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Biomedical subjects

R A Larson

Publications and source records attributed to R A Larson.

At least 163 records · Page 9Linked to original sources
PubMed1984

Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia.

Cytogenetic specimens were obtained from blood or bone marrow in 27 patients with acute promyelocytic leukemia, including four with the microgranular variant. A 15;17 translocation was identified in 21 to 100 percent of metaphase cells from all 27 patients. The structural rearrangement was identical in every case, and the breakpoints were assigned to 15q22 and 17q21.1. Twelve patients had complete remission, and two (both with the microgranular variant) have had unmaintained continuous remission longer than four years. These data indicate that the 15;17 translocation may be found in every patient with acute promyelocytic leukemia if optimal chromosome analysis is performed.

Adolescent↗
PubMed1984

The DNA synthetic response of normal and abnormal human lymphocytes to mevalonic acid: the role of granulocytes as a helper population.

In order to investigate the role of neutrophils in the DNA synthetic response of human peripheral blood lymphocytes to mevalonic acid, we obtained preparations of both cells each free of cross-contamination by the other. Purified lymphocytes respond poorly to mevalonic acid, but their response can be significantly enhanced by one half their number of neutrophils. Preincubation of lymphocytes with neutrophils for 24 hr, even in the absence of mevalonic acid, further increases the lymphocyte response. We have been unable to demonstrate the production by granulocytes of either an intracellular or extracellular mevalonate-derived growth factor that in turn stimulates lymphocytes. Granulocytes preexposed to mevalonate do not acquire the ability to stimulate lymphocyte DNA synthesis in the absence of mevalonate. Our experiments suggest that neither neutrophil lysosomal enzymes nor reactive oxygen species generated by neutrophils are responsible for the help neutrophils provide. Normal E rosette-positive lymphocytes fail to respond to mevalonate, whereas E rosette-negative cells do. The mevalonate response of normal E rosette-negative cells is enhanced by the presence of granulocytes in contrast to B cell-chronic lymphocytic leukemia cells that synthesize DNA briskly in response to mevalonic acid in the absence of neutrophil help. These observations add to our knowledge of the relationship between mevalonate metabolism and the regulation of cellular DNA synthesis and mitosis.

Animals↗
PubMed1984

A morphologic and cytochemical study of acute myelomonocytic leukemia with abnormal marrow eosinophils associated with inv(16)(p13q22).

Nineteen patients with acute nonlymphocytic leukemia were found to have a pericentric inversion of chromosome 16. All were classified as having acute myelomonocytic leukemia (M4) according to French-American-British Cooperative Group (FAB) criteria. Consistent abnormalities of marrow eosinophils were present. In 15 of the 19 patients, the number of eosinophils was increased. Morphologic abnormalities of eosinophils were present in all patients, the most striking being the presence of large basophilic staining granules in 18 of the 19 patients. In most cases we also found a population of cells with morphologic features of both eosinophils and monocytes. Eosinophils showed atypical cytochemical reactions with PAS in ten of ten cases studied, with naphthol ASD Chloroacetate in ten of ten cases, and with combined naphthol ASD Chloroacetate esterase- chlorazol fast pink in seven of nine cases tested. The presence of inv(16) defines a distinct subset of ANLL with consistent morphologic and cytochemical features.

Adolescent↗
PubMed1984

Use of decline in D-xylose absorption to predict infection following intensive chemotherapy.

Oral D-xylose absorption and urinary excretion were measured before and after 32 courses of intensive chemotherapy in 14 patients with acute leukemia in complete remission. The incidence of severe and life-threatening infectious complications was greatest in those patients in whom the absorption and excretion of D-xylose fell below normal immediately following 4-7 days of chemotherapy. Gram-negative bacilli and staphylococci were the most common organisms to cause bacteremia in these patients.

Acute Disease↗
PubMed1984

Mevalonic acid induces DNA synthesis in chronic lymphocytic leukemia cells.

