First-in-man evaluation of 124I-PGN650: A PET tracer for detecting phosphatidylserine as a biomarker of the solid tumor microenvironment

Purpose: PGN650 is a F(ab′) 2 antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with 124 I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer. Methods: Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) 124 I-PGN650 intravenously and underwent positron emission tomography–computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models). Results: Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq. Conclusion: Although 124 I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies

Compensating for ecological harm - the state of play in New Zealand

Ecological compensation involves measures to create positive conservation outcomes intended to offset the residual impacts of development (e.g. restoration planting, pest control). Rarely, however, have the exchanges arranged been subject to objective assessment. Here we assess 110 cases of ecological compensation involving diverse New Zealand ecosystems on the basis of how they addressed the six key implementation issues identified by McKenney and Kiesecker (2010: Environmental Management 45: 165–176): equivalence, location (i.e. spatial proximity), additionality, timing, duration and compliance, and currencies. Our research showed that habitat enhancement and protection is the most common form of ecological compensation, and that 72 of 110 case studies undertook compensation on the same site or immediately adjacent. The great majority (94.5%) of compensation was required by condition of resource consent to be demonstrated after the development had proceeded, with an average of 11.3 years of continuing management or monitoring required. The most common form of security other than a consent condition was a covenant (29 of 110 cases) followed by a resource management bond (25). We also found that in 97 cases there was no objective quantification of the compensation needed to make up for impact losses, with the requirements being devised by negotiation between parties with the assistance of expert input. We recognise the potential of ecological compensation as a policy tool, but recommend that significant improvements are made to its implementation to enhance ecological outcomes

Ecological compensation: an evaluation of regulatory compliance in New Zealand

Ecological compensation is an example of a trade-off whereby loss of natural values is remedied or offset by a corresponding compensatory action on the same site or elsewhere, determined through the process of Environmental Impact Assessment (EIA). Ecological compensation actions are often criticised for having low levels of compliance: meaning that they are achieved only partially or not at all, while development activity proceeds with much greater certainty. Our research investigated compliance with 245 conditions relating to ecological compensation across 81 case studies across New Zealand under the Resource Management Act 1991. Our results show that present tools and practice in New Zealand are not adequately securing the necessary benefits from ecological compensation requirements, with 35.2% of requirements not being achieved. Significant variation in non-compliance with ecological compensation occurs between different activities, applicant types and condition types, while critical variables within the planning process influence levels of compliance. Our research demonstrates the importance of understanding the nature of non-compliance and of providing a consistent and robust decision-making framework for the consideration of ecological compensation in practic

Self-Assembling Peptide Detergents Stabilize Isolated Photosystem Ion a Dry Surface for an Extended Time

We used a class of designed peptide detergents to stabilize photosystem I (PS-I) upon extended drying under N(2) on a gold-coated-Ni-NTA glass surface. PS-I is a chlorophyll-containing membrane protein complex that is the primary reducer of ferredoxin and the electron acceptor of plastocyanin. We isolated the complex from the thylakoids of spinach chloroplasts using a chemical detergent. The chlorophyll molecules associated with the PS-I complex provide an intrinsic steady-state emission spectrum between 650 and 800 nm at −196.15 °C that reflects the organization of the pigment-protein interactions. In the absence of detergents, a large blue shift of the fluorescence maxima from approximately 735 nm to approximately 685 nm indicates a disruption in light-harvesting subunit organization, thus revealing chlorophyll−protein interactions. The commonly used membrane protein-stabilizing detergents, N-dodecyl-β-D-maltoside and N-octyl-β-D-glucoside, only partially stabilized the approximately 735-nm complex with approximately 685-nm spectroscopic shift. However, prior to drying, addition of the peptide detergent acetyl- AAAAAAK at increasing concentration significantly stabilized the PS-I complex. Moreover, in the presence of acetyl- AAAAAAK, the PS-I complex is stable in a dried form at room temperature for at least 3 wk. Another peptide detergent, acetyl-VVVVVVD, also stabilized the complex but to a lesser extent. These observations suggest that the peptide detergents may effectively stabilize membrane proteins in the solid-state. These designed peptide detergents may facilitate the study of diverse types of membrane proteins

Lactation and neonatal nutrition: defining and refining the critical questions.

