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PubMed1992

Phenotypes of murine leukemia virus-induced tumors: influence of 3' viral coding sequences.

Murine leukemia viruses (MuLVs) induce leukemias and lymphomas in mice. We have used fluorescence-activated cell sorter analysis to determine the hematopoietic phenotypes of tumor cells induced by a number of MuLVs. Tumor cells induced by ecotropic Moloney, amphotropic 4070A, and 10A1 MuLVs and by two chimeric MuLVs, Mo(4070A) and Mo(10A1), were examined with antibodies to 13 lineage-specific cell surface markers found on myeloid cell, T-cell, and B-cell lineages. The chimeric Mo(4070A) and Mo(10A1) MuLVs, consisting of Moloney MuLV with the carboxy half of the Pol region and nearly all of the Env region of 4070A and 10A1, respectively, were constructed to examine the possible influence of these sequences on Moloney MuLV-induced tumor cell phenotypes. In some instances, these phenotypic analyses were supplemented by Southern blot analysis for lymphoid cell-specific genomic DNA rearrangements at the immunoglobulin heavy-chain, the T-cell receptor gamma, and the T-cell receptor beta loci. The results of our analysis showed that Moloney MuLV, 4070A, Mo(4070A), and Mo(10A1) induced mostly T-cell tumors. Moloney MuLV and Mo(4070A) induced a wide variety of T-cell phenotypes, ranging from immature to mature phenotypes, while 4070A induced mostly prothymocyte and double-negative (CD4- CD8-) T-cell tumors. The tumor phenotypes obtained with 10A1 and Mo(10A1) were each less variable than those obtained with the other MuLVs tested. 10A1 uniformly induced a tumor consisting of lineage marker-negative cells that lack lymphoid cell-specific DNA rearrangements and histologically appear to be early undifferentiated erythroid cell-like precursors. The Mo(10A1) chimera consistently induced an intermediate T-cell tumor. The chimeric constructions demonstrated that while 4070A 3' pol and env sequences apparently did not influence the observed tumor cell phenotypes, the 10A1 half of pol and env had a strong effect on the phenotypes induced by Mo(10A1) that resulted in a phenotypic consistency not seen with other viruses. This result implicates 10A1 env in an active role in the tumorigenic process.

Animals↗
PubMed1976

Relation of alpha-1-antitrypsin phenotype to the performance of pulmonary function tests and to the prevalence of respiratory illness in a working population.

Individuals with severe alpha-1-antitrypsin (alpha1AT) deficiency (phenotype Pi ZZ) are abnormally liable to develop emphysema, but it is uncertain whether those with partial alpha1AT deficiency (phenotypes Pi MS and MZ) are similarly susceptible. This study was undertaken to determine the frequency of the various Pi phenotypes in a working population in Northern Ireland and to compare the performance of simple pulmonary function tests and prevalence of respiratory symptoms and chest illness between different phenotypes. The population sample consisted of 1995 working men and women aged between 35 and 70 years. The MRC Questionnaire (1966) was used to assess respiratory symptoms, a forced expiratory spirogram was recorded, and a blood sample was analysed for alpha1AT phenotype by acid starch gel electrophoresis and antigen-antibody crossed electrophoresis in every case. The percentage frequencies of the alpha1AT phenotypes were: Pi MM 86-5; MS 7-97; MZ 3-86; IM 0-6; FM 0-4; SZ 0-25; M 0-15; SS 0-1; Z 0-05; MP 0-05; FS 0-05. Respiratory symptoms and a history of previous chest illness occurred with similar frequency among the Pi M, MS, and MZ phenotypes, and a comparison of the regression coefficients for FEV1, FVC, and MMF on age for each phenotype group showed no significant differences between them overall, or when subdivided according to smoking habits or dust exposure. These findings provide no evidence that individuals of phenotype Pi MS or MZ are more than usually liable to develop chronic airways obstruction.

Adult↗
PubMed1995

Phenotypic changes among hybrid rat mast cells.

