Evolution of Cooperative Thought, Theory, and Purpose

The evolution of agricultural cooperative thought, theory, and purpose in the United States is reviewed from the standpoint of the reemergence of interest in how cooperatives can provide some of the security and benefits that might be lost with gradual phasing out of federal government farm support programs. By accomplishing group action for self-help, the early development of cooperatives drew considerable attention from economists, social theorists, and politicians. Alternative schools of cooperative thought developed, but most proponents of cooperatives regarded them as having enormous potential to provide a public service role in building a more economically stable and democratic society This paper also surveys how cooperative theory was developed more rigorously in the post-WWII period. It has provided better analytical tools for understanding how and why cooperatives have changed in response to technological and economic developments, as well as to social trends, like individualism. Given the new perspectives on cooperative theory and the scope of changes in how cooperatives operate and are structured, cooperatives have even greater potential for coordinating self-help actions, but this potential needs the support of cooperative education services.Agribusiness,

Internalisation of membrane progesterone receptor-α after treatment with progesterone: Potential involvement of a clathrin-dependent pathway

This article has been made available through the Brunel Open Access Publishing Fund.Internalisation and recycling of seven trans-membrane domain receptors is a critical regulatory event for their signalling. The mechanism(s) by which membrane progesterone receptor-α (mPRα) number is regulated on the cell surface is unclear. In this study, we investigated the cellular distribution of mPRα and mechanisms of mPRα trafficking using a cell line derived from a primary culture of human myometrial cells (M11) as an experimental model. RT-PCR and immunofluorescent analysis demonstrated expression of mPRα in M11 cells with mPRα primarily distributed on the cell surface under basal conditions. For the first time, plasma membrane localisation of mPRα was confirmed using immuno-gold transmission electron microscopy. Stimulation of M11 cells with progesterone (P4, 100 nM) resulted in internalisation of mPRα from the plasma membrane to the cytoplasm (10 min) and subsequent partial translocation back to the cell surface (20 min). We investigated potential endocytotic pathways involved in trafficking of mPRα after its internalisation. Partial co-localisation of clathrin with mPRα was obvious after 10 min of P4 treatment. Of note, chlorpromazine (inhibitor of clathrin-mediated pathway) inhibited the endocytosis of mPRα, whereas treatment with nystatin (inhibitor of caveolae-mediated pathway) did not affect internalisation. Collectively, these data suggest that mPRα is expressed on the cell surface of M11 cells and undergoes endocytosis after P4 stimulation primarily via a clathrin-mediated pathway.This article is available through the Brunel Open Access Publishing Fun

Exploring fMRI Results Space : 31 Variants of an fMRI Analysis in AFNI, FSL, and SPM

Data sharing is becoming a priority in functional Magnetic Resonance Imaging (fMRI) research, but the lack of a standard format for shared data is an obstacle (Poline et al., 2012; Poldrack and Gorgolewski, 2014). This is especially true for information about data provenance, including auxiliary information such as participant characteristics and task descriptions. The three most commonly used analysis software packages [AFNI1 (Cox, 1996), FSL2 (Jenkinson et al., 2012), and SPM3 (Penny et al., 2011)] broadly conduct the same analysis, but differ in how fundamental concepts are described, and have a myriad of differences in the pre-processing and modeling steps. The practical consequence is that sharing analyzed data is further complicated by the idiosyncrasies of the particular software used

HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer.

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.Methods/designHERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.DiscussionThe HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.Trial registrationClinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014

Economic inequalities in the effectiveness of a primary care intervention for depression and suicidal ideation.

BACKGROUND: Economic disadvantage is associated with depression and suicide. We sought to determine whether economic disadvantage reduces the effectiveness of depression treatments received in primary care. METHODS: We conducted differential-effects analyses of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial, a primary-care-based randomized, controlled trial for late-life depression and suicidal ideation conducted between 1999 and 2001, which included 514 patients with major depression or clinically significant minor depression. RESULTS: The intervention effect, defined as change in depressive symptoms from baseline, was stronger among persons reporting financial strain at baseline (differential effect size = -4.5 Hamilton Depression Rating Scale points across the study period [95% confidence interval = -8.6 to -0.3]). We found similar evidence for effect modification by neighborhood poverty, although the intervention effect weakened after the initial 4 months of the trial for participants residing in poor neighborhoods. There was no evidence of substantial differences in the effectiveness of the intervention on suicidal ideation and depression remission by economic disadvantage. CONCLUSIONS: Economic conditions moderated the effectiveness of primary-care-based treatment for late-life depression. Financially strained individuals benefited more from the intervention; we speculate this was because of the enhanced treatment management protocol, which led to a greater improvement in the care received by these persons. People living in poor neighborhoods experienced only temporary benefit from the intervention. Thus, multiple aspects of economic disadvantage affect depression treatment outcomes; additional work is needed to understand the underlying mechanisms

