In Silico Identification of Specialized Secretory-Organelle Proteins in Apicomplexan Parasites and In Vivo Validation in Toxoplasma gondii

Apicomplexan parasites, including the human pathogens Toxoplasma gondii and Plasmodium falciparum, employ specialized secretory organelles (micronemes, rhoptries, dense granules) to invade and survive within host cells. Because molecules secreted from these organelles function at the host/parasite interface, their identification is important for understanding invasion mechanisms, and central to the development of therapeutic strategies. Using a computational approach based on predicted functional domains, we have identified more than 600 candidate secretory organelle proteins in twelve apicomplexan parasites. Expression in transgenic T. gondii of eight proteins identified in silico confirms that all enter into the secretory pathway, and seven target to apical organelles associated with invasion. An in silico approach intended to identify possible host interacting proteins yields a dataset enriched in secretory/transmembrane proteins, including most of the antigens known to be engaged by apicomplexan parasites during infection. These domain pattern and projected interactome approaches significantly expand the repertoire of proteins that may be involved in host parasite interactions

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

“Not merely wifely devotion”: Collaborating in the Construction of Science at Terling Place

In this chapter I critique the literary construction of the scientific practice of John Strutt, Third Baron Rayleigh as a solitary pursuit within a domain separated from family life, and I analyze, instead, the science of his home, Terling Place, as a collaboration with his wife Evelyn Strutt, Baroness Rayleigh. As opposed to judging the character of their marital collaboration anachronistically through a professional lens, I analyze Terling science within the context of late-Victorian country-house society characterized by an aristocratic, evangelical-Anglican orientation. This case demonstrates how collaboration can be an unstable construct reliant upon the meanings imbued by the historical subjects and their discursive representations

Attending to Spirituality in Issues of Science and Religion: Challenges and Triumphs

Addressing students’ authentic selves and spiritual journeys poses pedagogical challenges, particularly for new faculty. The author reflects on his challenges and triumphs experienced while teaching Issues in Science and Religion at DePaul University’s School for New Learning, to highlight three effective strategies: multiple and varied means for students to expose their authentic selves in safe environments; disclosure of one’s authentic self to students to model spiritual reflection; and frequent reinforcement and clarification of course objectives and assessment criteria. The author provides examples of practices and discusses the value of collegial and institutional support and faculty development opportunities

\u27A Triumph of Brains over Brute\u27: Women and Science at the Horticultural College, Swanley, 1890-1910

The founding of Britain\u27s first horticultural college in 1889 advanced a scientific and coeducational response to three troubling national concerns: a major agricultural depression; the economic distress of single, unemployed women; and imperatives to develop the colonies. Buoyed by the technical instruction and women\u27s movements, the Horticultural College and Produce Company, Limited, at Swanley, Kent, crystallized a transformation in the horticultural profession in which new science-based, formalized study threatened an earlier emphasis on practical apprenticeship training, with the effect of opening male-dominated trades to women practitioners. By 1903, the college closed its doors to male students, and new pathways were forged for women students interested in pursuing further scientific study. Resistance to the Horticultural College\u27s model of science-based women\u27s horticultural education positioned science and women as contested subjects throughout this period of horticulture\u27s expansion in the academy

Introduction The Conchologist\u27s Companion

This introduction to the reprint of Mary Roberts\u27s popular conchology text (1831) sets it within the broader scope of her writing on marine biology and explains the influence of the Evangelical Revival on her meditative style

\u27A Triumph of Brains over Brute\u27: Women and Science at the Horticultural College, Swanley, 1890-1910

The founding of Britain\u27s first horticultural college in 1889 advanced a scientific and coeducational response to three troubling national concerns: a major agricultural depression; the economic distress of single, unemployed women; and imperatives to develop the colonies. Buoyed by the technical instruction and women\u27s movements, the Horticultural College and Produce Company, Limited, at Swanley, Kent, crystallized a transformation in the horticultural profession in which new science-based, formalized study threatened an earlier emphasis on practical apprenticeship training, with the effect of opening male-dominated trades to women practitioners. By 1903, the college closed its doors to male students, and new pathways were forged for women students interested in pursuing further scientific study. Resistance to the Horticultural College\u27s model of science-based women\u27s horticultural education positioned science and women as contested subjects throughout this period of horticulture\u27s expansion in the academy

Co-operative Comradeships Versus Same-Sex Partnerships: Historicizing Collaboration Among Homosexual Couples in the Sciences

In this chapter I consider a range of methodological challenges that complicate historical analysis of same-sex partnerships in science and then adopt Joan Scott\u27s concept of imbrications of subjective experiences with political discourses to analyze the sexual-science discourse of Edward Carpenter\u27s homosocial, country ménage near Sheffield, Britain at the turn of the twentieth century. Based on my analysis, I suggest Carpenter\u27s case necessitates an expansion of the category collaborative couples beyond a focus on cohabitating, married partners, and I introduce the contemporary term, co-operative comradeship as a more historically salient means by which to describe Carpenter\u27s collaborative industry

\u27Back to the land\u27: Lady Warwick and the Movement for Women\u27s Collegiate Agricultural Education

Within the late-Victorian and Edwardian movement to promote women\u27s advancement in farming and gardening, Frances Greville, countess of Warwick, founded the first women-only collegiate centre for agricultural education in 1898. Initially affiliated with the University Extension College, Reading, her scheme relocated to Studley, Warwickshire in 1903, where it flourished as an independent, private college. Historians have previously described the founding, development, and ultimate fate of Warwick\u27s project, but in this article I consider the question of its status within the broader movement for women\u27s collegiate agricultural education. As I show, Warwick\u27s advocacy for a \u27Back to the Land\u27 ideology and women\u27s scientific and practical instruction in the \u27lighter branches of agriculture\u27 added a decidedly rural, agrarian orientation to a movement otherwise dominated by an emphasis on urban horticulture; yet, despite her efforts, throughout its first decade, the scheme remained effectively trapped within the mould of horticultural education. The mismatch between Warwick\u27s ideals and practical achievements established her as a visionary whose contributions ironically reinforced the very tendencies she hoped to counteract