B cell early response gene expression coupled to B cell receptor,CD40 and interleukin-4 receptor co-stimulation: evidence for a role of the egr-2/krox20 transcription factor in B cell proliferation

B lymphocytes are activated following antigen stimulation of the B cell receptor but require co-stimulation with accessory molecules provided by interleukin (IL)-4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross-linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c-myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL-4. Co-stimulation with the proliferative combination of anti-μ, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox20 expression over that seen with anti-μ alone. Egr-2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr-2 activity elicited a dose-dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.     

Patterns of nuclear proto-oncogene expression during induced differentiation and proliferation of human B chronic lymphocytic leukaemia cells.

Phorbol ester-induced differentiation of human B-chronic lymphocytic leukaemic cells was found to be preceded by a rapid transient induction in expression of the c-jun proto-oncogene, which paralleled that of c-fos. Induced expression of c-myc but not of c-fos/c-jun proto-oncogenes was markedly higher in a proliferating variant leukaemic cell population compared with that seen in typical lymphocytic leukaemia cells. These data suggest that the c-fos/c-jun nuclear oncogenes play a role in induced differentiation, whilst c-myc is more important in the proliferative response of B lymphocytes.     

Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides

An influenza A virus, A/turkey/Oregon/71, was shown by protein gel analysis to code for an NS1 protein approximately half the size of those of other influenza A viruses. Sequence analysis of the NS gene of this virus revealed a 10 nucleotide deletion resulting in an NS1 protein of only 124 amino acids. This truncated NS1 polypeptide retained its karyophilic pattern as detected by indirect immunofluorescence analysis of virus infected cells. Also, A/turkey/Oregon/71 virus grew to high titer in embryonated chicken eggs comparable to other influenza A viruses. We also identified a laboratory variant of an influenza B virus, clone 201, which codes for a truncated NS1 protein. Sequence analysis revealed a 13 nucleotide deletion resulting in a shortened NS1 protein of only 127 amino acids as compared to other influenza B virus NS1 proteins possessing a length of 281 amino acids. Again as shown for the NS1 proteins of other influenza B viruses the NS1 polypeptide of B virus clone 201 was found to localize in the nucleus of infected cells. It appears that large deletions in the carboxyl terminus of the NS1 proteins of influenza A and B viruses can be tolerated without affecting the functional integrity of the NS1 polypeptide.     

A randomized trial of high-dose methotrexate versus standard-dose methotrexate following cyclophosphamide, doxorubicin (adriamycin), vincristine, and prednisone with or without bleomycin in the therapy of diffuse large cell lymphoma: preliminary report of Cancer and Leukemia Group B Study 7851

Between 1979 and 1985, 166 patients with diffuse large cell (histiocytic) lymphoma were randomized to receive therapy with 3 courses of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone (CAVP), with or without low-dose bleomycin, by continuous iv infusion. Responders were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 g/m2 iv weekly with leukovorin rescue) or low-dose methotrexate (30 mg/m2 orally weekly without rescue). Therapy was concluded with 3 additional courses of CAVP. No significant differences among the 4 treatment programs were observed in complete response rates (ranging from 46% to 51%) or in failure-free survival. Of the 38 relapses that have occurred in patients treated with low-dose methotrexate, 5 included relapse in the central nervous system in conjunction with systemic relapse. However, none of 31 relapses observed in patients receiving high-dose methotrexate have occurred with involvement of the central nervous system. Patients entering this study with "B" symptoms had significantly poorer treatment results than those patients entering study without "B" symptoms.     

Aggressive resection of metastatic disease in selected patients with malignant gastrinoma.

Fifteen patients with Zollinger-Ellison syndrome followed at the National Institutes of Health with extensive metastatic disease had an actuarial 5-year survival of 20%. Therefore, in 1982 a prospective study to examine the effect and feasibility of removing all gross tumor in selected patients with extensive metastatic disease was instituted. Five patients with extensive metastatic gastrinoma confined to the abdomen in whom imaging studies suggested the possibility of complete surgical resection were entered into this study and underwent attempted complete surgical resection and chemotherapy with streptozotocin, doxorubicin, and 5-fluorouracil. Median follow-up was 24 months. Surgical resection of all gastrinoma was possible in 4/5 patients attempted. In one patient in whom all gross disease could not be resected, the residual tumor progressed and the patient died 19 months after operation. All four patients with all disease resected appeared to benefit since all of them had a significant reduction in antisecretory medications and are enjoying normal activity and work. Three patients have had no detectable tumor on follow-up, and two of these patients are clinically and biochemically "cured" with normal fasting gastrin levels and negative provocative gastrin tests at 14 and 32 months. Therefore, aggressive resection of metastatic disease in selected patients with malignant gastrinoma is recommended.     

Comparison of multiple oncotype DX® from the same patient

For women with breast cancer in whom multiple Oncotype DX^® Recurrence Scores (RS) are obtained, RS concordance utilizing current NCCN recommendations has not been evaluated. Patients with two or more RS were identified. RS were stratified by NCCN guidelines and compared for concordance. Twenty-four patients were evaluated. RS concordance varied by tumor type: 100% in the same tumor, 91.7% in multiple ipsilateral tumors, 71.4% in contralateral tumors, and 66.7% in in-breast recurrent tumors. RS concordance for multiple assays in the same patient is not high enough to omit Oncotype DX^® testing for each tumor.