Mevalonic acid can stimulate leukemic cells from some patients with B cell chronic lymphocytic leukemia (CLL) to enter the cell cycle in vitro and to synthesize DNA. Unlike normal human peripheral blood lymphocytes, which require the presence of granulocytes for a maximal DNA synthetic response to mevalonic acid, CLL cells do not require a helper cell. Only the physiologically active R(-) enantiomer of mevalonic acid is active in initiating DNA synthesis, and no stimulatory effect is noted after addition of the precursors of mevalonic acid or of its known products. The mitogenic responses to mevalonic acid measured in CLL cells from 35 patients varied widely (range of stimulation indices, 1.2-18.6), but the DNA synthetic response of CLL cells from 9 patients to mevalonic acid exceeded those seen with such common lymphocyte mitogens as concanavalin A, phytohemagglutinin, poke-weed mitogen, or a phorbol ester. The mevalonate-responsive CLL cell was enriched in the E(-), M(+) rosette subpopulation. When CLL cells were incubated in lipoprotein-depleted serum-containing medium, the presence of low density lipoprotein (LDL) cholesterol increased their sensitivity to mevalonic acid transformation, suggesting that a nonsterol product of mevalonic acid metabolism may be involved. Mevalonic acid, which is essential for the growth of cells programmed to divide or stimulated to divide by mitogens, can by itself initiate cell replication in relatively inert G0 phase normal and neoplastic lymphocyte populations.

B-Lymphocytes↗
PubMed1983

Neutrophil-assisted DNA synthesis by human lymphocytes in response to mevalonic acid; enhancement by cytochalasin B.

Mevalonic acid is capable of initiating DNA synthesis, morphologic transformation, and cell division in cultures of human peripheral blood lymphocytes. Pure populations of lymphocytes respond poorly to mevalonic acid, but their response can be enhanced by peripheral blood neutrophils. Addition of cytochalasin B (0.5-1.0 micrograms/ml), but not cytochalasin A, to mixed neutrophil-lymphocyte cultures enhances the response of lymphocytes to both Con A and mevalonate, but the increment in mevalonate-induced DNA synthesis (+343%) far exceeds the enhancement which cytochalasin B produces in the Con A response (+24%). As a consequence, the DNA synthetic response in mevalonate (10(-2) M) containing cultures averages 39% of the response to an optimal dose of Con A. The cytochalasin B-enhanced response of mixed neutrophil-lymphocyte cultures to mevalonate is abolished by prior X irradiation of the lymphocytes, or their pretreatment with mitomycin C, as well as by the addition of hydroxyurea to the cultures but is not altered by prior X irradiation or mitomycin C pretreatment of the neutrophil helper population. These experiments suggest that the enhancing effect of cytochalasin B in the response of mixed neutrophil-lymphocyte cultures to mevalonic acid results from its ability to potentiate a time-dependent conditioning effect on lymphocytes which neutrophils exert. The conditioning effect of neutrophils cannot be achieved by cell-free neutrophil lysosomal enzymes released by exocytosis, and reactive oxygen species potentially generated by neutrophils are not involved. Attempts to demonstrate the production by neutrophils of a soluble mediator induced by mevalonate in the presence of cytochalasin B were without success. In the presence of cytochalasin B, only the metabolically active R(-) enantiomeric form of mevalonate is capable of initiating DNA synthesis in mixed neutrophil-lymphocyte cultures. The cytochalasin B-potentiated response of mixed neutrophil-lymphocyte cultures to mevalonic acid is preferentially displayed in cultures containing E-rosette-negative, as opposed to E-rosette-positive, lymphocytes. These observations add to the growing knowledge about the relationship between mevalonate metabolism, DNA synthesis, and cell replication.

Cell Cycle↗
PubMed1983

Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association.

