Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

: Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents' pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system

Paramagnetic Phase of a Heavy-Fermion Compound, CeFePO, Probed by 57Fe M\"{o}ssbauer Spectroscopy

57Fe M\"{o}ssbauer spectroscopy was applied to an iron-based layered compound CeFePO. At temperatures from 9.4 to 293 K, no magnetic splitting was observed in the M\"ossbauer spectra of CeFePO indicating a paramagnetic phase of the Fe magnetic sublattice. All the spectra were fitted with a small quadrupole splitting, and the Debye temperature of CeFePO was found to be \sim448 K. The isomer shift at room temperature, 0.32 mm/s, was almost equal to those of LnFeAsO (Ln = La, Ce, Sm). Comparing s-electron density using the isomer shifts and unit cell volumes, it was found that the Fe of CeFePO has a similar valence state to other layered iron-based quaternary oxypnictides except LaFePO

Metallic behaviour of carrier-polarized C60_{60} molecular layers: Experiment and Theory

Although C$_{60}$ is a molecular crystal with a bandgap E$_g$ of ~2.5 eV, we show that E$_g$ is strongly affected by injected charge. In sharp contrast to the Coulomb blockade typical of quantum dots, E$_g$ is {\it reduced} by the Coulomb effects. The conductance of a thin C$_{60}$ layer sandwiched between metal (Al, Ag, Au, Mg and Pt) contacts is investigated. Excellent Ohmic conductance is observed for Al electrodes protected with ultra-thin LiF layers. First-principles calculations, Hubbard models etc., show that the energy gap of C$_{60}$ is dramatically reduced when electrons hop from C$_{60}^-$ to C$_{60}$.Comment: 4 PRL style pages, 2 figures. email: [email protected]

Self Consistent Molecular Field Theory for Packing in Classical Liquids

Building on a quasi-chemical formulation of solution theory, this paper proposes a self consistent molecular field theory for packing problems in classical liquids, and tests the theoretical predictions for the excess chemical potential of the hard sphere fluid. Results are given for the self consistent molecular fields obtained, and for the probabilities of occupancy of a molecular observation volume. For this system, the excess chemical potential predicted is as accurate as the most accurate prior theories, particularly the scaled particle (Percus-Yevick compressibility) theory. It is argued that the present approach is particularly simple, and should provide a basis for a molecular-scale description of more complex solutions.Comment: 6 pages and 5 figure

A Local Moment Approach to magnetic impurities in gapless Fermi systems

A local moment approach is developed for the single-particle excitations of a symmetric Anderson impurity model (AIM), with a soft-gap hybridization vanishing at the Fermi level with a power law r > 0. Local moments are introduced explicitly from the outset, and a two-self-energy description is employed in which the single-particle excitations are coupled dynamically to low-energy transverse spin fluctuations. The resultant theory is applicable on all energy scales, and captures both the spin-fluctuation regime of strong coupling (large-U), as well as the weak coupling regime. While the primary emphasis is on single particle dynamics, the quantum phase transition between strong coupling (SC) and (LM) phases can also be addressed directly; for the spin-fluctuation regime in particular a number of asymptotically exact results are thereby obtained. Results for both single-particle spectra and SC/LM phase boundaries are found to agree well with recent numerical renormalization group (NRG) studies. A number of further testable predictions are made; in particular, for r < 1/2, spectra characteristic of the SC state are predicted to exhibit an r-dependent universal scaling form as the SC/LM phase boundary is approached and the Kondo scale vanishes. Results for the `normal' r = 0 AIM are moreover recovered smoothly from the limit r -> 0, where the resultant description of single-particle dynamics includes recovery of Doniach-Sunjic tails in the Kondo resonance, as well as characteristic low-energy Fermi liquid behaviour.Comment: 52 pages, 19 figures, submitted to Journal of Physics: Condensed Matte

Photoemission study of the metal-insulator transition in VO_2/TiO_2(001) : Evidence for strong electron-electron and electron-phonon interaction

We have made a detailed temperature-dependent photoemission study of VO_2/TiO_2(001) thin films, which show a metal-insulator transition at \sim 300 K. Clean surfaces were obtained by annealing the films in an oxygen atmosphere. Spectral weight transfer between the coherent and incoherent parts accompanying the metal-insulator transition was clearly observed. We also observed a hysteretic behavior of the spectra for heating-cooling cycles. We have derived the ``bulk'' spectrum of the metallic phase and found that it has a strong incoherent part. The width of the coherent part is comparable to that given by band-structure calculation in spite of its reduced spectral weight, indicating that the momentum dependence of the self-energy is significant. This is attributed to by ferromagnetic fluctuation arising from Hund's rule coupling between different d orbitals as originally proposed by Zylbersztejn and Mott. In the insulating phase, the width of the V 3d band shows strong temperature dependence. We attribute this to electron-phonon interaction and have reproduced it using the independent boson model with a very large coupling constant.Comment: 7 pages, 7 figures, submitted to Phys. Rev.

