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F O Smith

Publications and source records attributed to F O Smith.

At least 55 records · Page 3Linked to original sources
PubMed1994

Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes.

Cytogenetic studies have previously identified abnormalities of chromosome band 11q23 in many cases of infant acute leukemia. Recent studies by ourselves and others have demonstrated breakpoint clustering in acute leukemias bearing translocations involving 11q23, and a Drosophila trithorax gene homologue (called MLL, HRX, or ALL-1) has been shown to span the 11q23 breakpoints of these translocations. To determine if this gene is affected in infant acute myeloid leukemia (AML), we have analyzed 26 infant AML cases for molecular alterations of this 11q23 gene. 15 out of 26 cases studied (58%) showed rearrangement of the MLL gene at the molecular level, and these rearrangements were clustered within an approximately 11-kb region containing nine exons of this gene. Moreover, 14 of the 15 cases with 11q23 rearrangements (93%) had myelomonocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively), both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenotype (P = 0.00002). Rearrangement also correlated significantly with hyperleukocytosis (P = 0.02), another clinical parameter associated with poor outcome in this disease. Our results demonstrate that molecular rearrangements of MLL are common in M4 or M5 infant AML, and suggest that alteration of this gene may result in abnormal control of proliferation and differentiation in monocytic progenitor cells.

Acute Disease↗
PubMed1993

Specific antibody production to a recall or a neoantigen by SCID mice reconstituted with human peripheral blood lymphocytes.

To explore the extent of immune reconstitution of SCID mice by human peripheral blood lymphocytes (hu-PBL-SCID mice), we studied the production of immunoglobulin isotypes and specific antibody (Ab) by the engrafted human cells. Human IgG was detectable in 94% of hu-PBL-SCID mice. IgE synthesis by hu-PBL-SCID mice correlated with the IgE levels observed in human donors. All SCID mice receiving PBL obtained from human donors previously immunized with the T-cell-dependent Ag, bacteriophage phi x 174 (phage), produced phage neutralizing antibody. Quantity and quality (Ig isotypes) of phage-specific Ab produced by hu-PBL-SCID mice correlated with that observed in the donor serum. Human B cells alone failed to engraft, and T cells were required for the production of Ig and anti-phage Ab. Phage-specific Ab production occurred without direct Ag exposure of the hu-PBL-SCID mice, suggesting that the specific Ab production was induced directly by polyclonal activation of the engrafted human cells. Intravenous phage injections given 4 wk after cell transfer failed to further increase the anti-phage Ab titer. Phage neutralizing Ab production could not be boosted if spleen cells obtained from hu-PBL-SCID mice were cultured in the presence of Ag. However, hu-PBL-SCID mice produced increased amounts of anti-phage Ab, providing they were injected with phage at the time of cell transfer. Injection of phage at the time of cell transfer, but not 4 wk later, to mice receiving PBL from nonimmunized donors induced production of minute amounts of anti-phage Ab. We conclude that human peripheral blood lymphocytes transferred into SCID mice become maximally stimulated presumably by xenogeneic murine Ag, resulting in polyclonal expansion of the graft and spontaneous production of Ab to Ag the human donor was previously exposed to, and in loss of responses to subsequent Ag exposure. Ab production to neoantigen, however, can be induced and that to recall Ag can be modified if PBL are exposed to Ag at the time of cell transfer.

Adult↗
PubMed1993

Ontogeny of hematopoietic stem cell development: reciprocal expression of CD33 and a novel molecule by maturing myeloid and erythroid progenitors.

We have identified a molecule expressed by human marrow granulocyte/monocyte colony-forming cells (CFU-GM), erythroid colony-forming cells (CFU-E), and erythroid burst-forming units (BFU-E), but not their precursors detectable in long-term bone marrow culture. This antigen, detected by flow microfluorimetry using monoclonal antibody 7B9, is coexpressed with CD33 on many CD34+ CFCs, although only the 7B9 antigen was detected on a portion of BFU-E and CFU-E, whereas only CD33 was found on a portion of CFU-GM. Antibody 7B9 appears to be useful for isolating subsets of progenitors based on their common or selective expression of 7B9 antigen and CD33.

