Plan for fish ponds; estate of Mr. James A. Allison

Black and red ink on linen; some pencil. Location of ponds, buildings and gardens; elevations; two cross-section details of pond depth and drainage; some penciled topographical lines, elevations and changes in location of buildings, walkways and ponds. 93 cm. x 57 cm. [Marion College] [from photographic copy by Lance Burgharrdt]

Topographical survey; grounds of Mr. James A. Allison

Ink on linen. Elevations, location of drainage tiles, buildings and vegetation. Includes some penciled lines and notes. 94 cm. x 80 cm. Scale: 1"= 50' [Marion College] [from photographic copy by Lance Burgharrdt]

Design for boulder bridge; grounds of Mr. James A. Allison

Red and black ink on linen. View from top, side and end elevations and cross-section with distances and grades. 111 cm. x 50 cm. Scale: 1/4" = 1'. Signed. [Marion College] [from photographic copy by Lance Burgharrdt]

Topographical survey; grounds of Mr. James A. Allison

Black and red ink on linen. Elevations, topographical lines, location of vegetation, buildings and drainage tiles; locations of (proposed?) gardens, walkways, ponds, stables, etc. penciled in. 92 cm. x 83 cm. Scale: 1" = 50'. [Marion College] [from photographic copy by Lance Burgharrdt]

General plan; grounds of Mr. James A. Allison

Pencil and red ink on linen. Indicates location of buildings, ponds, gardens, vegetation, sewers, etc. Signed. 92 cm x 84 cm. Scale: 1" = 50'. Signed. [Marion College] [from photographic copy by Lance Burgharrdt]

Planting plan for gardens; estate of Mr. James A. Allison

Red and black ink on linen. Instructions on location, type and amount of vegetation. Signed. 103 cm. x 88 cm. Scale: 1" = 20'. Signed. [Marion College] [from photographic copy by Lance Burgharrdt]

Plan showing location of tennis court, vegetable garden and walls, and grounds of James A. Allison

Pencil on linen. Elevations for walls and gates. Signed. 106 cm. x 27 cm. Scale: 1" = 20'. [Marion College] [from photographic copy by Lance Burgharrdt]

The several social constructions of James, Jenks, and Prout: A contribution to the sociological theorization of childhood

The article is intended to contribute to the ongoing debate over theorizations of childhood, especially in the terms articulated by Allison James, Chris Jenkins and Alan Prout. The article focuses on the notion of social construction as a theory of childhood. There are four valid approaches to theorizing childhood. The tribal approach treats childhood as a kind of exotic tribe with its own beliefs, practices and institutions. The social structural approach treats childhood as a structurally necessary stratum in any society. The minority group approach treats childhood as an oppressed minority group, able to some extent to represent themselves and exert quasi-political action. The socially constructed approach constitutes the sociological view of childhood. The key role played by the idea of social construction is made extremely clear in the earlier work, Constructing and Reconstructing Childhood by James and Prout. Social constructionism is said to be an interpretive approach, related historically to research on children's understanding of adult experimenters' intentions. The senses of social construction that emerge from critical psychology overlap a great deal with those articulated in the new sociology of childhood.

Design for garden pool; grounds of Mr. J.A. Allison

Black and red ink on tracing paper. Plan and detailed cross-sections of pool and drainage details with measurements and materials specified. Signed. 72 cm. x 51 cm. Scale: 1/2 " = 1'. [Marion College] [from photographic copy by Lance Burgharrdt]

