose in eradicating oral candidiasis, when assessed mycologically (one trial: RR = 2.00, 95% CI 1.11 to 3.60). Only one of the ten trials was assessed as at low risk of bias. Authors' conclusions There is insufficient evidence to claimor refute a benefit for any antifungal agent in treating candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed. Clinicians need to make a decision on whether to prevent or treat oral candidiasis in patients receiving treatment for cancer. This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2010, Issue 7. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.</p

Optical device for measuring a surface characteristic of an object by multi-color interferometry

An interferometer having a light beam source that produces a plurality of separate and distinct wavelengths of light. Optic fibers are used to transport the wavelengths of light toward an object surface and to allow light reflected from the object to pass through a polarizer to improve the polarization ratio of the reflected light to determine a characteristic of the object surface

Optimal Control of the Thermistor Problem in Three Spatial Dimensions

This paper is concerned with the state-constrained optimal control of the three-dimensional thermistor problem, a fully quasilinear coupled system of a parabolic and elliptic PDE with mixed boundary conditions. This system models the heating of a conducting material by means of direct current. Local existence, uniqueness and continuity for the state system are derived by employing maximal parabolic regularity in the fundamental theorem of Pr\"uss. Global solutions are addressed, which includes analysis of the linearized state system via maximal parabolic regularity, and existence of optimal controls is shown if the temperature gradient is under control. The adjoint system involving measures is investigated using a duality argument. These results allow to derive first-order necessary conditions for the optimal control problem in form of a qualified optimality system. The theoretical findings are illustrated by numerical results

Low heat conduction in white dwarf boundary layers?

X-ray spectra of dwarf novae in quiescence observed by Chandra and XMM-Newton provide new information on the boundary layers of their accreting white dwarfs. Comparison of observations and models allows us to extract estimates for the thermal conductivity in the accretion layer and reach conclusions on the relevant physical processes. We calculate the structure of the dense thermal boundary layer that forms under gravity and cooling at the white dwarf surface on accretion of gas from a hot tenuous ADAF-type coronal inflow. The distribution of density and temperature obtained allows us to calculate the strength and spectrum of the emitted X-ray radiation. They depend strongly on the values of thermal conductivity and mass accretion rate. We apply our model to the dwarf nova system VW Hyi and compare the spectra predicted for different values of the thermal conductivity with the observed spectrum. We find a significant deviation for all values of thermal conductivity that are a sizable fraction of the Spitzer conductivity. A good fit arises however for a conductivity of about 1% of the Spitzer value. This also seems to hold for other dwarf nova systems in quiescence. We compare this result with thermal conduction in other astrophysical situations. The highly reduced thermal conductivity in the boundary layer requires magnetic fields perpendicular to the temperature gradient. Locating their origin in the accretion of magnetic fields from the hot ADAF-type coronal flow we find that dynamical effects of these fields will lead to a spatially intermittent, localized accretion geometry at the white dwarf surface.Comment: 8 pages, 5 figs, to appear in Astronomy & Astrophysic

XX/XY Sex Chromosomes in the South American Dwarf Gecko (\u3cem\u3eGonatodes humeralis\u3c/em\u3e)

Sex-specific genetic markers identified using restriction site-associated DNA sequencing, or RADseq, permits the recognition of a species’ sex chromosome system in cases where standard cytogenetic methods fail. Thus, species with male-specific RAD markers have an XX/XY sex chromosome system (male heterogamety) while species with female-specific RAD markers have a ZZ/ZW sex chromosome (female heterogamety). Here, we use RADseq data from 5 male and 5 female South American dwarf geckos (Gonatodes humeralis) to identify an XX/XY sex chromosome system. This is the first confidently known sex chromosome system in a Gonatodes species. We used a low-coverage de novo G. humeralis genome assembly to design PCR primers to validate the male-specificity of a subset of the sex-specific RADseq markers and describe how even modest genome assemblies can facilitate the design of sex-specific PCR primers in species with diverse sex chromosome systems

Dimensional Control of Antilocalisation and Spin Relaxation in Quantum Wires

The spin relaxation rate $1/\tau_s (W)$ in disordered quantum wires with Rashba and Dresselhaus spin-orbit coupling is derived analytically as a function of wire width $W$. It is found to be diminished when $W$ is smaller than the bulk spin-orbit length $L_{\rm SO}$. Only a small spin relaxation rate due to cubic Dresselhaus coupling $\gamma$ is found to remain in this limit. As a result, when reducing the wire width $W$ the quantum conductivity correction changes from weak anti- to weak localization and from negative to positive magnetoconductivity.Comment: 4.0 pages, 3 figures, final version, Refs. updated, introduction and formula for spin relaxation rate adde

High efficiency of soft X-ray radiation reprocessing in supersoft X-ray sources due to multiple scattering

Detailed analysis of the lightcurve of CAL 87 clearly has shown that the high optical luminosity comes from the accretion disc rim and can only be explained by a severe thickening of the disc rim near the location where the accretion stream impinges. This area is irradiated by the X-rays where it faces the white dwarf. Only if the reprocessing rate of X-rays to optical light is high a luminosity as high as observed can be understood. But a recent detailed study of the soft X-ray radiation reprocessing in supersoft X-ray sources has shown that the efficiency is not high enough. We here propose a solution for this problem. As already discussed in the earlier lightcurve analysis the impact of the accretion stream at the outer disc rim produces a ``spray'', consisting of a large number of individual gas blobs imbedded in a surrounding corona. For the high mass flow rate this constitutes an optically thick vertically extended screen at the rim of the accretion disc. We analyse the optical properties of this irradiated spray and find that the multiple scattering between these gas blobs leads to an effective reprocessing of soft X-rays to optical light as required by the observations.Comment: 7 pages, 6 figures, accepted for publication in A&