Antibodies, Monoclonal↗
PubMed1993

Strain-dependent leakiness of mice with severe combined immune deficiency.

Mice with immunodeficiency provide an excellent in vivo model for cell transfer experiments. In this study, we compare the extent of immune deficiency of the original CB17 severe combined immune-deficient (SCID) mice with that of two other strains of immune-deficient mice, the recently developed C3H SCID mice and the beige/nude/X-linked immune-deficient (BNX) mice. Detectable levels of serum lg (higher than 0.4 microgram/ml) were found in 79% of CB17 SCID mice studied (n = 24) and in all BNX mice (n = 12); some leaky CB17 SCID mice had normal levels of Ig. In contrast, only 15% of C3H SCID mice (n = 61) had detectable serum lg; the highest Ig level in this strain was 9.6 micrograms/ml. Age had no effect on serum Ig concentrations of C3H SCID mice; in contrast, all old (> 1-year-old) CB17 SCID mice studied had detectable levels of serum Ig. Transfer of syngeneic, normal, neonatal thymocytes increased serum Ig of SCID mouse origin to near-normal levels in all CB17 SCID mice but had no effect on serum lg concentrations in C3H SCID mice. Treatment with anti-asialo-GM-1 antiserum to abrogate NK cell activity increased serum Ig levels in 37% of CB17 SCID mice but had no effect on Ig production in C3H SCID mice. Flow cytometric analysis failed to identify mature T or B cells in C3H SCID mice; in contrast, some leaky CB17 SCID mice had detectable numbers of T and B cells in the peritoneal cavity. After immunization with bacteriophage phi X 174, neither C3H nor CB17 SCID mice, including leaky mice, produced specific antibody to phage. In contrast, BNX mice produced small but significant amounts of anti-phage antibody. These results indicate that, of the three strains of immune-deficient mice, C3H SCID mice have the most severe immune defect. We predict that C3H SCID mice will be best suited for cell transfer experiments.

Animals↗
PubMed1993

Clonal remission in childhood acute myeloid leukemia is an infrequent event.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases that differ in pattern of both remission and lineage involvement. The observation that hematopoiesis remains clonal in some patients with AML in complete clinical remission suggests that the acute phase may develop from a clinically unrecognized preleukemic clone. To investigate the characteristics and significance of clonal remissions in childhood AML, we used X-chromosome-linked polymorphisms to study granulocytes obtained from pediatric female patients in complete clinical remission. Remission granulocytes from only one of 17 evaluable patients were clonally derived, suggesting that clonal remission is an infrequent event in childhood AML.

Acute Disease↗
PubMed1992

Blasts from patients with acute myelogenous leukemia express functional receptors for stem cell factor.

Stem cell factor (SCF) acts in concert with lineage-specific growth factors to stimulate the growth of hematopoietic colonies. To determine if neoplastic human hematopoietic cells would also respond to SCF, we cultured marrow mononuclear cells from 20 patients with newly diagnosed acute myelogenous leukemia (AML) and two normal donors with SCF, interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or combinations of growth factors in semisolid medium, and assessed colony growth. SCF receptors (c-kit receptors) were quantitated by equilibrium binding studies with 125I-SCF, and binding parameters were estimated using the ligand program. The cellular distribution of c-kit receptors was determined by autoradiography. Our results show that SCF alone or in combination with IL-3 or GM-CSF increased both the number and size of colonies in 10 of the patients. Receptors for SCF were identified on the blasts from all 20 AML patients. The number of receptors ranged from 600 to 29,000 per cell. In the majority of patients, both high- and low-affinity binding sites were identified. Neither the number of receptors per cell nor the finding of one or two classes of receptors correlated with growth response to SCF. Autoradiographic analysis of 125I-SCF binding to normal marrow mononuclear cells revealed grains associated with blasts and megakaryocytes. Grain counts on blasts from 10 AML patients and on normal marrow blasts suggested that high-affinity c-kit receptor expression on AML blasts is lower than or similar to that of normal blasts. These results identify c-kit receptors on human AML blasts, and indicate that SCF acts synergistically with IL-3 or GM-CSF to stimulate colony growth from the marrow cells of a portion of patients with AML.

