D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination.

INTRODUCTION: Proteins that undergo receptor-mediated endocytosis are subject to lysosomal degradation, requiring radioiodination methods that minimize loss of radioactivity from tumor cells after this process occurs. To accomplish this, we developed the residualizing radioiodination agent N(ϵ)-(3-[(*)I]iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-D-GEEEK (Mal-D-GEEEK-[(*)I]IB), which enhanced tumor uptake but also increased kidney activity and necessitates generation of sulfhydryl moieties on the protein. The purpose of the current study was to synthesize and evaluate a new D-amino acid based agent that might avoid these potential problems. METHODS: N(α)-(3-iodobenzoyl)-(5-succinimidyloxycarbonyl)-D-EEEG (NHS-IB-D-EEEG), which contains 3 D-glutamates to provide negative charge and a N-hydroxysuccinimide function to permit conjugation to unmodified proteins, and the corresponding tin precursor were produced by solid phase peptide synthesis and subsequent conjugation with appropriate reagents. Radioiodination of the anti-HER2 antibody trastuzumab using NHS-IB-D-EEEG and Mal-D-GEEEK-IB was compared. Paired-label internalization assays on BT474 breast carcinoma cells and biodistribution studies in athymic mice bearing BT474M1 xenografts were performed to evaluate the two radioiodinated D-peptide trastuzumab conjugates. RESULTS: NHS-[(131)I]IB-D-EEEG was produced in 53.8%±13.4% and conjugated to trastuzumab in 39.5%±7.6% yield. Paired-label internalization assays with trastuzumab-NHS-[(131)I]IB-D-EEEG and trastuzumab-Mal-D-GEEEK-[(125)I]IB demonstrated similar intracellular trapping for both conjugates at 1h ((131)I, 84.4%±6.1%; (125)I, 88.6%±5.2%) through 24h ((131)I, 60.7%±6.8%; (125)I, 64.9%±6.9%). In the biodistribution experiment, tumor uptake peaked at 48 h (trastuzumab-NHS-[(131)I]IB-D-EEEG, 29.8%±3.6%ID/g; trastuzumab-Mal-D-GEEEK-[(125)I]IB, 45.3%±5.3%ID/g) and was significantly higher for (125)I at all time points. In general, normal tissue levels were lower for trastuzumab-NHS-[(131)I]IB-D-EEEG, with the differences being greatest in kidneys ((131)I, 2.2%±0.4%ID/g; (125)I, 16.9%±2.8%ID/g at 144 h). CONCLUSION: NHS-[(131)I]IB-D-EEEG warrants further evaluation as a residualizing radioiodination agent for labeling internalizing antibodies/fragments, particularly for applications where excessive renal accumulation could be problematic.

Surviving as an underrepresented minority scientist in a majority environment.

I believe the evidence will show that the science we conduct and discoveries we make are influenced by our cultural experience, whether they be positive, negative, or neutral. I grew up as a person of color in the United States of America, faced with challenges that many had as members of an underrepresented minority group. I write here about some of the lessons I have learned that have allowed me to survive as an underrepresented minority -scientist in a majority environment.

Finite groups and geometries: a view on the present state and on the future

The model: groups of Lie-Chevalley type and buildingsThis paper is not the presentation of a completed theory but rather a report on a search progressing as in the natural sciences in order to better understand the relationship between groups and incidence geometry, in some future sought-after theory Τ. The search is based on assumptions and on wishes some of which are time-dependent, variations being forced, in particular, by the search itself.A major historical reference for this subject is, needless to say, Klein's Erlangen Programme. Klein's views were raised to a powerful theory thanks to the geometric interpretation of the simple Lie groups due to Tits (see for instance), particularly his theory of buildings and of groups with a BN-pair (or Tits systems). Let us briefly recall some striking features of this.Let G be a group of Lie-Chevalley type of rank r, denned over GF(q), q = pn, p prime. Let Xr denote the Dynkin diagram of G. To these data corresponds a unique thick building B(G) of rank r over the Coxeter diagram Xr (assuming we forget arrows provided by the Dynkin diagram). It turns out that B(G) can be constructed in a uniform way for all G, from a fixed p-Sylow subgroup U of G, its normalizer NG(U) and the r maximal subgroups of G containing NG(U).

