Biomedical subjects

D M Anderson

Publications and source records attributed to D M Anderson.

At least 19 recordsLinked to original sources

PubMed1992

Soluble forms of CD40 inhibit biologic responses of human B cells.

We have expressed the CD40 surface Ag as both a soluble 28-kDa molecule and a 57-kDa Fc fusion protein containing the human IgG1 Fc region. Soluble CD40 and the Fc fusion protein inhibited the proliferative response of anti-IgM-activated human B cells to the CD40 mAb G28-5. Similarly, G28-5- and IL-4-induced IgE secretion from PBMC depleted of T cells was effectively blocked by both forms of soluble CD40. Although the soluble constructs of CD40 had only a minimal inhibitory effect on IL-4-mediated proliferation of anti-IgM-activated B cells, IL-4-induced soluble CD23 shedding from both PBMC and T cells depleted of PBMC, and IgE secretion from PBMC, were significantly reduced in a concentration-dependent manner when soluble CD40 was present in the culture. The data presented demonstrate that both soluble forms of the CD40 molecule are biologically active, and suggest that the ligand for CD40 is inducible in IL-4-stimulated cultures and that it mediates both shedding of sCD23 and IgE secretion.

Antibodies, Monoclonal↗

PubMed1992

Molecular and biological characterization of a murine ligand for CD40.

The CD40 surface molecule is a 277-amino-acid glycoprotein expressed on B lymphocytes, epithelial cells and some carcinoma cell lines. Monoclonal antibodies against CD40 mediate a variety of effects on B lymphocytes, including induction of intercellular adhesion, short- and long-term proliferation, differentiation and enhanced tyrosine phosphorylation of proteins. In addition, germinal centre centrocytes are prevented from undergoing apoptosis by activation through CD40 and receptor for antigen. These data indicate that CD40 could be a receptor for an unknown ligand with important functions in B-cell development and activation. This hypothesis is strengthened by the homology of the extracellular region of the CD40 molecule with a family of cell-surface glycoproteins that includes the receptors for nerve growth factor and tumour necrosis factor. Here we report the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interleukin-4.

Amino Acid Sequence↗

PubMed1992

Promoting smoking cessation in the United States: effect of public service announcements on the Cancer Information Service telephone line.

BACKGROUND: Although many smokers report making attempts to quit, few seek help or are successful in their attempts. Some of the barriers to seeking help can be overcome by a telephone counseling and information service like that offered by the Cancer Information Service of the National Cancer Institute. This service has been promoted by antismoking public service announcements produced by the Office on Smoking and Health, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services. PURPOSE: We determined whether such nationally televised public service announcements were associated with increased use of the Cancer Information Service. We assessed the importance of specifically promoting the telephone line and identified the characteristics of the individuals who responded to such promotion. METHODS: We combined the frequency-of-call data from the Cancer Information Service with the data on the frequency and reach of the television spots. RESULTS: During this 5-year study (1983-1987), the Cancer Information Service received a notably disproportionate number of calls in 3 specific months (August 1983, January 1985, and January 1987). In each case, more than 20% of all calls in that year were received in that month (expected percentage = 8% if the calls had been evenly distributed). These peak periods were associated with the showing of the three public service announcements that mentioned the telephone number of the Cancer Information Service. These promotions were particularly effective in increasing the percentage of callers who were male, who were under the age of 40 years, or who had received a high school education or less. CONCLUSIONS: Television is an effective medium for supporting antismoking goals by motivating more smokers to seek help to quit. IMPLICATIONS: It is important to identify whether the aid offered by the Cancer Information Service hotline is effective in helping the caller to quit. Future work must concentrate on the most effective strategies for using this initial contact to provide aid to prevent relapse, thus maximizing the potential impact of the public service announcement campaigns.

Behavior Therapy↗

PubMed1992

c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas.

The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.

Cells, Cultured↗

PubMed1991

Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus.

Diamond-Blackfan anemia is a congenital disorder of erythropoiesis in humans, characterized by a macrocytic anemia often associated with physical anomalies. Mutations at either the W or Steel loci in the mouse also leads to a severe macrocytic anemia, as well as other developmental abnormalities. The W locus encodes the proto-oncogene c-kit, a member of the receptor tyrosine kinase family, while the Steel locus encodes a potent hematopoietic growth factor that is the ligand for c-kit. Growth of clonogenic marrow erythroid progenitor cells in vitro in the presence of the recombinant hematopoietic growth factors interleukin-3 (IL-3) and Steel was used to characterize this disease at the cellular level. Three patterns of in vitro marrow response to both recombinant IL-3 or Steel were observed among 10 Diamond-Blackfan patients: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at all. These results provide evidence for cellular heterogeneity underlying the pathogenesis of this disorder and therefore raise the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the structure of either the c-kit or Steel loci were observed in these patients. The normal response in culture of the progenitor cells from at least some patients to Steel with or without IL-3 raises the possibility of using this novel growth factor as a therapeutic agent in Diamond-Blackfan anemia.

