Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs

Use of the Trendelenburg Position in the Porcine Model Improves Carotid Flow During Cardiopulmonary Resuscitation

BACKGROUND: Cardiopulmonary resuscitation (CPR) is now widely used as a treatment for ventricular fibrillation, though numerous studies have shown the outcome of standard CPR to be dismal. Alternative methods of CPR, including interposed abdominal compression, constant aortic occlusion, and the use of intrathoracic pressure regulator, have been shown to increase cardiac output and affect the mortality rate of CPR.OBJECTIVES: Here we suggest the Trendelenburg position as yet another method of increasing cardiac output and therefore improving the effectiveness of chest compressions. We hypothesized that the use of the Trendelenburg position during CPR would increase cardiac output as measured by carotid blood flow.METHODS: We anaesthetized six pigs and measured their pre-arrest carotid flow rate for two minutes. We then induced ventricular fibrillation in those pigs and performed open-chest CPR on them. Post-arrest carotid blood flow was measured for two minutes each at 0 (supine position), 10, 20, and 30 degrees of head-down tilt in each pig. The mean carotid flow for each degree of tilt was compared to mean carotid flow at 0 degrees of tilt using a paired student t-test.RESULTS: We found an increase of up to 1.4-fold in carotid blood flow during CPR in the Trendelenburg position, though only 20 and 30 degrees of Trendelenburg showed a statistically significant increase from the 0 degrees of tilt in pigs.CONCLUSION: The Trendelenburg position can lead to increased blood flow through the carotid arteries during CPR in this pig model. Future studies should investigate whether this increased blood flow through the carotid arteries leads to improved brain perfusion and better neurologic outcomes

Measuring the robustness of resource allocations for distributed domputer systems in a stochastic dynamic environment

Heterogeneous distributed computing systems often must function in an environment where system parameters are subject to variations during operation. Robustness can be defined as the degree to which a system can function correctly in the presence of parameter values different from those assumed. We present a methodology for quantifying the robustness of resource allocations in a dynamic environment where task execution times vary within predictable ranges and tasks arrive randomly. The methodology is evaluated through measuring the robustness of three different resource allocation heuristics within the context of the stochastically modeled dynamic environment. A Bayesian regression model is fit to the combined results of the three heuristics to demonstrate the correlation between the stochastic robustness metric and the presented performance metric. The correlation results demonstrated the significant potential of the stochastic robustness metric to predict the relative performance of the three heuristics given a common objective function

Evolution of a Relativistic Electron Beam for Tracing Magnetospheric Field Lines

Tracing magnetic field-lines of the Earth\u27s magnetosphere using beams of relativistic electrons will open up new insights into space weather and magnetospheric physics. Analytic models and a single-particle-motion code were used to explore the dynamics of an electron beam emitted from an orbiting satellite and propagating until impact with the Earth. The impact location of the beam on the upper atmosphere is strongly influenced by magnetospheric conditions, shifting up to several degrees in latitude between different phases of a simulated storm. The beam density cross-section evolves due to cyclotron motion of the beam centroid and oscillations of the beam envelope. The impact density profile is ring shaped, with major radius ~22 m, given by the final cyclotron radius of the beam centroid, and ring thickness ~2 m given by the final beam envelope. Motion of the satellite may also act to spread the beam, however it will remain sufficiently focused for detection by ground-based optical and radio detectors. An array of such ground stations will be able to detect shifts in impact location of the beam, and thereby infer information regarding magnetospheric conditions

Nodal variations and long-term changes in the main tides on the coasts of China

The long-term changes in the main tidal constituents (O1, K1, M2, N2, and S2) along the coasts of China and in adjacent seas are investigated based on 17 tide-gauge records covering the period 1954–2012. The observed 18.61 year nodal modulations of the diurnal constituents O1 and K1 are in agreement with the equilibrium tidal theory, except in the South China Sea. The observed modulations of the M2 and N2 amplitudes are smaller than theoretically predicted at the northern stations and larger at the southern stations. The discrepancies between the theoretically predicted nodal variations and the observations are discussed. The 8.85 year perigean cycle is identifiable in the N2 parameters at most stations, except those in the South China Sea. The radiational component of S2 contributes on average 16% of the observed S2 except in the Gulf of Tonkin, on the south coast, where it accounts for up to 65%. We confirmed the existence of nodal modulation in S2, which is stronger on the north coast. The semidiurnal tidal parameters show significant secular trends in the Bohai and Yellow Seas, on the north coast, and in the Taiwan Strait. The largest increase is found for M2 for which the amplitude increases by 4–7 mm/yr in the Yellow Sea. The potential causes for the linear trends in tidal constants are discussed

Tailoring Chimeric Ligands for Studying and Biasing ErbB Receptor Family Interactions

Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways.National Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant U54-CA112967)National Institutes of Health (U.S.) (R01DE019523-13)Massachusetts Institute of Technology. Computational and Systems Biology Program. MIT-Merck Postdoctoral FellowshipSwiss National Science Foundation (Postdoctoral Fellowship)National Institute of Environmental Health Sciences (Training Grant in Environmental Toxicology 5-T32-ES007020

Relativistic Particle Beams as a Resource to Solve Outstanding Problems in Space Physics

The Sun\u27s connection with the Earth\u27s magnetic field and atmosphere is carried out through the exchange of electromagnetic and mass flux and is regulated by a complex interconnection of processes. During space weather events, solar flares, or fast streams of solar atmosphere strongly disturb the Earth\u27s environment. Often the electric currents that connect the different parts of the Sun-Earth system become unstable and explosively release the stored electromagnetic energy in one of the more dramatic expressions of space weather—the geomagnetic storm and substorm. Some aspects of the magnetosphere-ionosphere connection that generates auroral arcs during space weather events are well-known. However, several fundamental problems remain unsolved because of the lack of unambiguous identification of the magnetic field connection between the magnetosphere and the ionosphere. The correct mapping between different regions of the magnetosphere and their foot-points in the ionosphere, coupled with appropriate distributed measurements of plasma and fields in focused regions of the magnetosphere, is necessary to establish unambiguously that a given magnetospheric process is the generator of an observed arc. We present a new paradigm that should enable the resolution of the mapping ambiguities. The paradigm calls for the application of energetic electron beams as magnetic field tracers. The three most important problems for which the correct magnetic field mapping would provide closure to are the substorm growth phase arcs, the expansion phase onset arcs and the system of arcs that emerge from the magnetosphere-ionosphere connection during the development of the early substorm expansion phase phenomenon known as substorm current wedge (SCW). In this communication we describe how beam tracers, in combination with distributed measurements in the magnetosphere, can be used to disentangle the mechanisms that generate these critical substorm phenomena. Since the application of beams as tracers require demonstration that the beams can be injected into the loss cone, that the spacecraft potentials induced by the beam emission are manageable, and that sufficient electron flux reaches the atmosphere to be detectable by optical or radio means after the beam has propagated thousands of kilometers under competing effects of beam spread and constriction as well as effects of beam-induced instabilities, in this communication we review how these challenges are currently being addressed and discuss the next steps toward the realization of active experiments in space using relativistic electron beams