738 research outputs found

    Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway

    Get PDF
    Background Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis. Methods MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis). Results The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations. Conclusion Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential

    Is the pharmacy profession innovative enough?: meeting the needs of Australian residents with chronic conditions and their carers using the nominal group technique

    Get PDF
    Background Community pharmacies are ideally located as a source of support for people with chronic conditions. Yet, we have limited insight into what innovative pharmacy services would support this consumer group to manage their condition/s. The aim of this study was to identify what innovations people with chronic conditions and their carers want from their ideal community pharmacy, and compare with what pharmacists and pharmacy support staff think consumers want. Methods We elicited ideas using the nominal group technique. Participants included people with chronic conditions, unpaid carers, pharmacists and pharmacy support staff, in four regions of Australia. Themes were identified via thematic analysis using the constant comparison method. Results Fifteen consumer/carer, four pharmacist and two pharmacy support staff groups were conducted. Two overarching themes were identified: extended scope of practice for the pharmacist and new or improved pharmacy services. The most innovative role for Australian pharmacists was medication continuance, within a limited time-frame. Consumers and carers wanted improved access to pharmacists, but this did not necessarily align with a faster or automated dispensing service. Other ideas included streamlined access to prescriptions via medication reminders, electronic prescriptions and a chronic illness card. Conclusions This study provides further support for extending the pharmacist’s role in medication continuance, particularly as it represents the consumer’s voice. How this is done, or the methods used, needs to optimise patient safety. A range of innovative strategies were proposed and Australian community pharmacies should advocate for and implement innovative approaches to improve access and ensure continuity of care

    Identifying Prevalent Mathematical Pathways to Engineering in South Carolina

    Get PDF
    National data indicate that initial mathematics course placement in college is a strong predictor of persistence to degree in engineering, with students placed in calculus persisting at nearly twice the rate of those placed below calculus. Within the state of South Carolina, approximately 95% of engineering-intending students who initially place below calculus are from in-state. In order to make systemic change, we are first analyzing system-wide data to identify prevalent educational pathways within the state, and the mathematical milestones along those pathways taken by students in engineering and engineering-related fields. This paper reports preliminary analysis of that data to understand trends in major selection and mathematics preparation within the state

    Using global analysis, partial specifications, and an extensible assertion language for program validation and debugging

    Get PDF
    We discuss a framework for the application of abstract interpretation as an aid during program development, rather than in the more traditional application of program optimization. Program validation and detection of errors is first performed statically by comparing (partial) specifications written in terms of assertions against information obtained from (global) static analysis of the program. The results of this process are expressed in the user assertion language. Assertions (or parts of assertions) which cannot be checked statically are translated into run-time tests. The framework allows the use of assertions to be optional. It also allows using very general properties in assertions, beyond the predefined set understandable by the static analyzer and including properties defined by user programs. We also report briefly on an implementation of the framework. The resulting tool generates and checks assertions for Prolog, CLP(R), and CHIP/CLP(fd) programs, and integrates compile-time and run-time checking in a uniform way. The tool allows using properties such as types, modes, non-failure, determinacy, and computational cost, and can treat modules separately, performing incremental analysis

    The effect of progenitor age and metallicity on luminosity and 56Ni yield in Type Ia supernovae

    Get PDF
    Timmes, Brown & Truran found that metallicity variations could theoretically account for a 25% variation in the mass of 56Ni synthesized in Type Ia supernovae (SNe Ia), and thus account for a large fraction of the scatter in observed SN Ia luminosities. Higher-metallicity progenitors are more neutron-rich, producing more stable burning products relative to radioactive 56Ni. We develop a new method for estimating bolometric luminosity and 56Ni yield in SNe Ia and use it to test the theory with data from the Supernova Legacy Survey. We find that the average 56Ni yield does drop in SNe Ia from high metallicity environments, but the theory can only account for 7%--10% of the dispersion in SN Ia 56Ni mass, and thus luminosity. This is because the effect is dominant at metallicities significantly above solar, whereas we find that SN hosts have predominantly subsolar or only moderately above-solar metallicities. We also show that allowing for changes in O/Fe with the metallicity [Fe/H] does not have a major effect on the theoretical prediction of Timmes, Brown & Truran, so long as one is using the O/H as the independent variable. Age may have a greater effect than metallicity -- we find that the luminosity weighted age of the host galaxy is correlated with 56Ni yield, and thus more massive progenitors give rise to more luminous explosions. This is hard to understand if most SNe Ia explode when the primaries reach the Chandrasekhar mass. Finally, we test the findings of Gallagher et al., that the residuals of SNe Ia from the Hubble diagram are correlated with host galaxy metallicity, and we find no such correlation.Comment: ApJ, accepted, 34 pages, 11 figures, apologies for one column format -- necessary for the equation