Autoradiography↗
PubMed1992

Expression of lymphoid-associated cell surface antigens by childhood acute myeloid leukemia cells lacks prognostic significance.

The prognostic significance of cell surface antigens associated with lymphoid and myeloid lineage differentiation on the blasts of children with acute myeloid leukemia (AML) was evaluated. Leukemic blasts from 176 patients enrolled on Childrens Cancer Study Group Protocol 213 determined to have AML by standard morphologic and cytochemical criteria were immunophenotyped. Cell surface antigens associated with myeloid differentiation were found on blasts from 88.1% of patients (CD15, 44%; CD33, 65%; CD36, 53%; glycoprotein Ib, 9.3%). However, blasts from 30.7% of patients expressed surface antigens thought to be specific for lymphoid lineage differentiation (CD2, 9.4%; CD5, 2.7%; CD19, 34.5%; CD20, 0.8%). In addition, CD34, a glycoprotein found on immature cells of both myeloid and lymphoid lineages, was expressed on the blast cells of 48.2% of patients. With the exception of the lymphoid lineage nonspecific antigen CD4, no correlation was found between white blood cell count at diagnosis, age, and French-American-British morphology, and the expression of any of the lymphoid- or myeloid-associated cell surface antigens studied. Nor was the expression of these antigens prognostically significant with respect to response to induction therapy, death during induction, survival, event-free survival, or survival/event-free survival following remission induction. Multivariate analysis showed that CD4 expression was not an independent predictor of outcome. Thus, this prospective study suggests that expression of lymphoid-associated cell surface antigens as well as myeloid-associated antigens by childhood AML blasts lacks prognostic significance.

Adolescent↗
PubMed1992

Differences in the frequency of normal and clonal precursors of colony-forming cells in chronic myelogenous leukemia and acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 antigens, but their less mature precursors, detected by their ability to give rise to CFC in LTC, express only CD34. In three of the four patients with AML, the CD33-CD34+ cells produced CFC in LTC that appeared to be predominantly or completely normal (ie, nonclonal) in origin. In the fourth patient, a significant enrichment of nonclonal progenitors was obtained in the CD33-CD34+ population, but these cells may also have included significant numbers of clonal cells. In contrast, in four of five patients with CML, cultures of both the CD33-CD34+ and CD33+CD34+ populations produced CFC in LTC that were almost entirely clonal in origin, whereas in the fifth patient a substantial number originated from nonclonal stem cells. These data indicate that granulocyte/monocyte progenitors are predominantly clonally derived in CML and AML. In CML, their precursors are also predominantly clonal, but in some cases of AML they are not. These findings may have implications for understanding the success or failure of current therapies of AML and CML.

Antigens, CD↗
PubMed1992

Monoclonal antibodies in the study and therapy of hematopoietic cancers.

Recent advances utilizing monoclonal antibodies to phenotype acute leukemias have revealed no prognostic significance of the expression of lymphoid-associated antigens by acute myeloid leukemia blasts and conflicting results regarding 'biphenotypic' acute myeloid leukemia. Several studies treating patients with refractory lymphoma with immunotoxins reported encouraging results but significant production of anti-mouse or anti-toxin antibody. Radiolabeled antibodies that react with panhematopoietic antigens have delivered selective radiation to marrow, spleen and lymph nodes in animal models and are being used in Phase I studies of marrow transplantation for acute leukemia.