Rat peritoneal mast cells and 6-thioguanine-resistant rat basophilic leukemia cells, representative of connective tissue-type (CTMC) and mucosal (MMC) mast cells, respectively, were fused using polyethylene glycol. Four out of 14 primary hybrid mast cell lines contained more than 50% of CTMC as demonstrated by histochemical staining. Two cell lines, one predominantly of the CTMC and the other of the MMC phenotype, were selected for further study. Among these, the phenotype was also confirmed by analysis for rat mast cell protease I and by mediator release triggered by compound 48/80 and ionophore A23187. The CTMC phenotype disappeared after culturing cells for 2 weeks. The change in phenotype did not significantly alter the mediator release due to calcium ionophore A23187. Repeated cloning of cells bearing the CTMC phenotype did not yield a cloned line of cells expressing the CTMC phenotype only, although it prolonged the persistence of this phenotype. During the period of CTMC phenotype loss, a drop in cellular DNA content occurred, suggesting that chromosome instability may, at least partially, have been responsible for the phenotypic changes.

Animals↗
PubMed1987

Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.

The Lp(a) lipoprotein represents a quantitative genetic trait. It contains two different polypeptide chains, the Lp(a) glycoprotein and apo B-100. We have demonstrated the Lp(a) glycoprotein directly in human sera by sodium dodecyl sulfate-gel electrophoresis under reducing conditions after immunoblotting using anti-Lp(a) serum and have observed inter- and intraindividual size heterogeneity of the glycoprotein with apparent molecular weights ranging from approximately 400,000-700,000 D. According to their relative mobilities compared with apo B-100 Lp(a) patterns were categorized into phenotypes F (faster than apo B-100), B (similar to apo B-100), S1, S2, S3, and S4 (all slower than apo B-100), and into the respective double-band phenotypes. Results from neuraminidase treatment of isolated Lp(a) glycoprotein indicate that the phenotypic differences do not reside in the sialic acid moiety of the glycoprotein. Family studies are compatible with the concept that Lp(a) glycoprotein phenotypes are controlled by a series of autosomal alleles (Lp[a]F, Lp[a]B, Lp[a]S1, Lp[a]S2, Lp[a]S3, Lp[a]S4, and Lp[a]0) at a single locus. Comparison of Lp(a) plasma concentrations in different phenotypes revealed a highly significant association of phenotype with concentration. Phenotypes B, S1, and S2 are associated with high and phenotypes S3 and S4 with low Lp(a) concentrations. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and Lp(a) lipoprotein concentrations in plasma and is the first indication for structural differences underlying the quantitative genetic Lp(a)-trait.

Apolipoproteins B↗
PubMed1999

A new method for haptoglobin phenotyping.

Haptoglobin is an acute-phase protein with three major phenotypes: Hp 1-1, Hp 2-1 and Hp 2-2. Studies have shown that functional differences between these phenotypes have important consequences in a number of pathological disorders (e.g. cardiovascular disease, autoimmune disorders, infectious disease), making phenotype determination of potential use in the clinical field. Previous methods for haptoglobin phenotyping have involved electrophoresis (starch, acetate and polyacrylamide gels) with phenotype visualization by peroxidase-sensitive stains that were often carcinogenic. Less hazardous immunoblotting and isoelectric focusing procedures are also available but the methods are lengthy, expensive and often complex. Here, we describe a new method for haptoglobin phenotyping using commercially available agarose gels and a non-carcinogenic stain (3,3',5,5'-tetramethylbenzidine). Our method showed 100% agreement with starch gel electrophoresis and reliably distinguished between commercial haptoglobin phenotype standards and serum samples from patients (n = 125). We obtained a sensitivity of 0.4 g/L for all phenotypes and the gels were stable for up to 2 months. This safer and easier to use method may permit increased access to knowledge of haptoglobin phenotype, allowing improved patient management and better tailoring of treatment in a variety of clinical conditions.

Electrophoresis, Agar Gel↗
PubMed2006

Discordance between N-acetyltransferase 2 phenotype and genotype in a population of Hmong subjects.

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 +/- 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.

Acetylation↗
PubMed1998

The apolipoprotein E phenotype has a strong influence on tracking of serum cholesterol and lipoprotein levels in children: a follow-up study from birth to the age of 11 years.