This paper resulted from a conference entitled "Lactation and Milk: Defining and refining the critical questions" held at the University of Colorado School of Medicine from January 18-20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond

The Kuroshio and Luzon Undercurrent east of Luzon Island

Author Posting. © The Oceanography Society, 2015. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 28, no. 4 (2015): 54–63, doi:10.5670/oceanog.2015.81.Current structure, transport, and water mass properties of the northward-flowing Kuroshio and the southward-flowing Luzon Undercurrent (LU) were observed for nearly one year, June 8, 2012–June 4, 2013, across the Kuroshio path at 18.75°N. Observations were made from four platforms: an array of six subsurface ADCP moorings, two Seagliders, fivepressure inverted echo sounders (PIES), and five horizontal electric field (HEF) sensors, providing the most detailed time series of the Kuroshio and Luzon Undercurrent water properties to date. Ocean state estimates of the western boundary current system were performed using the MIT general circulation model—four-dimensional variational assimilation (MITgcm-4D-Var) system. Prominent Kuroshio features from observations are simulated well by the numerical model. Annual mean Kuroshio transport, averaged over all platforms, is ~16 Sv with a standard deviation ~4 Sv. Kuroshio and LU transports and water mass pathways east of Luzon are revealed by Seaglider measurements. In a layer above the salinity maximum associated with North Pacific Tropical Water (NPTW), Kuroshio transport is ~7 Sv and contains North Equatorial Current (NEC) and Western Philippine Sea (WPS) waters, with an insignificant amount of South China Sea water on the shallow western flank. In an intermediate layer containing the core of the NPTW, Kuroshio transport is ~10 Sv, consisting mostly of NEC water. In the lower layer of the Kuroshio, transport is ~1.5 Sv of mostly North Pacific Intermediate Water (NPIW) as a part of WPS waters. Annual mean Luzon Undercurrent southward transport integrated to 1,000 m depth is ~2.7 Sv with a standard deviation ~2 Sv, carrying solely WPS waters below the salinity minimum of the NPIW. The transport of the western boundary current integrated over the full ocean depth east of Luzon Island is ~14 ± 4.5 Sv. Sources of the water masses in the Kuroshio and Luzon Undercurrent are confirmed qualitatively by the numerical model.This work was supported by the US Office of Naval Research (N00014-10-1-0273 and N00014-15-1-2285 to BDC, N00014-10-1-0273 to GG, N00014-14-1-0065 to ALG, N00014-10-1-0468 to TBS, N0001-10-1-0273 to LRC, N00014-10-1-0308 to CML, N00014-10-1-0397 and N00014-10-1-0273 to BM, N00014-10-1-0397 to RCL, and N00014-10-1-0268 to SRJ) and the Taiwan Ministry of Science and Technology. Yang, Chang, and Mensah are supported by the Taiwan Ministry of Science and Technology

What Do Unions Do for Economic Performance?

Twenty years have passed since Freeman and Medoff's What Do Unions Do? This essay assesses their analysis of how unions in the U.S. private sector affect economic performance - productivity, profitability, investment, and growth. Freeman and Medoff are clearly correct that union productivity effects vary substantially across workplaces. Their conclusion that union effects are on average positive and substantial cannot be sustained, subsequent evidence suggesting an average union productivity effect near zero. Their speculation that productivity effects are larger in more competitive environments appears to hold up, although more evidence is needed. Subsequent literature continues to find unions associated with lower profitability, as noted by Freeman and Medoff. Unions are found to tax returns stemming from market power, but industry concentration is not the source of such returns. Rather, unions capture firm quasi-rents arising from long-lived tangible and intangible capital and from firm-specific advantages. Lower profits and the union tax on asset returns leads to reduced investment and, subsequently, lower employment and productivity growth. There is little evidence that unionization leads to higher rates of business failure. Given the decline in U.S. private sector unionism, I explore avenues through which individual and collective voice might be enhanced, focusing on labor law and workplace governance defaults. Substantial enhancement of voice requires change in the nonunion sector and employer as well as worker initiatives. It is unclear whether labor unions would be revitalized or further marginalized by such an evolution

The Peculiar SN 2005hk: Do Some Type Ia Supernovae Explode as Deflagrations?

We present extensive u'g'r'i'BVRIYJHKs photometry and optical spectroscopy of SN 2005hk. These data reveal that SN 2005hk was nearly identical in its observed properties to SN 2002cx, which has been called ``the most peculiar known type Ia supernova.'' Both supernovae exhibited high ionization SN 1991T-like pre-maximum spectra, yet low peak luminosities like SN 1991bg. The spectra reveal that SN 2005hk, like SN 2002cx, exhibited expansion velocities that were roughly half those of typical type Ia supernovae. The R and I light curves of both supernovae were also peculiar in not displaying the secondary maximum observed for normal type Ia supernovae. Our YJH photometry of SN 2005hk reveals the same peculiarity in the near-infrared. By combining our optical and near-infrared photometry of SN 2005hk with published ultraviolet light curves obtained with the Swift satellite, we are able to construct a bolometric light curve from ~10 days before to ~60 days after B maximum. The shape and unusually low peak luminosity of this light curve, plus the low expansion velocities and absence of a secondary maximum at red and near-infrared wavelengths, are all in reasonable agreement with model calculations of a 3D deflagration which produces ~0.25 M_sun of 56Ni.Comment: Accepted by PASP, to appear in April 2007 issue, 63 pages, 16 figures, 11 table

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD