Adam Smith and the theory of punishment

A distinctive theory of punishment plays a central role in Smith's moral and legal theory. According to this theory, we regard the punishment of a crime as deserved only to the extent that an impartial spectator would go along with the actual or supposed resentment of the victim. The first part of this paper argues that Smith's theory deserves serious consideration and relates it to other theories such as utilitarianism and more orthodox forms of retributivism. The second part considers the objection that, because Smith's theory implies that punishment is justified only when there is some person or persons who is the victim of the crime, it cannot explain the many cases where punishment is imposed purely for the public good. It is argued that Smith's theory could be extended to cover such cases. The third part defends Smith's theory against the objection that, because it relies on our natural feelings, it cannot provide an adequate moral justification of punishment

Loss of oestrogen receptor alpha in long-term antioestrogen-resistant cells: reversal by a c-src inhibitor

Background Tamoxifen still remains the most frequently used antioestrogen for the treatment of breast cancer. However, its efficacy is often limited by the emergence of acquired resistance and it has been suggested that, in some instances, this may involve oestrogen receptor (ER) loss. This study addresses this issue by examining long-term tamoxifen treatment of breast cancer cells and identifies that progressive ER loss does occur, leading to greatly increased aggressive tumour cell behaviour. Encouragingly, even after 30 months treatment, ER loss is reversible by a c-src inhibitor. Our data therefore provide a new model to study the cellular mechanisms associated with antihormone promoted ER loss and its possible prevention/reversal by signal transduction inhibitors. Methods Using quantitative PCR based on SYBR Green fluorescence, the expression of total ERα mRNA and its constituent mRNA variants were quantified in MCF7 cells and in our in vitro developed tamoxifen-resistant breast cancer cells (TamR), which have been cultured in the presence of tamoxifen for 30 months. Specific PCR amplification of all ERα mRNA variants was possible using forward primers designed to bind specifically to the 5' untranslated regions of ERα mRNA and used separately with a common reverse primer that anneals to the 5' end of the protein encoding region of exon 1 of ERα cDNA. Expression of ERα protein was assessed by western blot and immunohistochemistry. Results In MCF7 cells, the ERα mRNA isoforms A, B and C were detected as the most predominant variants, with C ERα mRNA showing the highest expression level. In TamR cells, about a 40% fall in total ERα mRNA was observed in comparison with MCF7 cells and was most apparent for the C variant. Extension of the tamoxifen treatment period to 30 months produced a further dramatic decrease in ERα mRNA (all variants) and protein levels, resulting in ER negativity being recorded in >90% of the cells by immunohistochemistry. These cells show increased levels of phosphorylated Erk 1&2, AKT, PKCα and src, and are highly aggressive in their growth behaviour, with increased cell motility and invasiveness. Treatment of the cells with the demethylating agent 5-azacytidine did not restore ERα expression, suggesting that epigenetic alterations are unlikely to be responsible for the reduced ER levels. However, Affymetrix data in the TamR cells showed that some positive regulators of ER expression, such as p53 and Foxo3A, are downregulated during the development of the resistant phenotype and their continued absence may contribute to the progressive ER loss. Significantly, pathway inhibitor studies revealed c-src to be an important regulator of ER loss, since its inhibition rapidly restored ER levels. Conclusion Our data indicate that considerable ER loss can occur during antihormonal treatment of breast cancer cells and that this can lead to a more aggressive phenotype. Encouragingly, however, even after 30 months exposure to tamoxifen, the process is reversible by inhibition of c-src. These data suggest that combinations of antihormones with signal transduction inhibitors could retain ER functions in treated cells and prevent a drift towards more aggressive cancer cell behaviour

Growth and Development of F-1 (Brahman x Hereford) Heifers Under Various Short-Term Grazing Pressures

Last updated: 6/1/200

Tandem Cylinder Noise Predictions

In an effort to better understand landing-gear noise sources, we have been examining a simplified configuration that still maintains some of the salient features of landing-gear flow fields. In particular, tandem cylinders have been studied because they model a variety of component level interactions. The present effort is directed at the case of two identical cylinders spatially separated in the streamwise direction by 3.7 diameters. Experimental measurements from the Basic Aerodynamic Research Tunnel (BART) and Quiet Flow Facility (QFF) at NASA Langley Research Center (LaRC) have provided steady surface pressures, detailed off-surface measurements of the flow field using Particle Image Velocimetry (PIV), hot-wire measurements in the wake of the rear cylinder, unsteady surface pressure data, and the radiated noise. The experiments were conducted at a Reynolds number of 166 105 based on the cylinder diameter. A trip was used on the upstream cylinder to insure a fully turbulent shedding process and simulate the effects of a high Reynolds number flow. The parallel computational effort uses the three-dimensional Navier-Stokes solver CFL3D with a hybrid, zonal turbulence model that turns off the turbulence production term everywhere except in a narrow ring surrounding solid surfaces. The current calculations further explore the influence of the grid resolution and spanwise extent on the flow and associated radiated noise. Extensive comparisons with the experimental data are used to assess the ability of the computations to simulate the details of the flow. The results show that the pressure fluctuations on the upstream cylinder, caused by vortex shedding, are smaller than those generated on the downstream cylinder by wake interaction. Consequently, the downstream cylinder dominates the noise radiation, producing an overall directivity pattern that is similar to that of an isolated cylinder. Only calculations based on the full length of the model span were able to capture the complete decay in the spanwise correlation, thereby producing reasonable noise radiation levels