Antibodies, Monoclonal↗
PubMed1991

Practice-based research: opportunities for the clinician.

Practice-based research is the performance of clinical trials in physicians' offices, often involving multiple sites in multicenter studies. The purpose of this presentation is to inform the clinician of the opportunities available in practice-based research, discussing both the contributions that clinicians can make and the advantages to them of participating in practice-based research. Clinician contributions to medical research include the addition of vital clinical perspective to preliminary findings from institutional research and the performance of long-term patient evaluation. Advantages to the physician include the opportunity to continue the scientific inquiry that is too often left behind upon entering private practice, a greater appreciation of the drug evaluation process, and new skills in office procedures and documentation.

Allied Health Personnel↗
PubMed1991

Adherence of Candida albicans to tissues from mice with genetic immunodeficiencies.

Ex vivo adherence comparisons were made between immunocompetent and immunocompromised mouse tissues, and the roles of serum immunoglobulin and macrophages in the adherence of Candida albicans were investigated. Spleen, lymph node, and kidney tissues were harvested from congenitally immunodeficient mice, including AKR/scid, C.B-17, C3Hscid, and N:NIH nu/bg/xid mice, and their normal counterparts into which the defects were bred (AKR/J, C3H/HeSnJ, and BALB/c-ByJ). Tissues were compared for the ability to bind C. albicans 219 in an ex vivo assay. In general, immunodeficiencies significantly decreased binding of C. albicans to spleen but not to lymph node or kidney tissue compared with immunocompetent mice. In C3Hscid and AKRscid mice, spleen tissues from "nonleaky" mice bound significantly fewer yeast cells (P = 0.0005 and 0.0009, respectively) than did those from C3H/HeSnJ or AKR/J mice. Numbers of adherent yeast cells were similar in "leaky" AKRscid and AKR/J mice. Yeast adherence to spleen tissue from N:NIH nu/bg/xid mice correlated with mouse age (P = 0.01). Measurements of total serum immunoglobulin indicated that the scid defect was most complete in C3Hscid mice and that yeast adherence in spleen tissue correlated with immunoglobulin titers. Results of adherence assays and macrophage-specific immunostains suggested that factors determining adherence differ among reticuloendothelial organs.

Animals↗
PubMed1986

Postpartum diseases.

This article includes discussions about postpartum care of the dam and postpartum disorders in the bitch such as hemorrhage, uterine prolapse, metritis, mastitis, eclampsia, and subinvolution of the placental sites.

Animals↗
PubMed1985

Effects of intravesical hydrostatic pressure and volume on the distensibility of the canine prostatic portion of the urethra.

Positive-contrast retrograde urethrocystograms were obtained serially on 12 male dogs weighing 11.4 to 23.2 kg before, during, and after the injection of contrast medium until the urinary bladder neck and prostatic and membranous portions of the urethra remained open and distended as viewed by fluoroscopy. Correlations of intravesical volumes and pressures required to achieve maximum distension of the midprostatic portion of the urethra with body weight and surface area were not significant. Because of the variability in intravesical volumes and pressures encountered at maximum distension of the prostatic portion of the urethra, a dose of contrast material expressed relative to body weight or surface area could not be determined for consistently providing maximum distension of the prostatic portion of the urethra.

Animals↗
PubMed1983

X-Chromosome monosomy (37,XO) in a Burmese cat with gonadal dysgenesis.

A 37,XO-chromosome complement was detected in a 21/2-year-old sable Burmese cat examined because of primary anestrus. The cat was smaller than its littermates; other somatic abnormalities associated with the XO karyotype in other species were not present. The ovaries, which did not respond to gonadotropin stimulation, contained inactive germinal epithelium (lacking follicles and primordial germ cells), which was similar to that of adult human patients with XO-gonadal dysgenesis.

Animals↗