In vitro ecotoxicological assessment of pelagic ecosystems

The ICES biological effects monitoring in pelagic ecosystems (BECPELAG) workshop is a multi-national, multi-disciplinary workshop aimed at establishing suitable techniques for monitoring the effects of contaminants on pelagic ecosystems. One of the many activities that have been performed concurrently is the extraction of water samples using semi-permeable membrane devices (SPMDs) and large volume solid phase extraction (SPE) followed by in vitro testing and targeted chemical analysis of the concentrated extracts. The following in vitro assays were used: DR-CALUX, yeast oestrogen and androgen screen (YES & YAS), blue mussel (Mytilus edulis) embryo, Tisbe battagliai, and Skeletonema costatum. Data from the study are presented along with recommendations on procedures for the use of in vitro in the monitoring of the pelagic environment

The X-ray Warm Absorber in NGC3516

The Seyfert 1 galaxy, NGC3516 has been the subject of many absorption line studies at both ultraviolet and X-ray wavelengths. In the UV, strong, broad, variable associated metal line absorption with velocity width $\sim 2000$ \kms\ is thought to originate in gas with nh larger than about $10^{19}$ cm$^{-2}$ lying between 0.01 and 9 pc from the central active nucleus. The Ginga X-ray data are consistent with several possibilities: a warm absorber and a cold absorber combined either with partial covering or an unusually strong reflection spectrum. We present ROSAT observations of NGC3516 which show a strong detection of a warm absorber dominated by a blend of OVII/OVIII edges at $\sim$ 0.8 keV with nh $\sim 7\times 10^{21}$ cm$^{-2}$ and U: 8--12. We argue that NGC3516 contains an outflowing `XUV' absorber showing the presence of X-ray absorption edges, that are consistent with the presence of broad absorption lines in the old IUE spectra and their disappearance in the new UV observations. Our dynamical model suggests that the OVII absorption edge will continue to weaken compared to the OVIII edge, an easily testable prediction with future missions like AXAF. Eventually the source would be transparent to the X-rays unless a new absorption system is produced.Comment: 24 pages with 5 figures. To appear in the Ap.J. Requires AAS macro

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: A phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w

Non-Thermal X-ray Emission from the Northwestern Rim of the Galactic Supernova Remnant G266.2-1.2 (RX J0852.0-4622)

We present a detailed spatially-resolved spectroscopic analysis of two X-ray observations (with a total integration time of 73280 seconds) made of the luminous northwestern rim complex of the Galactic supernova remnant (SNR) G266.2-1.2 (RX J0852.0-4622) with the Chandra X-ray Observatory. G266.2-1.2 is a member of a class of Galactic SNRs which feature X-ray spectra dominated by non-thermal emission: in the cases of these SNRs, the emission is believed to have a synchrotron origin and studies of the X-ray spectra of these SNRs can lend insights into how SNRs accelerate cosmic-ray particles. The Chandra observations have clearly revealed fine structure in this rim complex and the spectra of these features are dominated by non-thermal emission. We have measured the length scales of the upstream structures at eight positions along the rim and derive lengths of 0.02-0.08 pc (assuming a distance of 750 pc to G266.2-1.2). We have also extracted spectra from seven regions in the rim complex and fit these spectra with such models as a simple power law as well as the synchrotron models SRCUT and SRESC. We have constrained our fits to the latter two models using estimates for the flux densities of these filaments at 1 GHz as determined from radio observations made with the Australia Telescope Compact Array (ATCA). Statistically-acceptable fits to all seven regions are derived using each model: differences in the fit parameters (such as photon index and cutoff frequency) are seen in the different regions, which may indicate variations in shock conditions and the maximum energies of the cosmic-ray electrons accelerated at each region. Finally, we estimate the maximum energy of cosmic-ray electrons accelerated along this rim complex to be approximately 40 TeV. We include a summary of estimated maximum energies for both Galactic SNRs as well as SNRs located in the Large Magellanic Cloud.Comment: 56 Pages, 11 Figures, Accepted for publication in the Astrophysical Journa