The extent to which an individual maintains his position relative to the rest of the population is called tracking. The objective of this study was to examine the effect of the apolipoprotein E (apoE) phenotype on the tracking of serum cholesterol and lipoproteins from birth to the age of 11 y. In a longitudinal follow-up study of healthy children, concentrations of total serum cholesterol and triglyceride were determined at birth (n = 193), and at the ages of 2 (n = 192), 4 (n = 192), 6 (n = 190), 9 (n = 188), and 12 mo (n = 196), and 5 (n = 162) and 11 y (n = 153). Concentrations of total HDL, HDL2, and HDL3, VLDL, and LDL cholesterol were determined at 2, 6, 9, and 12 mo (n = 36), and 5 (n = 162) and 11 y (n = 153). The apoE phenotype was determined in 151 children. The children had the following apoE phenotypes: 4 had type 4/4 and 40 type 3/4 (group apoE4), 94 had type 3/3 (group apoE3), and 11 had type 2/3 and 2 type 2/4 (group apoE2). The correlation coefficients for total cholesterol levels during childhood compared with the level at 11 y of age were: 0.03 at birth, 0.26 (p < 0.001) at 2 mo, 0.24 (p < 0.001) at 4 mo, 0.24 (p < 0.001) at 6 mo, 0.28 (p < 0.001) at 9 mo, 0.41 (p < 0.001) at 12 mo, and 0.60 (p < 0.001) at 5 y. When the children were divided into three groups according to their apoE phenotypes, these three groups had the following correlation coefficients at 4 mo, 12 mo, or 5 y of age compared with the level at the age of 11 y; group apoE2: r = 0.65 (p < 0.01), r = 0.59 (p < 0.01), and r = 0.72 (p < 0.01); group apoE3: r = 0.27 (p < 0.01), 0.43 (p < 0.001), and r = 0.64 (p < 0.001); and group apoE4: r = 0.14 (p = NS), r = 0.33 (p < 0.05), and 0.42 (p < 0.01). The apoE phenotype also strongly influenced the tracking of the LDL cholesterol levels; the correlation coefficients between 5 and 11 y of age were for group apoE2 r = 0.84 (p < 0.001), for group apoE3 r = 0.70 (p < 0.001), and for group apoE4 r = 0.37 (p < 0.05). Our results indicate that the apoE phenotype strongly influences the tracking of lipids. The children having apoE 2/3, 2/4, and 3/3 phenotypes maintained their relative cholesterol and lipoprotein levels better than the others throughout the first 11 y of age. Because the apoE phenotype strongly affects the tracking of serum cholesterol, the usefulness of cholesterol screening in predicting future cholesterol values should be analyzed, keeping the apoE phenotype in mind.

Apolipoproteins E↗
PubMed2000

CYP2D6 genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting.

The emerging application of pharmacogenomics in the clinical trial setting requires careful comparison with more traditional phenotyping methodologies, particularly in the drug metabolism area where phenotyping is used extensively. The research objectives of this study were 1) to assess the utility of cytochrome P450 2D6 (CYP2D6) genotyping as an alternative to traditional phenotyping as a predictor of poor metabolizer status; 2) to identify issues for consideration when implementing CYP2D6 genotyping in clinical trials; and 3) to outline the advantages and disadvantages of CYP2D6 genotyping compared with phenotyping. DNA samples obtained from 558 previously phenotyped individuals were blindly genotyped at the CYP2D6 locus, and the genotype-phenotype correlation was then determined. The CYP2D6 genotyping methodology successfully predicted all but 1 of the 46 poor metabolizer subjects, and it was determined that this 1 individual had a novel (presumably inactive) mutation within the coding region. In addition, we identified 2 subjects with CYP2D6 genotypes indicative of poor metabolizers who had extensive metabolizer phenotypes as determined by dextromethorphan/dextrorphan ratios. This finding suggests that traditional phenotyping methods do not always offer 100% specificity. Our results suggest that CYP2D6 genotyping is a valid alternative to traditional phenotyping in a clinical trial setting, and in some cases may be better. We also discuss some of the issues and considerations related to the use of genotyping in clinical trials and medical practice.

Cytochrome P-450 CYP2D6↗
PubMed1997

Phenotypic characterization of rambouillet sheep expressing the callipyge gene: I. Inheritance of the condition and production characteristics.

