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Transforming growth factors (TGFs) are peptides that affect the growth and phenotype of cultured cells and bring about in nonmalignant fibroblastic cells phenotypic properties that resemble those of malignant cells. Two types of TGFs have been well characterized. One of these, TGF alpha, is related to epidermal growth factor (EGF) and binds to the EGF receptor, whereas the other, TGF beta, is not structurally or functionally related to TGF alpha or EGF and mediates its effects via distinct receptors. TGF beta is produced by a variety of normal and malignant cells. Depending upon the assay system employed, TGF beta has both growth-inhibitory and growth-stimulating properties. Many of the mitogenic effects of TGF beta are probably an indirect result of the activation of certain growth factor genes in the target cell. The ubiquitous nature of the TGF beta receptor and the production of TGF beta in a latent form by most cultured cells suggests that the differing cellular responses to TGF beta are regulated either by events involved in the activation of the factor or by postreceptor mechanisms. The combined effects of TGF beta with other growth factors or inhibitors evidently play a central role in the control of normal and malignant cellular growth as well as in cell differentiation and morphogenesis. Since transforming growth factor as a concept has partially proven misleading and insufficient, there is a need to find a new nomenclature for these regulators of cellular growth and differentiation.
Clinical and histopathologic data from 87 patients with primary non-Hodgkin's lymphoma of the gastrointestinal (GI) tract diagnosed between 1974 and 1984 were reviewed. B-cell lymphomas of intermediate- or high-grade histology constituted 78% of lesions. Stage of disease varied with histologic grade, with a preponderance of advanced disease (stages IIIE and IV) in patients with low-grade lymphoma (15 of 21) (71%), compared with higher grade lesions (38%, P = .01). Among patients with nonlocalized (stages IIE through IV) lymphoma of intermediate- or high-grade histology, surgical resection of the primary focus afforded a higher rate of complete remission (CR) (70% v 50%) and sustained CR (61% v 21%, P = .04) after cytotoxic therapy compared with the nonresected cohort. The median survival in the resected group was 51 months + compared with 13 months in the nonresected patients (P = .012). Differences in outcome were attributable to a high risk of treatment-related complications (perforation and/or hemorrhage) (43% v 0%, P = .001) and local relapse (29% v 4%, P = .05) in nonresected individuals. Life-threatening local complications were not observed in patients with low-grade lymphoma managed solely with medical therapy. Histologic findings from surgically staged patients identified presence of extravisceral disease and intermediate- or high-grade tumor histology as features predictive of transmural invasion, enabling potential identification of patients who might be optimally managed by resection of the primary GI focus before initiation of cytotoxic therapy.
Eleven patients received four consecutive weekly cycles of human recombinant interleukin 2 (IL-2) by continuous infusion for 4 days/week. Two dose levels were tested, 1 and 3 X 10(6) units/m2/day. Toxicities experienced by most patients included fever, rigors, fatigue, anemia, eosinophilia, and liver function abnormalities. All side effects from treatment reversed and no severe or life-threatening problems occurred. A marked lymphocytosis was seen following the 4 weeks of therapy. Fresh lymphocytes obtained during this lymphocytosis mediated enhanced destruction in vitro of a natural killer cell-resistant tumor cell line (Daudi). The increase in the absolute number of circulating lymphocytes and their enhanced ability to mediate direct lysis of Daudi targets resulted in a greater than 100-fold mean increase in cytotoxic potential by the end of IL-2 treatment. One patient, with renal carcinoma, who was treated at 3 X 10(6) units/m2/day experienced a sustained measurable response with greater than 50% regression of pulmonary and hepatic metastases. Five patients were retreated with a second course of IL-2, lasting 4 weeks. This therapy was well tolerated in four of these five patients, with similar immunological changes occurring. No further antitumor responses were seen in these patients. Thus, a relatively well tolerated immunotherapy regimen using IL-2 can induce dramatic increases in lymphocyte number and augment their in vitro antitumor reactivity.
Mammalian cells transformed by nononcogenic human adenoviruses exhibit high susceptibility to destruction by host mononuclear inflammatory cells. We have analyzed the viral gene regulation of the susceptibility of transformed cells to lysis by natural killer cells and activated macrophages. Comparisons of target cell lines transformed by overlapping segments of the adenovirus E1-transforming gene region revealed that isolated expression of a single oncogene, E1A, was sufficient to cause increased cytolytic susceptibility in the absence of detectable transformed cell-surface expression of viral transplantation antigens and irrespective of histocompatibility antigen identity between killer cells and target cells. These results suggest that oncogene functions that are not linked to the expression of previously recognized cell-surface target structures may actively induce neoplastic cell elimination by components of the host immune surveillance system.
Signal recognition particle (SRP), a small ribonucleoprotein required for targeting secretory proteins to the ER, has three known functions: signal recognition, elongation arrest, and translocation promotion. Because SRP is inactivated by the sulfhydryl alkylating reagent N-ethylmaleimide (NEM), we have attempted to establish structure-function relationships within SRP by assembling particles in which a single protein is modified. Alkylation of the 68/72 kd protein of SRP yields a particle that arrests elongation but fails to promote translocation and no longer interacts with SRP receptor. Alkylation of the 54 kd protein yields a particle that fails to recognize signal sequences. This approach has allowed us to map activities to specific protein domains on SRP, and should be generally useful for analyzing other ribonucleoproteins.
