No abstract

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

Ex-vivo regional gene therapy with bone marrow cells (BMCs) overexpressing bone morphogenetic protein-2 (BMP-2) has demonstrated efficacy in healing critical sized bone defects in preclinical studies. The purpose of this preclinical study was to compare the osteoinductive potential of a novel "same day" ex-vivo regional gene therapy versus a traditional two-step approach, which involves culture expansion of the donor cells before implantation. In the "same day" strategy buffy coat cells were harvested from the rat bone marrow, transduced with a lentiviral vector-expressing BMP-2 for 1 hour and implanted into a rat femoral defect in the same sitting. There was no significant difference (P = 0.22) with respect to the radiographic healing rates between the femoral defects treated with the "same day" strategy (13/13; 100%) versus the traditional two-step approach (11/14; 78%). However, the femoral defects treated with the "same day" strategy induced earlier radiographic bone healing (P = 0.004) and higher bone volume (BV) [micro-computed tomography (micro-CT); P < 0.001]. The "same day" strategy represents a significant advance in the field of ex-vivo regional gene therapy because it offers a solution to limitations associated with the culture expansion process required in the traditional ex vivo approach. This strategy should be cost-effective when adapted for human use.

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is primarily expressed on activated T cells and is known to enhance proliferation of T cells, prevent activation-induced cell death, and promote memory formation of CD8+ T cells. In particular, it is well acknowledged that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells rather than CD4+ T cells, but the underlying mechanism remains unclear. Here we found that 4-1BB triggering markedly increased IL-2Rα (CD25) and IL-2 expressions of CD8+ T cells but minimally for CD4+ T cells. Proliferation of CD8+ T cells was moderately enhanced by direct 4-1BB triggering in the absence of signaling through IL-2Rα/IL-2 interactions, but further promoted in the presence of IL-2Rα/IL-2 interactions. Among the TNFRSF members including OX40, GITR, CD30, and CD27, 4-1BB was superior in the ability to induce IL-2Rα expression on CD8+ T cells. When the primary and secondary expansions of CD8+ T cells in vivo were examined by adoptively transferring OVA-specific CD8+ T cells along with the treatment with agonistic anti-4-1BB and/or antagonistic anti-CD25 F(ab’)2 mAb, 4-1BB triggering enhanced both primary and secondary expansion of CD8+ T cells in vivo, and the 4-1BB effects were moderately suppressed in primary expansion while completely abolished in secondary expansion of OVA-specific CD8+ T cells by blocking IL-2Rα. These results suggest that 4-1BB-mediated increases of IL-2Rα and IL-2 prolong the effects of transient TCR- and 4-1BB-mediated signaling in CD8+ T cells, and that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells through the amplification of autocrine IL-2/IL-2R signaling loop.

Decision making at the early stages of a construction project has a significant impact on the project, and various scenarios created based on the owner's requirements should be considered for the decision making. At the early stages of a construction project, the information regarding the project is usually limited and uncertain. As such, it is difficult to plan and manage the project (especially cost planning). Thus, a cost model that could be varied according to the owner's requirements was developed. The cost model that was developed in this study is based on the case‐based reasoning (CBR) methodology. The model suggests cost estimation with the most similar historical case as a basis for the estimation. In this study, the optimization process was also conducted, using genetic algorithms that reflect the changes in the number of project characteristics and in the database of the model according to the owner's decision making. Two optimization parameters were established: (1) the minimum criteria for scoring attribute similarity (MCAS); and (2) the range of attribute weights (RAW). The cost model proposed in this study can help building owners and managers estimate the project budget at the business planning stage. Santruka Sprendimu priemimas ankstyvuoju statybos projekto etapu turi didele itaka projektui ir ivairiems scenarijams, remiantis savininko reikalavimais, kuriu turi būti laikomasi priimant sprendimus. Ankstyvaisiais statybos projekto etapais informacijos apie projekta paprastai yra nedaug ir ji nera patikima. Del to sudetinga planuoti ir taisyti projekta (ypač išlaidu planavima). Todel šio tyrimo metu buvo sukurtas kainos modelis, kuris galetu būti keičiamas atsižvelgiant i savininko poreikius. Kainos modelis, kuris buvo sukurtas šio tyrimo metu, remiasi atveju analize, pagrista argumentu metodika (angl. CBR). Modelis siūlo samatinius skaičiavimus su panašiausiais ankstesniais atvejais, kurie yra skaičiavimo pagrindas. Šio tyrimo metu procesas buvo optimizuotas naudojant genetinius algoritmus, rodančius projektu skaičiaus kitima tam tikro modelio duomenu bazeje pagal savininko priimamus sprendimus. Buvo nustatyti du optimizavimo parametrai: 1) minimalūs kriterijai veiksniu panašumui ivertinti (angl. MCAS); 2) veiksniu svoriu vertinimo intervalas (angl. RAW). Kainos modelis, pasiūlytas šiame tyrime, gali padeti pastatu savininkams ir valdytojams ivertinti projekto biudžeta verslo planavimo etape.