The objectives of this study were to determine the model of inheritance of the callipyge gene and to evaluate the growth, ADFI, feed efficiency, reproductive performance, and wool growth of sheep that are heterozygous for the callipyge gene. Ewes (n = 236) with a normal muscle phenotype and genotype were mated to three heterozygous rams that expressed the callipyge gene. Lambs (n = 311) were subjectively classified at weaning (90 to 120d) according to muscle phenotype by a panel of three evaluators working independently. The callipyge muscle phenotype was expressed in 150 lambs, whereas 161 lambs expressed a normal muscle phenotype. The percentage of lambs expressing the callipyge muscle phenotype (48.2%) did not differ (P > .1) from the expected 50%. Growth rate was similar for lambs of both phenotypes regardless of sex. Feed efficiency was superior (P < .05) for both male and female lambs with the callipyge muscle phenotype. Average daily feed intake was lower for male (P < .02) and female (P < .004) lambs with the callipyge muscle phenotype. Grease fleece weight and staple length at 12 mo were superior (P < .03) for ewes with a normal muscle phenotype. These results indicate that the callipyge gene in sheep is dominant when inherited from the paternal parent and lambs expressing the callipyge gene have increased feed efficiency and reduced ADFL.

Animals↗
PubMed2005

Phenotype matching of donor red blood cell units for nonalloimmunized sickle cell disease patients: a survey of 1182 North American laboratories.

CONTEXT: The transfusion of donor red blood cell units (RBCs) that lack certain red cell antigens (such as C, E, and K) when the corresponding antigens are absent from the recipient's red cells has been shown to reduce the risk of red cell alloimmunization in sickle cell disease patients. However, data are limited regarding the extent to which transfusion services routinely perform red cell antigen phenotype testing of nonalloimmunized sickle cell disease patients, and then use that information to select donor RBCs lacking 1 or more of the red cell antigens that the patient's red cells do not express. OBJECTIVE: To determine the extent to which transfusion services routinely perform red cell antigen phenotype testing of nonalloimmunized sickle cell disease patients, and then use that information to select donor RBCs lacking 1 or more of the red cell antigens that the patient's red cells do not express. DESIGN: An educational subsection of a College of American Pathologists Proficiency Testing Survey (J-C 2003) assessed transfusion service practices regarding performance of red cell antigen phenotype testing of nonalloimmunized sickle cell disease patients and how transfusion services use this information for the selection of donor RBCs. The data analysis of the survey included 1182 North American laboratories. RESULTS: Data from 1182 laboratories were included in the survey analysis, of which the majority (n = 743) reported that they did not routinely perform phenotype testing of sickle cell disease patients for antigens other than ABO and D. The other 439 laboratories reported that they did routinely perform phenotype testing of sickle cell disease patients for antigens in addition to ABO and D. The majority of these 439 laboratories (three fourths; n = 330) reported that they used these patient data for prophylactic matching with donor RBCs when sickle cell disease patients required transfusion. When phenotype-matched donor RBCs were used, the antigens most commonly matched (85% of the time) were C, E, and K. CONCLUSIONS: The majority of North American hospital transfusion service laboratories do not determine the red cell antigen phenotype of nonalloimmunized sickle cell disease patients beyond ABO and D. Those laboratories that do determine the red cell phenotype of nonalloimmunized sickle cell disease patients beyond ABO and D most commonly match for C, E, and K antigens when phenotype-matched donor RBCs are used.

ABO Blood-Group System↗
PubMed2001

Fibroblast growth factor reversal of the corneal myofibroblast phenotype.

PURPOSE: Keratocytes give rise to fibroblasts and myofibroblasts in wounded cornea. It is well established that treatment of fibroblasts with transforming growth factor (TGF) beta will induce myofibroblast differentiation. We investigated whether this differentiation could be reversed by the administration of fibroblast growth factor (FGF). METHODS: Cultured corneal myofibroblasts were plated at 200 cells/mm(2), and cells were grown in DMEM/F12 containing (1) 10% FBS or (2) 10% FBS with FGF and heparin or (3) 1% FBS or (4) 1% FBS with TGF-beta. As distinguished from the fibroblast phenotype, the myofibroblast phenotype was identified by the assembly of alpha-smooth muscle (SM) actin protein into the stress fiber cytoskeleton. To further characterize growth factor regulation of the two phenotypes, the phenotypic expression of TGF-beta receptor types I and II, cadherins, and connexin 43 by immunocytochemistry, Western blot analysis, and immunoprecipitation and of alpha-SM actin mRNA in Northern blot analysis were evaluated. RESULTS: Corneal myofibroblasts replated and grown in the presence of FGF-1 or FGF-2 (20 ng/ml) plus heparin (5 microg/ml) in 10% FBS medium had decreased expression of alpha-SM actin protein, TGF-beta receptors, and cadherins. Thus, FGF-heparin decreased the myofibroblast phenotype and promoted the fibroblast phenotype. Administration of either 20 ng/ml FGF or 5 microg/ml heparin alone was not effective. Addition of TGF-beta further enhanced the expression of alpha-SM actin mRNA and protein and cell surface expression of TGF-beta receptors in myofibroblast cultures. CONCLUSIONS: FGF-1 or -2 and heparin promoted the fibroblast phenotype and reversed the myofibroblast phenotype. This finding supports the idea that corneal myofibroblasts and fibroblasts are alternative phenotypes rather than terminally differentiated cell types.