We identified 18 patients with an inversion of chromosome 16, inv(16)(p13q22), among 308 patients with newly diagnosed acute nonlymphocytic leukemia. Each of these 18 patients had acute myelomonocytic leukemia (M4 subtype) and eosinophils with distinctly abnormal morphology, cytochemical staining, and ultrastructure. These eosinophils constituted from 1 to 33 per cent of the nucleated marrow cells. In our series, every patient with acute myelomonocytic leukemia and abnormal eosinophils also had an abnormal chromosome 16. This subgroup of M4 patients had a good response to intensive therapy designed to induce remission; 13 of 17 treated patients entered a complete remission, and 10 remain in first remission. Thus, patients with an inversion of chromosome 16 appear to represent a unique cytogenetic-clinicopathological subtype of acute nonlymphocytic leukemia with a favorable prognosis.

Adolescent↗
PubMed1983

The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970-1982).

When leukemic blood or marrow specimens from 148 adults with newly diagnosed acute nonlymphocytic leukemia (ANLL) were studied with chromosome banding techniques, 79 were found to have clonal abnormalities. Among 130 treated patients, the 53 with initially normal karyotypes had a significantly longer survival rate than the 16 in whom no normal metaphases were observed (p = 0.02). The 55 patients with both normal and abnormal metaphase cells had an intermediate survival. Once a complete remission had been attained, however, there was no significant difference in median survival between those patients with entirely normal karyotypes and those with abnormal karyotypes. Among the various FAB morphologic subsets of ANLL, the differences in complete remission rate and overall survival between the various cytogenetic subsets were greatest in acute myelogenous leukemia (AML, M1 + M2). The presence of an abnormal clone was a more important predictor of clinical outcome (p = 0.02) than the presence of normal stem cell clones. Aneuploidy alone (hyperdiploidy or hypodiploidy) was not of predictive value, indicating that the use of banding techniques to identify structural rearrangements in pseudodiploid cells was essential. Clonal chromosomal abnormalities were nonrandom and acquired, and specific abnormalities were closely associated with specific clinical-pathologic subsets of ANLL. All 13 patients with acute promyelocytic leukemia and adequate cytogenetic specimens had t(15;17); this translocation was not found in any other subset of ANLL. Six patients with AML (M2) had t(8;21) or a variant of this rearrangement. Seven patients had inv(16)(p13q22) associated with acute myelomonocytic leukemia (AMMoL, M4) and abnormal marrow eosinophils. Two patients had ins(3;3) and thrombocytosis. Four patients had a translocation involving 11q, but none of these had acute monocytic leukemia (AMoL, M5); no patient had del(11q).

Acute Disease↗
PubMed1983

Rates of cholesterol biosynthesis are related to early differentiation in acute non-lymphocytic leukaemia cells.

Cholesterol synthesis from acetate was studied in leukaemic cells from 20 patients with acute nonlymphocytic leukaemia. Marked differences in the rates of cholesterol biosynthesis were noted among three morphologically distinct types of leukaemia. As leukaemic cells differentiated along myeloid (acute promyelocytic) or monocytoid (acute myelomonocytic) pathways, their cholesterol-synthetic rates diverged and approached those of their respective mature cellular counterparts, the neutrophil or the peripheral blood monocyte. Enhanced sterol synthesis in leukaemic cells could not be explained by more rapid efflux of membrane cholesterol to the environment. In addition, the different rates of cholesterol biosynthesis in leukaemic-cell subgroups did not correlate with differences in their rates of cellular DNA synthesis. The normal divergence of sterol-synthesizing capacity found between mature neutrophils and monocytes develops at an early stage of differentiation and is detectable even in leukaemic cells.

Acetates↗
PubMed1983

Cytochalasin B is a potent mitogen for chronic lymphocytic leukemia cells in vitro.

