Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O6-methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a three-dimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment

Ordering of apolar and polar solutes in nematic solvents

The quadrupolar splittings of deuteriated para- and ortho-dichlorobenzene (1,4-DCB and 1,2-DCB, respectively) are measured by nuclear magnetic resonance(NMR) in the nematic solvents hexyl- and pentyloxy-substituted diphenyl diacetylene (DPDA-C6 and DPDA-OC5, respectively). Measurements are taken for all four combinations of the nominally apolar (1,4-DCB) and polar (1,2-DCB) solutes in the apolar (DPDA-C6) and polar (DPDA-OC5) solvents, and throughout the entire nematic temperature range of the solutions. The temperature dependence of the second-rank orientational order parameters of the solutes are obtained from these measurements and the respective order parameters of the mesogenic cores of solvent molecules are obtained independently from carbon-13 NMR measurements. The order parameter profiles of the two solutes are found to be very different but show little variation from one solvent to the other. The results are analyzed and interpreted in terms of the underlying molecular interactions using atomistic solvent–solute potentials. The influence of electrostaticinteractions on solute ordering is directly evaluated by computing the order parameters with and without the electrostatic component of the atomistic potential. It is observed to be small. It is also found that the important interactions in these solvent–solute systems are operative over short intermolecular distances for which the representation of the partial charge distributions in terms of overall molecular dipole and quadrupole moments is not valid

Towards Canonical Quantum Gravity for G1 Geometries in 2+1 Dimensions with a Lambda--Term

The canonical analysis and subsequent quantization of the (2+1)-dimensional action of pure gravity plus a cosmological constant term is considered, under the assumption of the existence of one spacelike Killing vector field. The proper imposition of the quantum analogues of the two linear (momentum) constraints reduces an initial collection of state vectors, consisting of all smooth functionals of the components (and/or their derivatives) of the spatial metric, to particular scalar smooth functionals. The demand that the midi-superspace metric (inferred from the kinetic part of the quadratic (Hamiltonian) constraint) must define on the space of these states an induced metric whose components are given in terms of the same states, which is made possible through an appropriate re-normalization assumption, severely reduces the possible state vectors to three unique (up to general coordinate transformations) smooth scalar functionals. The quantum analogue of the Hamiltonian constraint produces a Wheeler-DeWitt equation based on this reduced manifold of states, which is completely integrated.Comment: Latex 2e source file, 25 pages, no figures, final version (accepted in CQG

An electron correlation originated negative magnetoresistance in a system having a partly flat band

Inspired from an experimentally examined organic conductor, a novel mechanism for negative magnetoresistance is proposed for repulsively interacting electrons on a lattice whose band dispersion contains a flat portion (a flat bottom below a dispersive part here). When the Fermi level lies in the flat part, the electron correlation should cause ferromagnetic spin fluctuations to develop with an enhanced susceptibility. A relatively small magnetic field will then shift the majority-spin Fermi level to the dispersive part, resulting in a negative magnetoresistance. We have actually confirmed the idea by calculating the conductivity in magnetic fields, with the fluctuation exchange approximation, for the repulsive Hubbard model on a square lattice having a large second nearest-neighbor hopping.Comment: RevTex, 5 figures in Postscript, to be published in Phys. Rev.

The General Solution of Bianchi Type VIIhVII_h Vacuum Cosmology

The theory of symmetries of systems of coupled, ordinary differential equations (ODE) is used to develop a concise algorithm in order to obtain the entire space of solutions to vacuum Bianchi Einstein Field Equations (EFEs). The symmetries used are the well known automorphisms of the Lie algebra for the corresponding isometry group of each Bianchi Type, as well as the scaling and the time re-parametrization symmetry. The application of the method to Type VII_h results in (a) obtaining the general solution of Type VII_0 with the aid of the third Painlev\'{e} transcendental (b) obtaining the general solution of Type $VII_h$ with the aid of the sixth Painlev\'{e} transcendental (c) the recovery of all known solutions (six in total) without a prior assumption of any extra symmetry (d) The discovery of a new solution (the line element given in closed form) with a G_3 isometry group acting on T_3, i.e. on time-like hyper-surfaces, along with the emergence of the line element describing the flat vacuum Type VII_0 Bianchi Cosmology.Comment: latex2e source file, 27 pages, 2 tables, no fiure

The future of enterprise groupware applications

This paper provides a review of groupware technology and products. The purpose of this review is to investigate the appropriateness of current groupware technology as the basis for future enterprise systems and evaluate its role in realising, the currently emerging, Virtual Enterprise model for business organisation. It also identifies in which way current technological phenomena will transform groupware technology and will drive the development of the enterprise systems of the future

Does primary brachial plexus surgery alter palliative tendon transfer surgery outcomes in children with obstetric paralysis?