Actins↗
PubMed2004

Alpha-1 antitrypsin phenotypes in patients with lung, prostate and breast cancer.

OBJECTIVE: Determination of Alpha1-antitrypsin (alpha1-AT) phenotypes in Jordanian patients with lung, prostate and breast cancer to find a prevalent phenotype that could be recommended for the early diagnosis of cancer. METHODS: This study was conducted at Jordan University of Science and Technology, Irbid, Jordan, during the period May 2001 to May 2002. Alpha1-AT phenotypes for 83 Jordanian cancer patients distributed as follows, 25 lung cancer, 25 prostate cancer and 33 with breast cancer, were tested using isoelectric focusing gel electrophoresis and immunofixation techniques. RESULTS: Isoelectric focusing results demonstrated that 96% of lung cancer patients were of PiMM phenotype and 4% of PiFM phenotype. All prostate cancer patients (100%) were found to be of PiMM phenotype. Phenotypes of breast cancer patients were 94% PiMM, 3% PiFM and 3% PiMS. CONCLUSION: These findings demonstrated that there were no significant differences in the distribution of alpha1-AT phenotypes among Jordanian patients with lung, prostate and breast cancer and they matched those reported for healthy individuals. Thus, we cannot recommend a given alpha1-AT phenotype for early diagnosis of the above mentioned types of cancer.

Biomarkers, Tumor↗
PubMed2004

Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves.

BACKGROUND AND AIM OF THE STUDY: The roles of cardiac valvular interstitial cells (VIC) in extracellular matrix remodeling in fetal development, adaptation and response to injury are largely unknown. METHODS: The phenotype of VIC was studied in health (normal adult human and sheep), development (fetal human and sheep), disease (human mitral valves with myxomatous degeneration), adaptation (clinical pulmonary to aortic valve autografts) and tissue-engineered heart valves matured in vitro and remodeled in vivo. Cell phenotype was assessed using expression of vimentin (V), alpha-smooth muscle actin (SMA, A), matrix metalloproteinase (MMP)-13/collagenase-3 (M), and SMemb (S). RESULTS: VIC in normal adult valves were predominantly quiescent fibroblasts immunoreactive to vimentin (89.7 +/- 2.5%), but not MMP-13 or SMemb, with only 2.5 +/- 0.4% of alpha-SMA-positive cells ('normal/quiescent' phenotype: V+/A-/M-/S-). In contrast, fetal VIC were mostly activated myofibroblasts ('developing/activated' phenotype: V+/A+/M+/S+), with 62.1 +/- 5.0% of cells staining positive for alpha-SMA. VIC in myxomatous valves, short-term autografts and engineered valves in vitro were also activated myofibroblasts with coexpression of vimentin, alpha-SMA (36.2 +/- 3.7%, 19.3 +/- 2.4%, and 60.3 +/- 9% positive cells, respectively), strong MMP-13 activity indicative of collagen remodeling, and SMemb ('remodeling/activated' phenotype: V+/A+/M+/S+). In contrast, VIC in long-term pulmonary autografts and engineered valve explants had a mostly fibroblast-like phenotype, with sparse alpha-SMA expression (6.0 +/- 1% and 5.4 +/- 1.0% positive cells) (V+/A-/M-/S-). CONCLUSION: Most VIC in normal valves were quiescent with a fibroblast-like phenotype. VIC in developing, diseased, adapting and engineered valves adjust to a dynamic environment through VIC activation and secretion of proteolytic enzymes mediating extracellular matrix remodeling ('developing/ remodeling/activated' phenotype), followed by a normalization of phenotype.

Actins↗
PubMed1985

[Genetic transformation of somatic cells. VIII. The effect of the DNA methylation inhibitor 5-azacytidine on the stability of thymidine kinase-negative and -positive phenotypes of transformant clone cells].