Adolescent↗

PubMed1991

Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains.

Mice homozygous for the viable Sl allele steel-Dickie (Sld) are sterile, severely anemic, and black-eyed white. The nature of the Sld mutation was investigated at the molecular level and was found to be due to a 4.0-kilobase intragenic deletion in mast cell growth factor (MGF) genomic sequences, providing conclusive evidence that Sl encodes MGF. As a consequence of this deletion, Sld is only capable of encoding a soluble truncated growth factor that lacks both transmembrane and cytoplasmic domains. Northern analysis indicates that Sld mRNA is expressed at approximately wild-type levels in adult tissues, and yeast expression studies suggest that the Sld protein is as biologically active as wild-type soluble MGF. These studies provide a molecular basis for explaining the Sld phenotype, a description of a germ-line mutation in the transmembrane and cytoplasmic domains of a membrane-bound growth factor, and in vivo evidence for the importance of membrane-bound forms of growth factors in mammalian development.

Amino Acid Sequence↗

PubMed1991

Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development.

Mutations at the dominant white spotting (W) and Steel (Sl) loci in mouse exert deleterious effects on three migratory cell lineages (primordial germ cells, melanocytes and hematopoietic stem cells) resulting in loss of pigmentation, reduced fertility and anemia. The W locus encodes the c-kit protein tyrosine kinase (TK) receptor. More recently, the Sl locus has been shown to encode a ligand for c-kit, which is variously known as mast cell growth factor (MGF), stem cell growth factor and c-kit ligand. Here we report an in situ hybridization analysis comparing the expression profiles of MGF and c-kit transcripts during mouse embryogenesis. The data are consistent with the c-kit receptor-ligand complex providing a homing mechanism during stem cell migration in early development and in stem cell proliferation, differentiation, or survival in late development. In the nervous system, an unexpected and complex pattern of expression is uncovered that suggests involvement of the W and Sl gene products in the organization of the neural tube and brain.

Animals↗

PubMed1991

Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase.

Germline mutations at the Dominant White Spotting (W) and Steel (Sl) loci have provided conclusive genetic evidence that c-kit mediated signal transduction pathways are essential for normal mouse development. We have analysed the interactions of normal and mutant W/c-kit gene products with cytoplasmic signalling proteins, using transient c-kit expression assays in COS cells. In addition to the previously identified c-kit gene product (Kit+), a second normal Kit isoform (KitA+) containing an in-frame insertion, Gly-Asn-Asn-Lys, within the extracellular domain, was detected in murine mast cell cultures and mid-gestation placenta. Both Kit+ and KitA+ isoforms showed increased autophosphorylation and enhanced association with phosphatidylinositol (PI) 3' kinase and PLC gamma 1, when stimulated with recombinant soluble Steel factor. No association or increase in phosphorylation of GAP and two GAP-associated proteins, p62 and p190, was observed. The two isoforms had distinct activities in the absence of exogenous soluble Steel factor; Kit+, but not KitA+, showed constitutive tyrosine phosphorylation that was accompanied by a low constitutive level of association with PI-3' kinase and PLC gamma 1. Introduction of the point substitutions associated with W37 (Glu582----Lys) or W41 (Val831----Met) mutant alleles into c-kit expression constructs abolished (W37) or reduced (W41) the Steel factor-induced association of the Kit receptor with signalling proteins in a manner proportional to the overall severity of the corresponding W mutant phenotype. These data suggest a diversity of normal Kit signalling pathways and indicate that W mutant phenotypes result from primary defects in the Kit receptor that affect its interaction with cytoplasmic signalling proteins.

1-Phosphatidylinositol 4-Kinase↗

PubMed1991

Tobacco-use reduction among high-risk youth: recommendations of a National Cancer Institute Expert Advisory Panel.