It is widely accepted that the neoplastic B cells from patients with chronic lymphocytic leukemia (CLL) respond poorly to common mitogens. The fungal metabolite cytochalasin B (0.5 micrograms/ml) is a weak mitogen for normal lymphocytes. However, when peripheral blood lymphocytes from 19 patients with CLL of B cell origin (B-CLL) were cultured with 0.5 micrograms cytochalasin B/ml, significant new DNA synthesis ( [14C]thymidine incorporation) occurred in 18. Stimulation indices with cytochalasin B varied widely (range = 1.9-28.2, mean +/- SD = 10.6 +/- 7.5; delta cpm range = 1,157-153,818; n = 26) but in 11 cases exceeded those seen with concanavalin A (Con A), phytohemagglutinin, or pokeweed mitogen. In all 11, the mitogenic response to cytochalasin B exceeded that to pokeweed mitogen, which is believed to be a T cell-dependent B cell mitogen. In three cases, the responses to cytochalasin B were 8.6, 3.5, and 2.3 times greater than those to Con A. As with other mitogens, the DNA synthetic response to cytochalasin B was time and dose dependent. Peak thymidine incorporation occurred at 72-88 h and declined thereafter. Significant mitogenic effects were observed with 0.1-5 micrograms cytochalasin B/ml with a peak at 0.5-2 micrograms/ml. Stimulated DNA synthesis was abolished by 1 mM hydroxyurea. Cells from two patients with B-CLL were separated by rosetting with sheep erythrocytes (E). Depletion of E-rosette-positive cells from the CLL cell population abolished the response to Con A but did not affect the response to cytochalasin B. Cytochalasin B is a potent mitogen for B-CLL cells and may be useful in cytogenetic studies of this often indolent neoplasm.

Cell Transformation, Neoplastic↗
PubMed1983

Cholesterol and mevalonic acid are independent requirements for the in vitro proliferation of human bone marrow granulocyte progenitor cells: studies using ML-236B.

ML-236B is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the key regulatory enzyme in the sequence that catalyzes the conversion of acetate to mevalonic acid in cholesterol biosynthesis. This compound caused marked inhibition of human bone marrow granulocyte progenitor cell (CFU-C) proliferation, the 50% inhibitory concentration (IHD50) being 2.0 X 10(6)M. Inhibition of colony formation was reversed by mevalonic acid but not by cholesterol. ML-236B also inhibited DNA synthesis and acetate incorporation into cholesterol in marrow mononuclear cells (IHD50 = 5.6 x 10(6)M and 3.2 x 10(7)M, respectively). No inhibition of mevalonate incorporation into cholesterol was observed. These results differ from those observed with 25-hydroxycholesterol, another inhibitor of HMG CoA reductase. The latter compound also inhibited CFU-C proliferation and cholesterol biosynthesis from acetate; inhibition of colony formation was reversed by cholesterol but not by mevalonic acid. In addition, 25-hydroxycholesterol inhibited cholesterol synthesis from mevalonic acid precursor. We conclude that: (1) ML-236B is a potent inhibitor of CFU-C proliferation, DNA synthesis, and cholesterol biosynthesis from acetate precursor in marrow mononuclear cells; (2) the effects of ML-236B are completely reversed by mevalonic acid but not by cholesterol, suggesting that mevalonic acid per se or one or more of its nonsterol products are critical for cell growth; (3) the inhibitory effects of 25-hydroxycholesterol on CFU-C proliferation and cholesterol biosynthesis are not solely a result of its inhibition of HMG CoA reductase, but are due in part to inhibition of enzymatic steps distal to mevalonic acid in the sterol synthetic pathway; and (4) mevalonic acid and cholesterol are independent requirements for CFU-C proliferation and differentiation in vitro.

Acetates↗
PubMed1982

Response to 5-azacytidine in patients with refractory acute nonlymphocytic leukemia and association with chromosome findings.