A study was made of the effect of an DNA methylation inhibitor 5-azacytidine (azaC) on the frequency of reversion to a thymidine kinase-positive (TK+) phenotype in 5-bromodeoxy-uridine (BrdU)-resistant subclones obtained from clones of Chinese hamster cells transformed by thymidine kinase gene (tk-gene) of Herpes simplex virus type 1 (HSV1). It is shown that in 8 of 15 BrdU-resistant subclones azaC increases 2-1000-fold the frequency of reversion to TK+ phenotype. Variations in the inducibility of reversions to TK+ phenotype indicate that the DNA methylation associated with TK- phenotype affects but differently tk gene of HSV1. Cultivation of TK+ cells of transformant clones in the presence of azaC may lead to stabilization (or decrease in the rate of the loss) of TK+ phenotype, or may not influence the stability of transformant phenotype. The reaction of TK+ cells of transformant clones depends both on genetically determined rate of the loss of TK+ phenotype, and on the structure of transforming DNA introduced to cells. A conclusion is drawn that the TK- phenotype of transformant clone cells arises due to processes which are not associated with methylation of tk gene of HSV1 in spite of the fact that such a methylation may later stabilize significantly the TK- phenotype.

Animals↗
PubMed1984

Phenotypic shifts in the L5178Y lymphoma population during progression of the tumor-dormant state in DBA/2 mice.

We evaluated the phenotypic changes that take place in the L5178Y tumor cell population during the establishment, maintenance, and termination of the L5178Y tumor-dormant state in DBA/2 mice. Since there is considerable variation among DBA/2 mice in the course of the L5178Y tumor-dormant state, analysis of these phenotypic changes required prospective studies on individual mice. Therefore, we developed a partial peritoneal lavage technique which could be performed repeatedly on an individual mouse without killing the mouse and without terminating the tumor-dormant state. The partial peritoneal lavage technique provided cell samples that were quantitatively representative of the entire peritoneal cell contents without altering the relative proportions or total number of host peritoneal cell subpopulations. Tumor cell clones were isolated from the uncloned L5178Y cell inoculum that was used to initiate the tumor-dormant state, and from the partial peritoneal lavage performed on individual mice at regular intervals throughout the tumor-dormant state until each mouse developed an ascitic tumor. We found that the uncloned L5178Y cell population is heterogeneous, with the majority of the cells [approximately 80% of the clonal populations ("original" phenotype)] able to compete as well as the uncloned L5178Y cell population for immune cytolytic T-lymphocyte activity, and a smaller percentage [approximately 20% of the clones ("emergent" phenotype)] competing significantly less but similar to the tumor cell population which grows out as an ascitic tumor at the termination of the tumor-dormant state. However, both "original" and "emergent" phenotypes encompass a range of subpopulations which have the respective characteristics. There was a progressive enrichment in the tumor cell population for "emergent"-phenotype cells as mice progressed through the tumor-dormant state. In the 30-day period prior to tumor emergence, only "emergent"-phenotype cell clones were isolated. These data indicate that, during the course of the tumor-dormant state, there is continual selection by immune cytolytic T-lymphocytes for "emergent"-phenotype cells, which preexist in the L5178Y cell population used to initiate the tumor-dormant state, and that the progressive enrichment of "emergent"-phenotype cells in the peritoneal cavity is associated with and may be responsible for termination of the tumor-dormant state.

Animals↗
PubMed1984

Characterization of L5178Y cell phenotypes isolated during progression of the tumor-dormant state in DBA2 mice.

During the course of the L5178Y tumor-dormant state in DBA/2 mice, there is continual selection of a tumor cell subpopulation ("emergent" phenotype) from the uncloned original L5178Y population used to initiate the tumor-dormant state. In vivo and in vitro experiments show that the emergent-phenotype tumor cells are less capable than "original"-phenotype cells, which constitute the majority of the L5178Y cell inoculum, of restimulating cytolytic T-lymphocyte (CTL) activity in tumor-dormant mice and are less susceptible to lysis by those CTL. Both original- and emergent-phenotype tumor cells are capable of eliciting an immune CTL response in naive mice, but again emergent-phenotype cells are poorly lysed by this response. As a consequence of these characteristics, emergent-phenotype cells rapidly form ascitic tumors when used as a challenge in L5178Y cell-immunized mice and cannot establish a tumor-dormant state. Results presented here and in previous publications indicate that CTLs are the major host cells involved in the selection of emergent-phenotype L5178Y cells during the course of the tumor-dormant state. Heterogeneity of the tumor cell challenge inoculum is important in establishing the L5178Y tumor-dormant state. The state, once established, is maintained by an immune CTL response which is continuously being restimulated by the strongly immunogenic original-phenotype L5178Y cells. The tumor-dormant state terminates when the less immunogenic and more immunoresistant emergent-phenotype tumor cells predominate and escape the waning immune response.

