Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials

Sequential binding and sensing of Zn(II) by Bacillus subtilis Zur

Bacillus subtilis Zur (BsZur) represses high-affinity zinc-uptake systems and alternative ribosomal proteins in response to zinc replete conditions. Sequence alignments and structural studies of related Fur family proteins suggest that BsZur may contain three zinc-binding sites (sites 1–3). Mutational analyses confirm the essential structural role of site 1, while mutants affected in sites 2 and 3 retain partial repressor function. Purified BsZur binds a maximum of two Zn(II) per monomer at site 1 and site 2. Site 3 residues are important for dimerization, but do not directly bind Zn(II). Analyses of metal-binding affinities reveals negative cooperativity between the two site 2 binding events in each dimer. DNA-binding studies indicate that BsZur is sequentially activated from an inactive dimer (Zur2:Zn2) to a partially active asymmetric dimer (Zur2:Zn3), and finally to the fully zinc-loaded active form (Zur2:Zn4). BsZur with a C84S mutation in site 2 forms a Zur2:Zn3 form with normal metal- and DNA-binding affinities but is impaired in formation of the Zur2:Zn4 high affinity DNA-binding state. This mutant retains partial repressor activity in vivo, thereby supporting a model in which stepwise activation by zinc serves to broaden the physiological response to a wider range of metal concentrations

The OscSNS White Paper

There exists a need to address and resolve the growing evidence for short-baseline neutrino oscillations and the possible existence of sterile neutrinos. Such non-standard particles require a mass of $\sim 1$ eV/c$^2$, far above the mass scale associated with active neutrinos, and were first invoked to explain the LSND $\bar \nu_\mu \rightarrow \bar \nu_e$ appearance signal. More recently, the MiniBooNE experiment has reported a $2.8 \sigma$ excess of events in antineutrino mode consistent with neutrino oscillations and with the LSND antineutrino appearance signal. MiniBooNE also observed a $3.4 \sigma$ excess of events in their neutrino mode data. Lower than expected neutrino-induced event rates using calibrated radioactive sources and nuclear reactors can also be explained by the existence of sterile neutrinos. Fits to the world's neutrino and antineutrino data are consistent with sterile neutrinos at this $\sim 1$ eV/c$^2$ mass scale, although there is some tension between measurements from disappearance and appearance experiments. In addition to resolving this potential major extension of the Standard Model, the existence of sterile neutrinos will impact design and planning for all future neutrino experiments. It should be an extremely high priority to conclusively establish if such unexpected light sterile neutrinos exist. The Spallation Neutron Source (SNS) at Oak Ridge National Laboratory, built to usher in a new era in neutron research, provides a unique opportunity for US science to perform a definitive world-class search for sterile neutrinos.Comment: This white paper is submitted as part of the SNOWMASS planning proces

PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer

The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Fifty-micron paraffin sections were used for DNA extraction and 3-micron slides for immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH). ER, PR and HER2 IHC were repeated in a central laboratory for both primary and metastasis. PTEN levels were assessed by IHC and PI3K pathway mutations detected by a mass spectroscopy-based approach. Median age was 48 years (range, 30 to 83 years). Tumor subtype included 72% hormone receptor-positive/HER2-negative, 20% HER2-positive, and less than 7.8% triple receptor negative. Tissues were available for PTEN IHC in 46 primary tumors and 52 metastases. PTEN was lost in 14 (30%) primary tumors and 13 (25%) metastases. There were 5 cases of PTEN loss and eight cases of PTEN gain from primary to metastasis (26% discordance). Adequate DNA was obtained on 46 primary tumors and on 50 metastases for PIK3CA analysis. PIK3CA mutations were detected in 19 (40%) of primary tumors and 21 (42%) of metastases. There were five cases of PIK3CA mutation loss, and four cases of mutation gain (18% discordance). There was an increase of the level of PIK3CA mutations in four cases, and decrease in one from primary to metastasis. There is a high level of discordance in PTEN level, PIK3CA mutations, and receptor status between primary and metastatic disease that may influence patient selection and response to PI3K-targeted therapies

Reducing the Impact of the Next Influenza Pandemic Using Household-Based Public Health Interventions