Integrated viral sequences and adjacent cellular sequences from the polyoma virus (Py)-transformed 53-Rat and 82-Rat cell lines which contain two and three partial early regions respectively, each in a single viral insert, have been molecularly cloned. Each of the cloned partial early regions have been subcloned and assessed with regard to their transcription, translation products (T antigens, T Ags) and biological activity including their transforming ability. The 53-Rat 5.3 kb EcoRI fragment is an intact Py EcoRI linear genome (derived from within the tandem duplicated sequences) which transforms rat cells with high efficiency and produces infectious virus when circularized and transfected into mouse cells. The 82-Rat cell line expresses three novel T Ag species of 63K, 40K and 32K in addition to the Py middle and small T Ags. The 63K protein was found to be a truncated form of large T Ag produced as the result of an addition/deletion in early region B sequences unique to large T Ag. The 40K and 32K proteins are hybrid viral-cellular middle and large T Ags respectively, which are expressed from early region A that has been truncated by recombination with rat cellular DNA. Differences in the nuclear and cytoplasmic location of the different 82-Rat early region RNAs are due to RNA stability and/or transport from the nucleus to the cytoplasm most likely as a result of different cellular sequences at their 3' ends. Finally no common structural feature or sequence specificity was observed at the virus-host DNA joins of the two cell lines.
The phenotype of a differentiated cell results from the expression of a unique set of genes in that cell. The differentiation of F9 teratocarcinoma cells in response to retinoic acid and cyclic AMP is an excellent example of this process, as the appearance of several gene products during the course of the differentiation process has been documented. In principle, the activation of gene expression could be due to the appearance of positive-acting factors, the loss of negative-acting factors, or a combination of both. Since F9 cells have been shown to express a cellular E1A analog whereas differentiated F9 cells do not, and it is known that the viral E1A gene exerts a negative effect on transcription of both viral and cellular genes, we determined whether the cellular genes activated during F9 cell differentiation are subject to E1A negative control. We found that infection of differentiated F9 cells with wild-type adenovirus resulted in a decline in the levels of collagen type IV mRNA and plasminogen activator mRNA, both of which are induced by differentiation. At least for the collagen gene, this phenomenon appears to involve a transcriptional repression.
XIHbox 1 is expressed in a narrow band across the cervical region of Xenopus embryos. The gene produces two related proteins: "long" and "short" XIHbox 1 homeodomain proteins. Injection of antibodies to the long XIHbox 1 protein into 1-cell embryos caused a phenotype in which the anterior spinal cord was morphologically transformed into a hindbrain-like structure. This alteration was restricted to the region normally expressing long XIHbox 1 protein. Injection of long protein mRNA disrupted segmentation and tissue organization without inhibiting cell proliferation. Injection of short protein mRNA into 1-cell embryos produced spinal cord malformations similar, but not identical, to those caused by the antibodies, suggesting antagonistic roles for long and short XIHbox 1 proteins. We immunostained tadpoles carrying extended hindbrains for N-CAM and consistently found defective organization of spinal nerves over the affected region.
Spondyloarthropathies are rare in Africa and there is little data regarding HLA association. We prospectively studied 19 patients with spondyloarthropathy, recording clinical details and performing tissue typing (ABC loci). There were 9 patients with ankylosing spondylitis (8 males), all had severe spinal disease but none had ocular or cardiac involvement and HLA-B27 antigen was not found in any of the 7 patients tested; only one patient possessed a B7 crossreacting antigen. The 10 patients with Reiter's syndrome (8 males) had typical clinical features but again the HLA-B27 tissue type was not found. B7-CREG antigen was found in 7 of the 10 patients with Reiter's syndrome.
Non-MHC-restricted killer cells are cytotoxic lymphocytes that can mediate cytolysis of most tumor targets without apparent selectivity and restriction by the MHC, particularly when activated with IL-2. These effector cells include predominantly NK cells and T cells expressing the TCR-gamma/delta. We found that TCR-gamma/delta-1+, delta TSC1-, BB3+, Ti gamma A+ T cell clones mediate a characteristic cytolytic pattern of non-MHC-restricted cytolysis that is markedly different from NK clones and alpha/beta T cell clones derived from the peripheral blood of the same normal individuals. The characteristic finding is that all BB3/Ti gamma A+ gamma/delta clones mediate strong cytolysis of Daudi cells but they do not lyse Raji cells. In contrast, NK clones from the same donors mediate strong cytolysis of both Daudi and Raji targets. Cytotoxicity by the gamma/delta clones on certain target cells such as Daudi and Molt 4 can be specifically inhibited by mAbs reactive against the TCR-gamma/delta. Therefore, the TCR-gamma/delta on these clones either directly recognizes target epitopes on some tumor targets or it is involved in the regulation of their cytotoxic function. The expression of TCR-gamma/delta products reacting with the BB3 and Ti gamma A mAbs reflects the usage of identical TCR-gamma/delta V region genes that appear to be associated with the characteristic pattern of non-MHC-restricted cytotoxicity displayed by this major subset of human peripheral blood gamma/delta cells.