The National Cancer Institute's efforts to prevent tobacco-related cancers have resulted in numerous activities to reduce smoking prevalence throughout the United States. Two decades of research activity has provided much of the information needed for interventions through channels such as mass media, physician/dentist training, self-help strategies, and school-based prevention programs. However, in the area of adolescent tobacco-use reduction, it has been consistently observed that youth who have the highest tobacco-use rates are among those least likely to be reached through school-based or other programs. Thus, these youth, often labeled "high-risk," are seen as a cornerstone for tobacco use prevention efforts. Although they pose a particularly difficult access problem, many valuable recommendations for strategies to identify and reach this group were made by a recent NCI-convened Expert Advisory Panel on the Prevention and Cessation of Tobacco Use by High-Risk Youth. The Panel considered this issue from three perspectives--methods of identifying these youth, strategies for reaching them with appropriate tobacco-use prevention/cessation programs, and identification of research needs. Their recommendations and conclusions are summarized in this article. Support for research addressing the prevention and cessation of tobacco use among high-risk youth is currently being considered by the NCI.

Adolescent↗

PubMed1991

A clinical evaluation of temporomandibular joint disk plication surgery.

Clinical and radiographic examinations were performed preoperatively and an average of 18 1/2 months postoperatively on 33 patients who had undergone TMJ disk plication surgery because of significant TMJ dysfunction symptoms that had not been resolved by previous conservative therapy. The results indicated that the disk plication procedure reduced the overall frequency of symptoms by 75%. The frequency of TMJ intracapsular, otologic, and head and shoulder symptoms was reduced by more than 80% after surgery whereas dental symptoms such as bruxing and clenching showed only a 28% reduction in incidence. Of the sample 77% were either free of pain or experiencing only mild symptoms at their postoperative recall, with only nine joints still experiencing moderate or severe symptoms, compared with the 31 joints that were in this category before surgery.

Adolescent↗

PubMed1991

The relationship of neonatal alimentation practices to the occurrence of endemic necrotizing enterocolitis.

Enteric alimentation has been one of several factors implicated in the development of necrotizing enterocolitis (NEC). To examine this relationship further, the alimentation records of 19 patients who developed NEC were each compared with two matched patients controlled for birthweight and time of admission to the intensive care nursery. Parameters compared included total fluids provided, rate of enteral feed volume advancement, milk selection, and medications given. In addition, because there were no marked day-to-day differences between the mean values of most parameters and because we noted a marked fluctuation of formula intake and volume increments, we analyzed the maximum differences between the two groups. Maximum total fluids intake occurred on day 5 of life for the NEC patients and was 180.7 +/- 44 ml/kg. The control group on this same day received 149.7 +/- 35 ml/kg (p less than 0.01). Maximum enteral intake occurred on day 8 for the NEC patients at 124.3 +/- 5.7 ml/kg, whereas the control group had consumed only 83.5 +/- 60 ml/kg (p less than 0.05) on this matched day. The feed increment rate from initiation of feeds to day of maximum feeds was 27.8 +/- 16 ml/kg/day for the NEC patients and 16.8 +/- 11 for the control patients (p less than 0.0005). Furthermore, during the entire study period patients who developed NEC had the greatest 1 day increment compared with the controls (56.7 +/- 19.4 vs 44.6 +/- 26.2 ml/kg, p less than 0.05). Very rapid advancement of enteral feedings and excessive fluid volumes may predispose premature infants to the development of NEC and should be discouraged.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗

PubMed1991

The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor.

The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.

Animals↗

PubMed1991

Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22-q24.

Human mast cell growth factor (MGF) complementary DNAs (cDNAs) were cloned from HeLa cells using the polymerase chain reaction with oligonucleotides corresponding to murine and human MGF sequences. Sequencing of the cloned human MGF polymerase chain reaction products revealed two types of cDNA: a full length form corresponding in size to the murine cDNA, and an alternately spliced clone with a deletion of the sixth exon of the gene. Since membrane-bound MGF is predicted to be proteolytically cleaved within the sequences encoded by exon 6 to generate a soluble protein, this alternately spliced cDNA would likely encode a noncleavable, membrane-bound form of MGF. No difference in biological activity on human bone marrow cells was observed with recombinant, soluble forms of both types of human MGF protein. Our previous localization of the murine MGF gene to the Sl locus on chromosome 10 suggested (via conserved linkage groups) that the human MGF gene would be located on human chromosome 12. Therefore, rodent-human somatic cell hybrids with or without an entire human chromosome 12 and hybrids retaining partial 12 were tested by Southern blot analysis and used to show the presence of the human Mgf locus at chromosome region 12q. Chromosomal in situ hybridization localized the gene to 12q22-q24 in the region predicted by the comparative mapping of the murine Mgf/Sl locus.

Amino Acid Sequence↗

PubMed1990

Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms.

We have previously reported the identification of a novel mast cell growth factor (MGF) that was shown to be a ligand for c-kit and is encoded by a gene that maps near the steel locus on mouse chromosome 10. We now report the cloning of cDNAs encoding the MGF protein. The MGF protein encoded by this cDNA can be expressed in a biologically active form as either a membrane bound protein or as a soluble factor. The soluble protein promotes the proliferation of MGF-responsive cell lines and, in the presence of erythropoietin, stimulates the formation of macroscopic [corrected] erythroid and multilineage hematopoietic colonies.