    Calculations of collisions between cold alkaline earth atoms in a weak laser field

    Get PDF
    We calculate the light-induced collisional loss of laser-cooled and trapped magnesium atoms for detunings up to 50 atomic linewidths to the red of the ^1S_0-^1P_1 cooling transition. We evaluate loss rate coefficients due to both radiative and nonradiative state-changing mechanisms for temperatures at and below the Doppler cooling temperature. We solve the Schrodinger equation with a complex potential to represent spontaneous decay, but also give analytic models for various limits. Vibrational structure due to molecular photoassociation is present in the trap loss spectrum. Relatively broad structure due to absorption to the Mg_2 ^1Sigma_u state occurs for detunings larger than about 10 atomic linewidths. Much sharper structure, especially evident at low temperature, occurs even at smaller detunings due to of Mg_2 ^1Pi_g absorption, which is weakly allowed due to relativistic retardation corrections to the forbidden dipole transition strength. We also perform model studies for the other alkaline earth species Ca, Sr, and Ba and for Yb, and find similar qualitative behavior as for Mg.Comment: 20 pages, RevTex, 13 eps figures embedde

    Spitzer Sage Survey of the Large Magellanic Cloud. III. Star Formation and ~1000 New Candidate Young Stellar Objects

    Get PDF
    We present ~1000 new candidate Young Stellar Objects (YSOs) in the Large Magellanic Cloud selected from Spitzer Space Telescope data, as part of the Surveying the Agents of a Galaxy's Evolution (SAGE) Legacy program. The YSOs, detected by their excess infrared (IR) emission, represent early stages of evolution, still surrounded by disks and/or infalling envelopes. Previously, fewer than 20 such YSOs were known. The candidate YSOs were selected from the SAGE Point Source Catalog from regions of color-magnitude space least confused with other IR-bright populations. The YSOs are biased toward intermediate- to high-mass and young evolutionary stages, because these overlap less with galaxies and evolved stars in color-magnitude space. The YSOs are highly correlated spatially with atomic and molecular gas, and are preferentially located in the shells and bubbles created by massive stars inside. They are more clustered than generic point sources, as expected if star formation occurs in filamentary clouds or shells. We applied a more stringent color-magnitude selection to produce a subset of "high-probability" YSO candidates. We fitted the spectral-energy distributions (SEDs) of this subset and derived physical properties for those that were well fitted. The total mass of these well-fitted YSOs is ~2900 M_☉ and the total luminosity is ~2.1 × 10^6 L_☉ . By extrapolating the mass function with a standard initial mass function and integrating, we calculate a current star-formation rate of ~0.06 M_☉ yr^(–1), which is at the low end of estimates based on total ultraviolet and IR flux from the galaxy (~0.05 – 0.25 M_☉ yr^(–1)), consistent with the expectation that our current YSO list is incomplete. Follow-up spectroscopy and further data mining will better separate the different IR-bright populations and likely increase the estimated number of YSOs. The full YSO list is available as electronic tables, and the SEDs are available as an electronic figure for further use by the scientific community

    What Powers the 3000-Day Light Curve of SN 2006gy?

    Get PDF
    SN 2006gy was the most luminous supernova (SN) ever observed at the time of its discovery and the first of the newly defined class of superluminous supernovae (SLSNe). The extraordinary energetics of SN 2006gy and all SLSNe (>10^(51) erg) require either atypically large explosion energies (e.g. pair-instability explosion) or the efficient conversion of kinetic into radiative energy (e.g. shock interaction). The mass-loss characteristics can therefore offer important clues regarding the progenitor system. For the case of SN 2006gy, both a scattered and thermal light echo from circumstellar material (CSM) have been reported at later epochs (day ∼800), ruling out the likelihood of a pair-instability event and leading to constraints on the characteristics of the CSM. Owing to the proximity of the SN to the bright host-galaxy nucleus, continued monitoring of the light echo has not been trivial, requiring the high resolution offered by the Hubble Space Telescope (HST) or ground-based adaptive optics (AO). Here, we report detections of SN 2006gy using HST and Keck AO at ∼3000 d post-explosion and consider the emission mechanism for the very late-time light curve. While the optical light curve and optical spectral energy distribution are consistent with a continued scattered-light echo, a thermal echo is insufficient to power the K′-band emission by day 3000. Instead, we present evidence for late-time infrared emission from dust that is radiatively heated by CSM interaction within an extremely dense dust shell, and we consider the implications on the CSM characteristics and progenitor system
    corecore