Cancer classification using the Immunoscore: a worldwide task force

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein

CTLA-4 plays a critical role in regulating the immune response. It is mainly located in cytoplasmic vesicles and is expressed only transiently on the surface after T cell activation. In this study, we demonstrate that CTLA-4 is associated with AP50, the medium chain of the clathrin-associated coated pit adaptor protein complex AP2. In a yeast two-hybrid screen, three individual cDNA clones that encode mouse AP50 were isolated, all of which can interact specifically with the cytoplasmic domain of mouse CTLA-4, but not with the cytoplasmic domain of mouse CD28. We have shown that CTLA-4 can bind specifically to AP50 when CTLA-4 and AP50 are cotransfected into human 293T cells. A Y201 to F201 mutation in the YVKM intracellular localization motif of the CTLA-4 cytoplasmic domain significantly diminished its binding to AP50. We also found that AP50 bound to a CTLA-4 peptide containing unphosphorylated Y201 but not to a peptide containing phosphorylated Y201. Conversely, the p85 subunit of phosphatidylinositol 3-kinase and, to a lesser extent, protein tyrosine phosphatase SYP (SHP-2) and SHP (SHP-1) bind only to the CTLA-4 peptide containing phosphorylated Y201. Therefore, the phosphorylation status of Y201 in the CTLA-4 cytoplasmic domain determines the binding specificity of CTLA-4. These results suggest that AP50 and the coated pit adaptor complex AP2 may play an important role in regulating the intracellular trafficking and function of CTLA-4.

Thymocyte development is normal in CTLA-4-deficient mice

Recent studies indicate that CTLA-4 interaction with B7 ligands transduces an inhibitory signal to T lymphocytes. Mice homozygous for a null mutation in CTLA-4 have provided the most dramatic example of the functional importance of CTLA-4 in vivo. These animals develop a fatal lymphoproliferative disorder and were reported to have an increase in CD4+ and CD8+ thymocytes and CD4−CD8− thymocytes, and a decrease in CD4+CD8+ thymocytes. Based on these observations, it was proposed that CTLA-4 is necessary for normal thymocyte development. In this study, CTLA-4-deficient mice carrying an insertional mutation into exon 3 of the ctla-4 gene were generated. Although these mice display a lymphoproliferative disorder similar to previous reports, there was no alteration in the thymocyte profiles when the parathymic lymph nodes were excluded from the thymi. Further, thymocyte development was normal throughout ontogeny and in neonates, and there was no increase in thymocyte production. Finally, T cell antigen receptor signaling, as assessed by proximal and distal events, was not altered in thymocytes from CTLA-4−/− animals. Collectively, these results clearly demonstrate that the abnormal T cell expansion in the CTLA-4-deficient mice is not due to altered thymocyte development and suggest that the apparent altered thymic phenotype previously described was due to the inclusion of parathymic lymph nodes and, in visibly ill animals, to the infiltration of the thymus by activated peripheral T cells. Thus it appears that CTLA-4 is primarily involved in the regulation of peripheral T cell activation.

Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy

Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection. For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%. Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive C2 lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.

Lack of a role for transforming growth factor-β in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation

Similarities in the phenotypes of mice deficient for cytotoxic T lymphocyte antigen-4 (CTLA-4) or transforming growth factor-β1 (TGF-β1) and other observations have led to speculation that CTLA-4 mediates its inhibitory effect on T cell activation via costimulation of TGF-β production. Here, we examine the role of TGF-β in CTLA-4-mediated inhibition of T cell activation and of CTLA-4 in the regulation of TGF-β production. Activation of AND TCR transgenic mouse T cells with costimulatory receptor-specific antigen presenting cells results in efficient costimulation of proliferation by CD28 ligation and inhibition by CTLA-4 ligation. Neutralizing antibody to TGF-β does not reverse CTLA-4-mediated inhibition. Also, CTLA-4 ligation equally inhibits proliferation of wild-type, TGF-β1−/−, and Smad3−/− T cells. Further, CTLA-4 engagement does not result in the increased production of either latent or active TGF-β by CD4+ T cells. These results indicate that CTLA-4 ligation does not regulate TGF-β production and that CTLA-4-mediated inhibition can occur independently of TGF-β. Collectively, these data demonstrate that CTLA-4 and TGF-β represent distinct mechanisms for regulation of T cell responses.

Journal of the Military Service Institution of the United States.

No more published.