Amino Acid Sequence↗

PubMed1990

Composition of the gum from Combretum paniculatum and four other gums which are not permitted food additives.

Only three gum exudates are permitted for pharmaceutical and food use by international regulatory authorities, viz. gum tragacanth (Asiatic Astragalus spp.), gum karaya (Sterculia spp.) and gum arabic [Acacia senegal (L.) Willd.], but a wide range of other tree exudates is used for a variety of uses in their countries of origin. This paper presents analytical data for the gum exudates from Atalaya hemiglauca, Cassine aethiopica, Combretum paniculatum, Sclerocarya birrea, and Pseudocedrela kotschyi. These gums may have local technological applications, but are not recommended for addition to foodstuffs.

Amino Acids↗

PubMed1990

Toxin composition variations in one isolate of the dinoflagellate Alexandrium fundyense.

A commonly accepted paradigm in the study of saxitoxin-producing dinoflagellates is that the total concentration of all toxins (toxin content) in one isolate can vary with growth conditions, but that the relative abundance of each toxin (toxin composition) does not change. We demonstrate here that dramatic changes in toxin composition do occur in one isolate of Alexandrium fundyense. In nitrogen- and phosphorus-limited semi-continuous cultures, toxin composition varied systematically with growth rate. When cells grew slowly under severe nutrient limitation, toxin composition was dominated by one or at most two toxin epimer pairs; as nutrient stresses eased at higher growth rates, the toxin profiles became more heterogeneous. Steady-state, sustained nitrogen limitation favored the production of toxins C 1,2 and GTX I,IV, whereas phosphorus limitation produced cells with high relative abundance of GTX II,III. STX reached its highest relative abundance when growth was most rapid. The lack of observed compositional changes in most past studies is probably not due to inherent differences in toxin biosynthetic pathways between the strains of Alexandrium examined, but rather to differences in the physiology of cells grown under different culturing modes (batch vs semi-continuous), methods of toxin analysis, and dominant toxins in the particular isolates examined.

Animals↗

PubMed1990

Meeting information needs of significant others: use of the Cancer Information Service.

Although significant others (spouses, relatives and friends) of cancer patients play an important role in providing support and assistance to the patient, their need for information regarding the disease is frequently overlooked by the health care system. This analysis examines information needs of (1) diagnosed cancer patients, (2) significant others of diagnosed cancer patients and (3) the general public, as reflected in their calls to the Cancer Information Service (CIS), a national toll-free telephone inquiry service. Major focus is on the types of cancer-related subjects significant others inquire about, as well as how they first found out about the CIS. Results indicate that significant others are similar to diagnosed cancer patients in their need for additional information on specific cancer sites, treatment, and referrals for second opinions, but differ in their request for information on counseling services and clinical trials. Additionally, significant others and cancer patients are similar in how they find out about the CIS. In contrast, significant others differ from the general public in their information requirements, as well as in their source of referral to the CIS. While the CIS appears to be a channel of communication capable of addressing the dynamic information needs of significant others, further research concerning the effectiveness of the CIS and other channels of cancer information in satisfying the information requirements of significant others is recommended.

Adult↗

PubMed1989

Paralytic shellfish poisoning in northwest Spain: the toxicity of the dinoflagellate Gymnodinium catenatum.

The highly productive mussel fishery in the Rias Bajas region of northwest Spain has experienced several outbreaks of paralytic shellfish poisoning (PSP) beginning in 1976. In this study, similarities in the HPLC analyses of extracts from toxic shellfish, plankton tows and cultured dinoflagellates from the Rias Vigo and Pontevedra clearly indicate that Gymnodinium catenatum Graham is the organism responsible for recent PSP episodes. The toxin profile of the dinoflagellate contains an unusually high proportion of the low potency sulfocarbamoyl toxins (ca. 90-95 mole %), although a major portion of the overall toxicity is due to the more potent saxitoxin that is present at 5-10% of the total. Toxin profiles of shellfish showed approximately the same composition as that of the dinoflagellate, although the shellfish contained several carbamate toxins (GTX I, GTX II, GTX IV and NEO) that were not detected in G. catenatum culture extracts. The shellfish also contained decarbamoyl toxins (dc-GTX II and dc-GTX-III) at approximately 2% of the total profile. Since these were not detected in the dinoflagellate, their presence reflects either chemical or enzymatic conversion within the shellfish.

Animals↗