897 patients received radiotherapy in Scotland for tumours of the testis between 1950-1969. 299 patients who died within two years of treatment, and a further 51 patients with inadequate follow-up data, were excluded from a survey of the incidence of second tumours. 547 patients with a mean follow-up of 15.4 years were included in the study. Fifty-one second and six third malignancies were found. The observed incidence is significantly higher than expected (ratio 1.87; p less than 0.001), both in the irradiated sites (ratio 1.94; p less than 0.05) and in unirradiated sites (ratio 1.99; p less than 0.01). These patients have a higher incidence of second testicular tumours (ratio 23.1; p less than 0.001). Analysis of the incidence of new malignancies in successive quinquennia after irradiation shows a significantly higher incidence in two periods. Within five years the greater incidence (p less than 0.05) is due mainly to the occurrence of second testicular tumours. In the period 15-19 years after irradiation the higher incidence (p less than 0.01) is accounted for by tumours arising in the urinary and gastro-intestinal tracts. The increased risk of developing a second cancer is low and there was no observed increase in radiation-related leukaemia.
A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (T1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells. We found that stimulation of the T cell receptor (TCR)-CD3 complex was associated with a reduction in the apparent molecular mass of CD46 in a manner that depended on O-glycosylation. CD3-stimulated changes in CD46 O-glycosylation status reduced CD46 processing and subsequent T cell signaling. During T cell activation, CD46 was recruited to the immune synapse in a manner that required its serine-, threonine-, and proline-rich (STP) region, which is rich in O-glycosylation sites. Recruitment of CD46 to the immune synapse switched T cells from producing the inflammatory cytokine interferon-γ (IFN-γ) to producing IL-10. Furthermore, CD4 T cells isolated from MS patients did not exhibit a CD3-stimulated reduction in the mass of CD46 and thus showed increased amounts of cell surface CD46. Together, these data suggest a possible mechanism underlying the regulatory function of CD46 on T cells. Our findings may explain why this pathway is defective in patients with MS and provide insights into MS pathogenesis that could help to design future immunotherapies.
Tumorigenicity of human lymphoma and lymphoblastoid B-cell lines was assessed by their ability to form growing and transplantable masses on subcutaneous inoculation into neonatally thymectomized, Ara-C-protected, total-body-irradiated mice. By these criteria, 12 lines of known malignant origin were tumorigenic, 11 lymphoblastoid lines, tested after less than one year of in vitro growth, were non-tumorigenic and 8/18 long-established lymphoblastoid lines produced transplantable tumours. All of the long-established lines had acquired karyotypic changes on prolonged culture, the predominant characteristic being a gain of whole chromosomes or of major chromosome segments. None showed the classical 8:14 translocation associated with Burkitt's lymphoma. Comparisons with nontumorigenic precursors (recovered from liquid nitrogen storage) and with other non-tumorigenic but chromosomally abnormal, lymphoblastoid lines suggest that imbalance of the dosage of genes carried on chromosomes 7,8 and 9 may be important in determining the tumorigenic phenotype.
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