Exploiting evolution to treat drug resistance: Combination therapy and the double bind

Although many anti cancer therapies are successful in killing a large percentage of tumour cells when initially administered, the evolutionary dynamics underpinning tumour progression mean that often resistance is an inevitable outcome, allowing for new tumour phenotypes to emerge that are unhindered by the therapy. Research in the field of ecology suggests that an evolutionary double bind could be an effective way to treat tumours. In an evolutionary double bind two therapies are used in combination such that evolving resistance to one leaves individuals more susceptible to the other. In this paper we present a general evolutionary game theory model of a double bind to study the effect that such approach would have in cancer. Furthermore we use this mathematical framework to understand recent experimental results that suggest a synergistic effect between a p53 cancer vaccine and chemotherapy. Our model recapitulates the experimental data and provides an explanation for its effectiveness based on the commensalistic relationship between the tumour phenotypes

Laser diffraction particle sizing: Instrument probe volume relocation and elongation

The effective probe volume of laser diffraction particle sizing instruments depends on many instrument parameters. In particular the probe volume axial boundaries and its location along laser beam are essentially defined by the onset of a vignetting effect where light scattered at large angles from small particles misses the transform lens. This vignetting effect results in a probe volume that must be inconveniently close to the lens in order to detect smaller diameter particles (less than 100 micrometers). With the addition of an appropriately designed Keplerian telescope, the probe volume may be relocated and elongated. The theory of operation of this supplemental optical system is described. Design considerations for these supplemental optical systems are described, including recommendations for lens specifications, assembly and use. An image transfer system is described which has been designed for use on a Malvern 2600HSD instrument. Experimental validation of this image transfer system is described

Magnetic Instability in Strongly Correlated Superconductors

Recently a new phenomenological Hamiltonian has been proposed to describe the superconducting cuprates. This so-called Gossamer Hamiltonian is an apt model for a superconductor with strong on-site Coulomb repulsion betweenthe electrons. It is shown that as one approaches half-filling the Gossamer superconductor, and hence the superconducting state, with strong repulsion is unstable toward an antiferromagnetic insulator an can undergo a quantum phase transition to such an insulator if one increases the on-site Coulomb repulsion

Novel secondary somatic mutations in Ewing's sarcoma and desmoplastic small round cell tumors.

BackgroundEwing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT.MethodologyTwenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics.Principal findingsNovel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n = 1), PTPRD (n = 1), GRB10 (n = 2), MET (n = 2) and PIK3CA (n = 1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression.ConclusionsWe have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy

Organizational Design for Spill Containment in Deepwater Drilling Operations in the Gulf of Mexico: Assessment of the Marine Well Containment Company (MWCC)

The Deepwater Horizon oil spill in the Gulf of Mexico in April 2010 led to the deaths of 11 workers, a six-month moratorium on deepwater drilling in the Gulf, and nearly three months of massive engineering and logistics efforts to stop the spill. The series of failures before the well was finally capped and the spill contained revealed an inability to deal effectively with a well in deepwater and ultradeepwater. Ensuring that containment capabilities are adequate for drilling operations at these depths is therefore a salient challenge for government and industry. In this paper we assess the Marine Well Containment Company (MWCC), a consortium aimed at designing and building a system capable of containing future deepwater spills in the Gulf. We also consider alternatives for long-term readiness for deepwater spill containment. We focus on the roles of liability and regulation as determinants of readiness and the adequacy of incentives for technological innovation in oil spill containment technology to keep pace with advances in deepwater drilling capability. Liability and regulation can significantly influence the strength of these incentives. In addition, we discuss appropriate governance structure as a major determinant of the effectiveness of MWCC.oil spill, containment, industry R&D, liability, regulation, governance, innovation

Economic Dimensions of Fees and Access Control under the Fishery Conservation and Management Act of 1976

This article is devoted to an analysis of how these new management tools can be used most effectively as applied to domestic and foreign fishermen

A Degenerate Bose-Fermi Mixture of Metastable Atoms

We report the observation of simultaneous quantum degeneracy in a dilute gaseous Bose-Fermi mixture of metastable atoms. Sympathetic cooling of helium-3 (fermion) by helium-4 (boson), both in the lowest triplet state, allows us to produce ensembles containing more than 10^6 atoms of each isotope at temperatures below 1 micro-Kelvin, and achieve a fermionic degeneracy parameter of T/Tf=0.45. Due to their high internal energy, the detection of individual metastable atoms with sub-nanosecond time resolution is possible, permitting the study of bosonic and fermionic quantum gases with unprecedented precision. This may lead to metastable helium becoming the mainstay of quantum atom optics.Comment: 4 pages, 3 figures submitted to PR

Photoluminescence modification by high-order photonic band with abnormal dispersion in ZnO inverse opal

We measured the angle- and polarization-resolved reflection and photoluminescence spectra of ZnO inverse opals. Significant enhancement of spontaneous emission is observed. The enhanced emission not only has good directionality but also can be linearly polarized. A detailed theoretical analysis and numerical simulation reveal that such enhancement is caused by the abnormal dispersion of a high-order photonic band. The frozen mode at a stationary inflection point of a dispersion curve can strongly modify the intensity, directionality and polarization of spontaneous emission.Comment: 22 pages, 11 figures, figures modified, references added, more explanation adde