Animals↗
PubMed1994

[Respiratory involvement in ankylosing spondylarthritis: relations to alpha-1-antitrypsin phenotypes and tobacco consumption].

The distribution of alpha-1-antitrypsin phenotypes was similar in 555 controls and 98 patients with ankylosing spondylitis: the MM phenotype (including "main" MM subtypes, i.e., M2M2 and M3M3, and "secondary" MM subtypes) was found in 86% of subjects and "rare" phenotypes combining M, F, S, and Z in 14%. Six per cent of the controls and none of the ankylosing spondylitis patients had the M4M4 phenotype (p < 0.01). Respiratory function tests were performed in 49 patients with axial ankylosing spondylitis and 30 controls matched on sex, age, body mass index, smoking status, nonsteroidal antiinflammatory drug use and distribution of "main" and "secondary" phenotypes (no subjects in this study had "rare" phenotypes); the significant reduction in chest expansion seen in the ankylosing spondylitis group (5.6 +/- 2.7 cm versus 8.7 +/- 1.2; p < 0.001) was correlated with total capacity (p < 0.04) and vital capacity (p < 0.001). Restrictive ventilatory dysfunction was seen in four ankylosing spondylitis patients versus no controls (p < 0.02). Proximal airway obstruction, pulmonary distension and decreases in the diffusing capacity for carbon monoxide were seen in similar proportions of ankylosing spondylitis patients and controls. In the ankylosing spondylitis group, evidence of pulmonary distension included increases in mean residual functional capacity and mean residual volume (105.6 +/- 21.2% versus 94.8 +/- 17.4, p < 0.03, and 100.3 +/- 22.8% versus 88.6 +/- 17.9, p < 0.04, respectively) and bullous emphysema in the lung bases in two patients (versus no controls). In the small subgroup of ankylosing spondylitis patients with lung distension or a decreased diffusing capacity for carbon monoxide, smokers and nonsmokers were evenly balanced but subjects with "secondary" phenotypes outnumbered those with "main" phenotypes (p < 0.02); in contrast, our data suggested that smoking may play the central role in the proximal airway obstruction. Our findings suggest that in addition to previously established causes of pulmonary involvement in ankylosing spondylitis a "secondary" MM phenotype (i.e., neither M2M2 nor M3M3) may be a risk factor for lung distension and impaired diffusing capacity for carbon monoxide.

Adult↗
PubMed1995

Relationship among Lewis phenotype, clotting factors, and other cardiovascular risk factors in young adults.

An increased risk of ischemic heart disease has been reported in men with the Lewis blood group phenotype Le(a-b-). We have investigated the relationship between Lewis phenotype and cardiovascular risk factors in 1714 participants in the Coronary Artery Risk Development in Young Adults Study, an ongoing investigation on life-styles and evolution of cardiovascular risk factors. No significant differences were observed among Lewis phenotypes for body mass index, blood lipid levels, blood pressure, or clotting factors VII and fibrinogen. However, in white men with blood groups A, B, or AB, and the Le(a-b-) phenotype, significantly higher levels of factor VIII (p < 0.01) and von Willebrand factor (p < 0.03) were observed than in those with other Lewis phenotypes (Le[a+b-] or Le[a-b+]). Two-way analysis of variance indicated a significant interaction between blood group and Lewis phenotype (p = 0.0053) in terms of relationship to factor VIII. A similar trend was observed in black men with blood type A, B, or AB, and phenotype Le(a-b-) for factor VII/von Willebrand factor and in women with blood type A, B, or AB, and phenotype Le(a-b-) for factor VIII. Our data suggest that the Le(a-b-) phenotype and blood groups A, B, and AB, by virtue of their association with raised levels of factor VIII and von Willebrand factor, may be risk markers for future atherothrombotic disease.

ABO Blood-Group System↗