Extensive intraductal component (EIC) and estrogen receptor (ER) status in breast cancer

The extensive intraductal component (EIC) of primary breast carcinoma is a special spread pattern observed In the breast. Extensive intradwtal component may extend diffusely over the entim breast. Therefore, EIC Is considered to be an important risk factor for local recurrence in breast-conserving therapy. However, the pathogenesis of EIC remains uncertain. Whether or not the estrogen receptor (ER) has an influence on its biologic behavior has not been fully studied. A consecutive series of 142 breast carcinomas submitted to the pathology department were examined on step gross dons of 5.0 mm thick. Extensive intraductal component was determined and divided into three types. Estrogen receptor was examined using both immunohistochemistry (ER-IHC) and enzyme immunoassay (ER-EIA). Extensive intraductal component was found In 78 of 138 (56.52%) invaslve carcinomas including invasive ductal carcinoma with a predominant intraductal component. Estrogen receptor-IHC positivity was 42.96% (61/142) in the Invasive breast carcinoma. Estrogen receptor positivity showed no significant difference between ElC-positive and -negative cases, as well as between EIC and Invasive main tumor in the ElC-positive cases. But within the ElC-positive group, ER positivity was found to be higher in the peripheral type of ElC-II and ElC-III than in the central type of ElC-I ( P <0.05). Although ER may not play an essential role in the pathogenesis of EIC, it has shown some significance in the development of peripheral type EIC because of its higher presence in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I.     

Dynamics of Cytotoxic T Lymphocyte Precursors in Vivo Assessed by Change in the Radiation Sensitivity

The dynamics of cytotoxic T lymphocyte precursors (CTL-p) in mice injected with allogeneic spleen cells (SC) was studied with special reference to changes in their radiation sensitivity. Whole-body 400 rad X-ray irradiation of allo-SC-primed and unprimed mice virtually abolished the capacity of their SC to proliferate and to generate CTL in primary or secondary mixed leucocyte culture (MLC). However, the impaired ability of SC to generate CTL in the primary MLC was restored by interleukin 2 (IL-2). This showed that helper cells whose activity was replaceable with IL-2 (IL-2-producing cells) were functionally more radiation-sensitive than CTL-p in unprimed mice. In contrast, the radiation-impaired activity in secondary MLC was not restored by IL-2, suggesting that memory CTL-p in allo-SC-primed mice were unexpectedly sensitive to radiation. The D37 values determined from the percentage of residual CTL-p activity of SC in bulk cultures 1 day after irradiation were 525 rad for virgin CTL-p and 75 rad for memory CTL-p. Further studies demonstrated that the radiation-sensitive memory CTL-p were generated from relatively radiation-resistant precursors, largely independent of radiation-sensitive IL-2-producing cells and of cellular proliferation. The mean frequency of CTL-p in SC measured by limiting dilution assay was not significantly increased by the priming. This supports our conclusion that the development of the memory CTL-p activity in allo-SC-primed mice did not depend on clonal expansion. Whole-body 400 rad-irradiation reduced the frequency of CTL-p in SC from unprimed mice to 1/2-1/3 and that in SC from allo-SC-primed mice to 1/8-1/15. This supports the view that the majority of radiation-resistant virgin CTL-p functionally mature to radiation-sensitive memory CTL-p without cellular proliferation in allo-SC-primed mice.     

Intra‐articular injection of mesenchymal stem cells expressing coagulation factor ameliorates hemophilic arthropathy in factor VIII‐deficient mice

Summary. Background: Transplantation of cells overexpressing a target protein represents a viable gene therapeutic approach for treating hemophilia. Here, we focused on the use of autologous mesenchymal stem cells (MSCs) expressing coagulation factor for the treatment of coagulation factor VIII (FVIII) deficiency in mice. Methods and Results: Analysis of luciferase gene constructs driven by different promoters revealed that the plasminogen activator inhibitor‐1 (PAI‐1) gene promoter coupled with the cytomegalovirus promoter enhancer region was one of the most effective promoters for producing the target protein. MSCs transduced with the simian immunodeficiency virus (SIV) vector containing the FVIII gene driven by the PAI‐1 promoter expressed FVIII for several months, and this expression was maintained after multiple mesenchymal lineage differentiation. Although intravenous injection of cell supernatant derived from MSCs transduced with an SIV vector containing the FVIII gene driven by the PAI‐1 promoter significantly increased plasma FVIII levels, subcutaneous implantation of the MSCs resulted in a transient and weak increase in plasma FVIII levels in FVIII‐deficient mice. Interestingly, intra‐articular injection of the transduced MSCs significantly ameliorated the hemarthrosis and hemophilic arthropathy induced by knee joint needle puncture in FVIII‐deficient mice. The therapeutic effects of a single intra‐articular injection of transduced MSCs to inhibit joint bleeding persisted for at least 8 weeks after administration. Conclusions: MSCs provide a promising autologous cell source for the production of coagulation factor. Intra‐articular injection of MSCs expressing coagulation factor may offer an attractive treatment approach for hemophilic arthropathy.