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Background: Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study., Methods and Results: One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (+/-SEM) were 40.8+/-3.5 and 20.7+/-1.0 U/L, respectively (P<.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (r=.352 and -.387, respectively P<.001). Twenty-one of 62 patients (33.9%) with D/D genotype, 13 of 80 (16.3%) with I/D genotype, and 1 of 34 (2.9%) with I/I genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele D., Conclusions: In a selected cohort of patients, both the D/D genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted.

In a series of untreated patients with B-cell chronic lymphocytic leukemia (B-CLL), the capacity of the neoplastic B-cell population to release an interleukin-2 like factor (IL-2lf) was assessed. While unstimulated purified leukemic B-cells showed no IL-2lf production, in 16 of the 27 cases tested (59.2%) significant amounts of IL-2lf (4.3-125 U) were released following activation with phytohemagglutinin (PHA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In seven further cases (25.9%), small quantities of IL-2lf (0.2-1.7 U) were detected, while only in four (14.8%) no release was found. In 11 of the 20 cases (55%), PHA alone was also capable of inducing the production of limited amounts of IL-2lf (0.4-8 U). Only small amounts were released from B lymphocytes isolated from normal tonsils both with PHA and PHA plus TPA. Further purification using a fluorescence activated cell sorter suggests that the IL-2lf is truly produced by leukemic B cells and blocking experiments with the PC-61 monoclonal antibody indicate that IL-2lf and IL-2 use the same cell membrane receptor. However, co-cultures of leukemic B cells with small amounts of autologous or allogeneic T lymphocytes enhanced the amount of IL-2lf released into the supernatant to values markedly higher than those released by T- or B cells alone. Unlike normal B lymphocytes, unstimulated purified leukemic B cells from 17 out of 23 B-CLL cases (73.9%) were capable of absorbing variable amounts of exogenous IL-2. In addition, in six of the 11 cases tested (54.5%) IL-2 alone was capable of producing a 2-4 fold increase of thymidine uptake. In six out of eight cases (75%), a 2-5 fold enhancement of the proliferative response was observed when the leukemic B cells were co-stimulated with Staphylococcus aureus Cowan 1 (SAC) and IL-2. Moreover, when the cells were pre-activated with SAC or with PHA plus TPA and then further stimulated with IL-2, a 2-20 fold increase in proliferative response was found in the majority of cases studied. These findings indicate that elevated quantities of IL-2lf may be released in B-CLL particularly due to the B- and T cell interconnections, and that the leukemic B cells appear capable of absorbing IL-2 and of proliferating after costimulation with IL-2.(ABSTRACT TRUNCATED AT 400 WORDS)

A new synthetic derivative, N-alpha-5 (1,6-dihydro-6-oxo-9-purinyl) pentyloxy-carbonyl-L-arginine (PCF-39) has been evaluated in vitro and in vivo in order to clarify its immunopharmacologic profile. In vitro, PCF-39 did not modify spleen cell functions, whereas parenteral administration in mice of 2.5 and 25 mg/kg (50 and 500 micrograms/mouse) induced an increase in spleen and lymph node cellularity that resulted in a significant resistance to the growth of two distinct syngeneic transplanted tumors. These in vivo findings show that PCF-39 is a potent immunotherapeutic agent with an antitumor effect.

A new human leukaemic cell line (M-O7) with the phenotypic characteristics of CFU-mega is described. Its cells are positive for T200 leucocyte common antigen (LCA) and negative with MAbs recognizing T and B cells and mature myelomonocytic antigens. In contrast, they react with MAbs recognizing antigenic determinants common to multi-lineage (CD13, CD33, CD34) and to bipotent erythromegakaryoblastic (CD36, H25) haemopoietic precursors, and with MAbs specific for platelet glycoproteins (CD41w, CD42w). A small proportion (10%) of the cells were large and multinucleated, and on electron-microscopy examination showed peripheral splitting of platelet-like cytoplasm particles. When transferred to a serum-free Iscove modified Dulbecco's medium supplemented with human insulin and transferrin, M-O7 cells stop proliferating. Of the haemopoietic growth factors tested for their ability to restore the proliferative activity of this quiescent population, only rH IL-3 proved effective. Moreover, it also increased the cloning efficiency in methylcellulose more than any other CSFs. The M-O7 cell line may provide a valuable tool for the biological assay of IL-3, and a model for biochemical studies of the megakaryocytic lineage.

PF-382 is a human T-cell line that has been shown to elaborate factors that modulate normal hemopoiesis in vitro. In the present study we report that this cell line constitutively releases in both serum-containing and serum-free supernatants a potent enhancer of BFU-E growth. The factor(s), partially purified by gel filtration, is a heat-stable molecule(s) degradable by trypsin and 2-mercaptoethanol treatments, equally active on bone marrow and peripheral blood erythroid progenitor cells, but not on CFU-GM. Unlike other sources of BPA, this stimulatory factor(s) exerts its effect in the presence of mononuclear adherent cells. In fact, the addition of conditioned medium obtained by 48 hr preincubation of isolated monocytes with 10% PF-382 supernatant (M-CM2) or the concomitant addition of supernatant from PF-382 cells (PF-382-CM) and from unstimulated monocytes (M-CM1) are capable of fully replacing the presence of monocytes in the BFU-E assay. Since the independent addition of PF-382-CM or of M-CM1 is devoid of stimulatory function, we suggest that the PF-382 derived BFU-E growth inducer, which differs from IL-1, IL-3, IL-4, GM and G-CSF, exerts its activity "via" a synergistic mechanism with a monokine.

The human leukemia cell line K562 expresses constitutively high levels of c-myc mRNA and can be induced to differentiate along the erythroid lineage. Treatment of K562 cells with the antineoplastic drugs 1-beta-D-arabinofuranosylcytosine and daunomycin causes differentiation into hemoglobin-producing cells. The differentiation process is associated with an early block of cellular proliferation occurring during the first 24 h of treatment. RNA synthesis is progressively reduced to 20 to 30% of the control levels after 3 days of exposure to the drugs. Dot and Northern blot analyses were performed to evaluate the levels of c-myc or globin mRNA during the differentiation of K562. Daunomycin and 1-beta-D-arabinofuranosylcytosine, despite their distinct chemical nature, induced similar modulation of mRNA levels. Globin mRNA did not change during the first 24 h of culture and began to increase after 48 h of treatment with drugs, reflecting the kinetic of appearance of hemoglobin-producing cells. In contrast, a transient decrease of c-myc mRNA was observed after the first 24 h of drug treatment, followed by a return to normal levels of c-myc mRNA after 48 h of treatment. Thus, the expression of c-myc mRNA in K562 did not reflect their proliferative activity nor their stage of differentiation. We speculate that the transient down-regulation of c-myc mRNA may be an initial event in the erythroid differentiation of K562.