Fifteen patients with acute nonlymphocytic leukemia (ANLL) who either had a relapse after a previous complete remission (nine patients) or progressive disease after initial induction attempts with combination chemotherapy (six patients) were treated with 5-azacytidine. Five patients (33%) achieved a complete remission (CR); of these, three had a relapse and died 30, 35, and 38 weeks after 5-azacytidine therapy was begun. Two patients are still alive at 39 and 138 weeks. Chromosomes were analyzed at the time of diagnosis; ten patients had a normal karyotype and five had an abnormal karyotype. Three of the five CR patients had an abnormal karyotype initially. Two of these individuals had a translocation of chromosomal material from a No. 8 chromosome to a No. 21 chromosome, t(8;21); this particular translocation has been associated with a better prognosis than have other types of chromosomal abnormalities in patients with ANLL. Even when abnormal chromosomes are present, 5-azacytidine can induce complete remission in patients with previously treated ANLL.

Adult↗
PubMed1982

Neutrophils are required for the DNA synthetic response of human lymphocytes to mevalonic acid: evidence suggesting that a nonsterol product of mevalonate is involved.

Human peripheral blood lymphocytes, in the presence of human neutrophils, initiate DNA synthesis and cell cycling when exposed to mevalonic acid. The ability of lymphocytes to respond in this manner is a radiosensitive property of cells, whereas the help provided by neutrophils is maintained despite their exposure to x-irradiation. Other organic acid anions, including precursors of mevalonic acid biosynthesis and a variety of products of mevalonate metabolism, fail to initiate DNA synthesis when added to human lymphocytes. Because only the metabolically active R(--) enantiomer of mevalonic acid initiates lymphocyte DNA synthesis, we presume that physiological pathways of mevalonate metabolism are involved. The response to mevalonic acid of ML-236B (compactin)-inhibited lymphocytes is increased, and the threshold concentration of meyalonate at which lymphocyte DNA synthesis first appears is decreased, when the cells are cultured in lipoprotein-containing (as opposed to lipoprotein-depleted) medium. The response to mevalonic acid of lymphocytes cultured in lipoprotein-depleted medium can be enhanced by addition to the cultures of low density lipoprotein but not by addition of high density lipoprotein. Based upon the flux diversion hypothesis of mevalonate metabolism, these observations suggest that a nonsterol product of mevalonate metabolism may be responsible for the initiation of lymphocyte DNA synthesis by mevalonic acid.

Cell Cycle↗
PubMed1982

Nonrandom chromosome abnormalities in angioimmunoblastic lymphadenopathy.

Cytogenetic and pathologic studies were performed on six patients with angioimmunoblastic lymphadenopathy (AILD). All six had diffuse lymphadenopathy; five had fever, four had weight loss, and four had a diffuse erythematous rash. All patients except one had a polyclonal elevation of immunoglobulin. All patients had diagnostic findings in lymph node (LN) and bone marrow (BM) biopsies. Two patients died of progressive AILD; one patient died after transformation of AILC to immunoblastic sarcoma (IBS); one patient died of gastrointestinal bleeding of unknown cause. The remaining two patients, who have achieved complete remission with intensive chemotherapy, are alive 20 and 8 mo after the diagnosis; one of these had AILD and the other, both AILD and IBS. Despite diagnostic BM biopsy findings, none of the patients had chromosome abnormalities in their BM cells. In studying LN cels of 5 patients, however, we found chromosome abnormalities in each; clonal abnormalities were detected in two, both clonal and nonclonal abnormalities in two, and only nonclonal single-cell abnormalities in one. An extra chromosome 3, seen in four patients, was clonal in two and nonclonal in the two others. Cells with +5, +15, +19, +21, +22 were seen in two patients. All patients had 50% or more normal dividing cells in their LN. The mosaicism of unrelated abnormal cells in their LN. The mosaicism of unrelated abnormal karyotypes that was seen in four patients suggests that this malignant tumor is not necessarily monoclonal in its early stages, but that one clone may be selected and predominate in the late stage. Because nonrandom acquired clonal chromosome abnormalities are a consistent feature of malignancies, our data suggest that AILD may be a malignant disease despite its original description as a benign proliferative process. Therefore, it may require aggressive chemotherapy.

Aged↗