<p>Abstract</p> <p>Background</p> <p>The surgical management of obstetrical brachial plexus palsy can generally be divided into two groups; early reconstructions in which the plexus or affected nerves are addressed and late or palliative reconstructions in which the residual deformities are addressed. Tendon transfers are the mainstay of palliative surgery. Occasionally, surgeons are required to utilise already denervated and subsequently reinnervated muscles as motors. This study aimed to compare the outcomes of tendon transfers for residual shoulder dysfunction in patients who had undergone early nerve surgery to the outcomes in patients who had not.</p> <p>Methods</p> <p>A total of 91 patients with obstetric paralysis-related shoulder abduction and external rotation deficits who underwent a modified Hoffer transfer of the latissimus dorsi/teres major to the greater tubercle of the humerus tendon between 2002 and 2009 were retrospectively analysed. The patients who had undergone neural surgery during infancy were compared to those who had not in terms of their preoperative and postoperative shoulder abduction and external rotation active ranges of motion.</p> <p>Results</p> <p>In the early surgery groups, only the postoperative external rotation angles showed statistically significant differences (25 degrees and 75 degrees for total and upper type palsies, respectively). Within the palliative surgery-only groups, there were no significant differences between the preoperative and postoperative abduction and external rotation angles. The significant differences between the early surgery groups and the palliative surgery groups with total palsy during the preoperative period diminished postoperatively (p < 0.05 and p > 0.05, respectively) for abduction but not for external rotation. Within the upper type palsy groups, there were no significant differences between the preoperative and postoperative abduction and external rotation angles.</p> <p>Conclusions</p> <p>In this study, it was found that in patients with total paralysis, satisfactory shoulder abduction values can be achieved with tendon transfers regardless of a previous history of neural surgery even if the preoperative values differ.</p

Magnetic field-dependent interplay between incoherent and Fermi liquid transport mechanisms in low-dimensional tau phase organic conductors

We present an electrical transport study of the 2-dimensional (2D) organic conductor tau-(P-(S,S)-DMEDT-TTF)_2(AuBr)_2(AuBr_2)_y (y = 0.75) at low temperatures and high magnetic fields. The inter-plane resistivity rho_zz increases with decreasing temperature, with the exception of a slight anomaly at 12 K. Under a magnetic field B, both rho_zz and the in-plane resistivity plane rho_xx show a pronounced negative and hysteretic magnetoresistance with Shubnikov de Haas (SdH)oscillations being observed in some (high quality)samples above 15 T. Contrary to the predicted single, star-shaped, closed orbit Fermi surface from band structure calculations (with an expected approximate area of 12.5% of A_FBZ), two fundamental frequencies F_l and F_h are detected in the SdH signal. These orbits correspond to 2.4% and 6.8% of the area of the first Brillouin zone(A_FBZ), with effective masses F_l = 4.0 +/- 0.5 and F_h = 7.3 +/- 0.1. The angular dependence, in tilted magnetic fields of F_l and F_h, reveals the 2D character of the FS and Angular dependent magnetoresistance (AMRO) further suggests a FS which is strictly 2-D where the inter-plane hopping t_c is virtually absent or incoherent. The Hall constant R_xy is field independent, and the Hall mobility increases by a factor of 3 under moderate magnetic fields. Our observations suggest a unique physical situation where a stable 2D Fermi liquid state in the molecular layers are incoherently coupled along the least conducting direction. The magnetic field not only reduces the inelastic scattering between the 2D metallic layers, but it also reveals the incoherent nature of interplane transport in the AMRO spectrum. The apparent ferromagnetism of the hysteretic magnetoresistance remains an unsolved problem.Comment: 33 pages, 11 figure

Using Smartphones and Machine Learning to Quantify Parkinson Disease Severity:The Mobile Parkinson Disease Score

IMPORTANCE: Current Parkinson disease (PD) measures are subjective, rater-dependent, and assessed in clinic. Smartphones can measure PD features, yet no smartphone-derived rating score exists to assess motor symptom severity in real-world settings. OBJECTIVES: To develop an objective measure of PD severity and test construct validity by evaluating the ability of the measure to capture intraday symptom fluctuations, correlate with current standard PD outcome measures, and respond to dopaminergic therapy. DESIGN, SETTING, AND PARTICIPANTS: This observational study assessed individuals with PD who remotely completed 5 tasks (voice, finger tapping, gait, balance, and reaction time) on the smartphone application. We used a novel machine-learning-based approach to generate a mobile Parkinson disease score (mPDS) that objectively weighs features derived from each smartphone activity (eg, stride length from the gait activity) and is scaled from 0 to 100 (where higher scores indicate greater severity). Individuals with and without PD additionally completed standard in-person assessments of PD with smartphone assessments during a period of 6 months. MAIN OUTCOMES AND MEASURES: Ability of the mPDS to detect intraday symptom fluctuations, the correlation between the mPDS and standard measures, and the ability of the mPDS to respond to dopaminergic medication. RESULTS: The mPDS was derived from 6148 smartphone activity assessments from 129 individuals (mean [SD] age, 58.7 [8.6] years; 56 [43.4%] women). Gait features contributed most to the total mPDS (33.4%). In addition, 23 individuals with PD (mean [SD] age, 64.6 [11.5] years; 11 [48%] women) and 17 without PD (mean [SD] age 54.2 [16.5] years; 12 [71%] women) completed in-clinic assessments. The mPDS detected symptom fluctuations with a mean (SD) intraday change of 13.9 (10.3) points on a scale of 0 to 100. The measure correlated well with the Movement Disorder Society Unified Parkinson Disease's Rating Scale total (r = 0.81; P < .001) and part III only (r = 0.88; P < .001), the Timed Up and Go assessment (r = 0.72; P = .002), and the Hoehn and Yahr stage (r = 0.91; P < .001). The mPDS improved by a mean (SD) of 16.3 (5.6) points in response to dopaminergic therapy. CONCLUSIONS AND RELEVANCE: Using a novel machine-learning approach, we created and demonstrated construct validity of an objective PD severity score derived from smartphone assessments. This score complements standard PD measures by providing frequent, objective, real-world assessments that could enhance clinical care and evaluation of novel therapeutics