Antibiotic knowledge, attitudes, and practices: new insights from cross-sectional rural health behaviour surveys in low- and middle-income South-East Asia

Introduction: Low- and middle-income countries (LMICs) are crucial in the global response to antimicrobial resistance (AMR), but diverse health systems, healthcare practices, and cultural conceptions of medicine can complicate global education and awareness-raising campaigns. Social research can help understand LMIC contexts but remains underrepresented in AMR research. Objective: To (1) describe antibiotic-related knowledge, attitudes, and practices of the general population in two LMICs and to (2) assess the role of antibiotic-related knowledge and attitudes on antibiotic access from different types of healthcare providers. Design: Observational study: cross-sectional rural health behaviour survey, representative on the population level. Setting: General rural population in Chiang Rai (Thailand) and Salavan (Lao PDR), surveyed between November 2017 and May 2018. Participants: 2141 adult members (≥18 years) of the general rural population, representing 712,000 villagers. Outcome measures: Antibiotic-related knowledge, attitudes, and practices across sites and healthcare access channels. Findings: Villagers were aware of antibiotics (Chiang Rai: 95.7%; Salavan: 86.4%; p<0.001) and drug resistance (Chiang Rai: 74.8%; Salavan: 62.5%; p<0.001), but the usage of technical concepts for antibiotics was dwarfed by local expressions like “anti-inflammatory medicine” in Chiang Rai (87.6%; 95% confidence interval [CI]: 84.9–90.0) and “ampi” in Salavan (75.6%; 95% CI: 71.4–79.4). Multivariate linear regression suggested that attitudes against over-the-counter antibiotics were linked to 0.12 additional antibiotic use episodes from public healthcare providers in Chiang Rai (95% CI: 0.01 – 0.23) and 0.53 in Salavan (95% CI: 0.16 – 0.90). Conclusions: Locally specific conceptions and counter-intuitive practices around antimicrobials can complicate AMR communication efforts and entail unforeseen consequences. Overcoming “knowledge deficits” alone will therefore be insufficient for global AMR behaviour change. We call for an expansion of behavioural AMR strategies towards “AMR-sensitive interventions” that address context-specific upstream drivers of antimicrobial use (e.g. unemployment insurance) and complement education and awareness campaigns

Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans

Rabies kills many people throughout the developing world every year. The murine monoclonal antibody (mAb) 62-71-3 was recently identified for its potential application in rabies postexposure prophylaxis (PEP). The purpose here was to establish a plant-based production system for a chimeric mouse-human version of mAb 62-71-3, to characterize the recombinant antibody and investigate at a molecular level its interaction with rabies virus glycoprotein. Chimeric 62-71-3 was successfully expressed in Nicotiana benthamiana. Glycosylation was analyzed by mass spectroscopy; functionality was confirmed by antigen ELISA, as well as rabies and pseudotype virus neutralization. Epitope characterization was performed using pseudotype virus expressing mutagenized rabies glycoproteins. Purified mAb demonstrated potent viral neutralization at 500 IU/mg. A critical role for antigenic site I of the glycoprotein, as well as for two specific amino acid residues (K226 and G229) within site I, was identified with regard to mAb 62-71-3 neutralization. Pseudotype viruses expressing glycoprotein from lyssaviruses known not to be neutralized by this antibody were the controls. The results provide the molecular rationale for developing 62-71-3 mAb for rabies PEP; they also establish the basis for developing an inexpensive plant-based antibody product to benefit low-income families in developing countries.—Both, L., van Dolleweerd, C., Wright, E., Banyard, A. C., Bulmer-Thomas, B., Selden, D., Altmann, F., Fooks, A. R., Ma, J. K.-C. Production, characterization, and antigen specificity of recombinant 62-71-3, a candidate monoclonal antibody for rabies prophylaxis in humans

Ordering of droplets and light scattering in polymer dispersed liquid crystal films

We study the effects of droplet ordering in initial optical transmittance through polymer dispersed liquid crystal (PDLC) films prepared in the presence of an electrical field. The experimental data are interpreted by using a theoretical approach to light scattering in PDLC films that explicitly relates optical transmittance and the order parameters characterizing both the orientational structures inside bipolar droplets and orientational distribution of the droplets. The theory relies on the Rayleigh-Gans approximation and uses the Percus-Yevick approximation to take into account the effects due to droplet positional correlations.Comment: revtex4, 18 pages, 8 figure

Effect of Finite Impurity Mass on the Anderson Orthogonality Catastrophe in One Dimension

A one-dimensional tight-binding Hamiltonian describes the evolution of a single impurity interacting locally with $N$ electrons. The impurity spectral function has a power-law singularity $A(\omega)\propto\mid\omega-\omega_0\mid^{-1+\beta}$ with the same exponent $\beta$ that characterizes the logarithmic decay of the quasiparticle weight $Z$ with the number of electrons $N$, $Z\propto N^{-\beta}$. The exponent $\beta$ is computed by (1) perturbation theory in the interaction strength and (2) numerical evaluations with exact results for small systems and variational results for larger systems. A nonanalytical behavior of $\beta$ is observed in the limit of infinite impurity mass. For large interaction strength, the exponent depends strongly on the mass of the impurity in contrast to the perturbative result.Comment: 26 pages, RevTeX, 7 figures included, to be published in Phys. Rev.