The Time-Dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, have elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonate treatment and timing on the disruption or promotion of vascular calcification and bone minerals in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicated that long-term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations might be associated with a higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of the bisphosphonate treatment

The Energetic Particle Detector (EPD) Investigation and the Energetic Ion Spectrometer (EIS) for the Magnetospheric Multiscale (MMS) Mission

Abstract The Energetic Particle Detector (EPD) Investigation is one of 5 fields-and-particles investigations on the Magnetospheric Multiscale (MMS) mission. MMS comprises 4 spacecraft flying in close formation in highly elliptical, near-Earth-equatorial orbits targeting understanding of the fundamental physics of the important physical process called magnetic reconnection using Earth’s magnetosphere as a plasma laboratory. EPD comprises two sensor types, the Energetic Ion Spectrometer (EIS) with one instrument on each of the 4 spacecraft, and the Fly’s Eye Energetic Particle Spectrometer (FEEPS) with 2 instruments on each of the 4 spacecraft. EIS measures energetic ion energy, angle and elemental compositional distributions from a required low energy limit of 20 keV for protons and 45 keV for oxygen ions, up to \u3e0.5 MeV (with capabilities to measure up to \u3e1 MeV). FEEPS measures instantaneous all sky images of energetic electrons from 25 keV to \u3e0.5 MeV, and also measures total ion energy distributions from 45 keV to \u3e0.5 MeV to be used in conjunction with EIS to measure all sky ion distributions. In this report we describe the EPD investigation and the details of the EIS sensor. Specifically we describe EPD-level science objectives, the science and measurement requirements, and the challenges that the EPD team had in meeting these requirements. Here we also describe the design and operation of the EIS instruments, their calibrated performances, and the EIS in-flight and ground operations. Blake et al. (The Flys Eye Energetic Particle Spectrometer (FEEPS) contribution to the Energetic Particle Detector (EPD) investigation of the Magnetospheric Magnetoscale (MMS) Mission, this issue) describe the design and operation of the FEEPS instruments, their calibrated performances, and the FEEPS in-flight and ground operations. The MMS spacecraft will launch in early 2015, and over its 2-year mission will provide comprehensive measurements of magnetic reconnection at Earth’s magnetopause during the 18 months that comprise orbital phase 1, and magnetic reconnection within Earth’s magnetotail during the about 6 months that comprise orbital phase 2

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro

Introduction: Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. Methods: In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR. Results: RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P <0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P <0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P <0.05). Co-treating with AZD8055 alongside tamoxifen (P <0.01) or oestrogen deprivation (P <0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. Conclusions: This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance

Multi-organ spatial stratification of 3-D dose distributions improves risk prediction of long-term self-reported severe symptoms in oropharyngeal cancer patients receiving radiotherapy:development of a pre-treatment decision support tool

PURPOSE: Identify Oropharyngeal cancer (OPC) patients at high-risk of developing long-term severe radiation-associated symptoms using dose volume histograms for organs-at-risk, via unsupervised clustering.MATERIAL AND METHODS: All patients were treated using radiation therapy for OPC. Dose-volume histograms of organs-at-risk were extracted from patients' treatment plans. Symptom ratings were collected via the MD Anderson Symptom Inventory (MDASI) given weekly during, and 6 months post-treatment. Drymouth, trouble swallowing, mucus, and vocal dysfunction were selected for analysis in this study. Patient stratifications were obtained by applying Bayesian Mixture Models with three components to patient's dose histograms for relevant organs. The clusters with the highest total mean doses were translated into dose thresholds using rule mining. Patient stratifications were compared against Tumor staging information using multivariate likelihood ratio tests. Model performance for prediction of moderate/severe symptoms at 6 months was compared against normal tissue complication probability (NTCP) models using cross-validation.RESULTS: A total of 349 patients were included for long-term symptom prediction. High-risk clusters were significantly correlated with outcomes for severe late drymouth (p &lt;.0001, OR = 2.94), swallow (p = .002, OR = 5.13), mucus (p = .001, OR = 3.18), and voice (p = .009, OR = 8.99). Simplified clusters were also correlated with late severe symptoms for drymouth (p &lt;.001, OR = 2.77), swallow (p = .01, OR = 3.63), mucus (p = .01, OR = 2.37), and voice (p &lt;.001, OR = 19.75). Proposed cluster stratifications show better performance than NTCP models for severe drymouth (AUC.598 vs.559, MCC.143 vs.062), swallow (AUC.631 vs.561, MCC.20 vs -.030), mucus (AUC.596 vs.492, MCC.164 vs -.041), and voice (AUC.681 vs.555, MCC.181 vs -.019). Simplified dose thresholds also show better performance than baseline models for predicting late severe ratings for all symptoms.CONCLUSION: Our results show that leveraging the 3-D dose histograms from radiation therapy plan improves stratification of patients according to their risk of experiencing long-term severe radiation associated symptoms, beyond existing NTPC models. Our rule-based method can approximate our stratifications with minimal loss of accuracy and can proactively identify risk factors for radiation-associated toxicity.</p