When the key is integrate : introduction to development of dormancy behavior groups weeds in agricultural crops

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Effect of agricultural management and weeds on feeding groups of nematode in Soybean

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The centrality of groups and classes

This paper extends the standard network centrality measures of degree, closeness and betweenness to apply to groups and classes as well as individuals. The group centrality measures will enable researchers to answer such questions as ‘how central is the engineering department in the informal influence network of this company?’ or ‘among middle managers in a given organization, which are more central, the men or the women?’ With these measures we can also solve the inverse problem: given the network of ties among organization members, how can we form a team that is maximally central? The measures are illustrated using two classic network data sets. We also formalize a measure of group centrality efficiency, which indicates the extent to which a group's centrality is principally due to a small subset of its members.

Ethnic variations in the experiences of mental health service users in England: results of a national patient survey programme

Background: Minority ethnic groups in the UK are reported to have a poor experience of mental health services, but comparative information is scarce. Aims: To examine ethnic differences in patients’ experience of community mental health services. Method: Trusts providing mental health services in England conducted surveys in 2004 and 2005 of users of community mental health services. Multiple regression was used to examine ethnic differences in responses. Results: About 27 000 patients responded to each of the surveys, of whom 10% were of minority ethnic origin. In the 2004 survey, age, living alone, the 2004 survey, age, living alone, detention and hospital admissions were stronger predictors of patient experience than ethnicity. Self-reported mental health status had the strongest explanatory effect. In the 2005 survey, the main negative differences relative to the White British were for Asians. Conclusions: Ethnicity had a smaller effect on patient experience than other variables. Relative to the White British, the Black group did not report negative experiences whereas the Asian group were most likely to respond negatively. However, there is a need for improvements in services for minority ethnic groups, including access to talking therapies and better recording of ethnicity.

Association for Learning Technology Annual Survey 2014 Data and Report

This is the first report from ALT’s new Annual Survey launched in December 2014. This survey was primarily for ALT members (individual or at an organisation which is an organisational member) it could however also be filled in by others, perhaps those interested in taking out membership. The report and data highlight emerging work areas that are important to the survey respondents. Analysis of the survey responses indicates a number of areas ALT should continue to support and develop. Priorities for the membership are ‘Intelligent use of learning technology’ and ‘Research and practice’, aligned to this is the value placed by respondent’s on by communication via the ALT Newsletter/News, social media and Research in Learning Technology. The survey also reveals ‘Data and Analytics’ and ‘Open Education’ are areas where the majority of respondents are finding are becoming increasingly important. As such our community may benefit from development opportunities ALT can provide. The survey is also a reminder that ALT has an essential role in enabling members to develop research and practice in areas which might be considered as minority interest. For example whilst the majority of respondents didn't indicate areas such as ‘Digital and Open Badges’, and ‘Game Based Learning’ as important there are still members who consider these areas are very significant and becoming increasingly valuable and as such ALT will continue to better support these groups within our community. Whilst ALT has conducted previous surveys of ALT membership this is the first iteration in this form. ALT has committed to surveying the sector on an annual basis, refining the core question set but trying to preserve an opportunity for longitudinal analysis.

What’s in a name: Dimensions of social learning in teacher groups

Induced by a literature review, this paper presents a framework of dimensions and indicators highlighting the underpinning aspects and values of social learning within teacher groups. Notions of social networks, communities of practice and learning teams were taken as the main perspectives to influence this social learning framework. The review exercise resulted in four dimensions: (1) practice, (2) domain and value creation, (3) collective identity and (4) organization. The indicators corresponding to these dimensions serve as the foundation for understanding social learning in practice. The framework of dimensions and indicators can be of assistance for researchers as well as teacher groups that aim to assess their views on social learning and analyse whether these views fit the learning goals of the group, or that adjustments are required. In this way, learning processes within groups of teachers can be improved.