BACKGROUND: The outbreak of highly pathogenic H5N1 influenza in domestic poultry and wild birds has caused global concern over the possible evolution of a novel human strain [1]. If such a strain emerges, and is not controlled at source [2,3], a pandemic is likely to result. Health policy in most countries will then be focused on reducing morbidity and mortality. METHODS AND FINDINGS: We estimate the expected reduction in primary attack rates for different household-based interventions using a mathematical model of influenza transmission within and between households. We show that, for lower transmissibility strains [2,4], the combination of household-based quarantine, isolation of cases outside the household, and targeted prophylactic use of anti-virals will be highly effective and likely feasible across a range of plausible transmission scenarios. For example, for a basic reproductive number (the average number of people infected by a typically infectious individual in an otherwise susceptible population) of 1.8, assuming only 50% compliance, this combination could reduce the infection (symptomatic) attack rate from 74% (49%) to 40% (27%), requiring peak quarantine and isolation levels of 6.2% and 0.8% of the population, respectively, and an overall anti-viral stockpile of 3.9 doses per member of the population. Although contact tracing may be additionally effective, the resources required make it impractical in most scenarios. CONCLUSIONS: National influenza pandemic preparedness plans currently focus on reducing the impact associated with a constant attack rate, rather than on reducing transmission. Our findings suggest that the additional benefits and resource requirements of household-based interventions in reducing average levels of transmission should also be considered, even when expected levels of compliance are only moderate

Public International Law: Environmental Law

Noteworthy international activity relating to the environment occurred in a wide variety of fora in 2000. This chapter provides brief updates on some of the most significant developments. Though by no means a comprehensive review, the chapter reflects the wide sweep of issues and large number of entities now involved in the development of international environmental law, at the start of this new century. It also reflects how critical and complex this international work is, and how much remains to be done

After retrotopia? The future of organizing and the thought of Zygmunt Bauman

The main body of work of Zygmunt Bauman concerns his home discipline of sociology, but his insights have been influential also in the field of organization studies. In this text, we provide an overview of the extent of this influence, providing some additional context for positioning the other contributions to this special section. Afterwards, we explore in more detail two notions central for Bauman’s late thought: that of liquidity and retrotopia. The former constitutes the root metaphor for theorizing the current global predicament. In this text, we analyse how two modes of interpreting it, using the assumptions behind Kurt Lewin’s CATS model and the alchemical tradition underpinning Carl Gustav Jung’s conception of archetypes respectively, can help us theorize the alternative modes of organizing and managing encountered in a study of contemporary alternative organizations. These insights form the starting point for our second goal: to explore Bauman’s notion of retrotopia as a potentially fruitful starting point for discussing both the deficiencies of current visions of our future society, and the possibilities and vicissitudes of developing new forms of organizing and managing. Such new forms, both as practice and as theoretical constructs, are urgently needed if we are to face the numerous, and potentially catastrophic global challenges facing our society today

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Implications of ICU triage decisions on patient mortality: a cost-effectiveness analysis

INTRODUCTION: Intensive care is generally regarded as expensive, and as a result beds are limited. This has raised serious questions about rationing when there are insufficient beds for all those referred. However, the evidence for the cost effectiveness of intensive care is weak and the work that does exist usually assumes that those who are not admitted do not survive, which is not always the case. Randomised studies of the effectiveness of intensive care are difficult to justify on ethical grounds; therefore, this observational study examined the cost effectiveness of ICU admission by comparing patients who were accepted into ICU after ICU triage to those who were not accepted, while attempting to adjust such comparison for confounding factors. METHODS: This multi-centre observational cohort study involved 11 hospitals in 7 EU countries and was designed to assess the cost effectiveness of admission to intensive care after ICU triage. A total of 7,659 consecutive patients referred to the intensive care unit (ICU) were divided into those accepted for admission and those not accepted. The two groups were compared in terms of cost and mortality using multilevel regression models to account for differences across centres, and after adjusting for age, Karnofsky score and indication for ICU admission. The analyses were also stratified by categories of Simplified Acute Physiology Score (SAPS) II predicted mortality (40%). Cost effectiveness was evaluated as cost per life saved and cost per life-year saved. RESULTS: Admission to ICU produced a relative reduction in mortality risk, expressed as odds ratio, of 0.70 (0.52 to 0.94) at 28 days. When stratified by predicted mortality, the odds ratio was 1.49 (0.79 to 2.81), 0.7 (0.51 to 0.97) and 0.55 (0.37 to 0.83) for 40% predicted mortality, respectively. Average cost per life saved for all patients was $103,771 (€82,358) and cost per life-year saved was$7,065 (€5,607). These figures decreased substantially for patients with predicted mortality higher than 40%, $60,046 (€47,656) and$4,088 (€3,244), respectively. Results were very similar when considering three-month mortality. Sensitivity analyses performed to assess the robustness of the results provided findings similar to the main analyses. CONCLUSIONS: Not only does ICU appear to produce an improvement in survival, but the cost per life saved falls for patients with greater severity of illness. This suggests that intensive care is similarly cost effective to other therapies that are generally regarded as essential