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PubMed1991

Aromatic and heterocyclic amine metabolism and phenotyping in humans.

Our method to evaluate acetylator phenotype and N-oxidation phenotype with a single caffeine dose and a single urine specimen collection has enabled us to examine acetylation and N-oxidation by two enzyme systems that have a known genetic polymorphism and are important in aromatic amine metabolism. Based on available data, we have hypothesized patients with urinary bladder cancer will have a higher frequency of rapid N-oxidation and slow acetylation phenotypes when compared to controls. On the other hand, patients with colorectal cancer should contain a higher proportion of both rapid N-oxidation phenotype and rapid acetylation phenotype when compared to the control group. In contrast, lung cancer patients, should contain an increased frequency of rapid arylamine N-oxidation phenotypes with the frequency of acetyltransferase phenotype being greater or perhaps the same as in the control group.

Acetyltransferases↗
PubMed1991

DNA polymorphisms in the controlling region of the human haptoglobin genes: a molecular explanation for the haptoglobin 2-1 modified phenotype.

A haptoglobin 2-1 modified (Hp2-1mod) phenotype results when the amount of Hp2 polypeptide synthesized in Hp2/Hp1 heterozygotes is less than that of Hp1 polypeptide. Cloned Hp2 DNA from an individual with the Hp2-1mod phenotype is here shown to have a C in place of the normal A at nucleotide position -61 in one of the interleukin-6 (IL-6) responsive elements of the haptoglobin promoter region. Direct sequencing of the haptoglobin promoter region, amplified by PCR, from DNA from unrelated American blacks showed a C at -61 in all of 10 individuals with the Hp2-1mod phenotype, in two of four with a "possible Hp2-1mod" phenotype, but in none of 15 with the Hp2-1 phenotype. Thus the -61C mutation in the Hp2-61C allele is strongly associated with the Hp2-1mod phenotype. Sequencing results also show that there are three other promoter sequences in the population studied; each can be associated with either Hp2 or Hp1. The variability seen in the Hp2-1mod phenotype, a variability which ranges from close to Hp2-1 to close to Hp1-1, can be explained, in part, by the existence of several Hp2 alleles differing in their promoters--and possibly, in part, by differences in the promoters of the accompanying Hp1 allele. A further part of the variability may be the consequence of differences in the way that the Hp2-61C and the Hp2 alleles respond to the IL-6-dependent factor during an acute-phase response.

Base Sequence↗
PubMed1990

DNA synthesis, apoptosis, and phenotypic expression as determinants of growth of altered foci in rat liver during phenobarbital promotion.

Carcinogenesis was initiated in female rat liver by a single dose of N-nitrosomorpholine; subsequently phenobarbital (PB) was administered via the diet at a daily dose of 50 mg/kg body weight for up to 49 weeks. Subgroups of rats were left untreated after 10 or 28 weeks on PB. PB produced the following changes: (a) accelerated appearance of neoplastic nodules and hepatocellular carcinoma (from 28 weeks onwards); (b) phenotypic changes in altered foci such as a shift from clear to eosinophilic appearance, enhanced expression of gamma-glutamyltranspeptidase and other markers, and more distinct borders from surrounding liver; (c) an increase in foci number; and (d) accelerated foci enlargement. The increase in foci number was found to be due to increased phenotypic expression of foci. DNA synthesis was measured by [3H]thymidine labeling at multiple time points. The rate of DNA synthesis was always approximately 10-fold higher in foci than in surrounding liver tissue. Despite this, after N-nitrosomorpholine alone foci grew little before 18-24 weeks. Continuous treatment with PB did not produce a persistent further increase of DNA synthesis in foci, although it accelerated foci growth. Furthermore, at early stages small and larger foci showed similar DNA synthesis activity. These findings indicate that the rate of cell replication as measured by DNA synthesis is not the only determinant of the growth rate of foci. Further studies showed that foci with indistinct borders (reflecting weak expression of the altered phenotype) grew much less than foci with distinct borders; this was at least in part due to an increased rate of cell death by apoptosis found in foci with indistinct borders. In conclusion, besides cell replication, apoptosis and the extent of phenotypic expression (remodeling) determine the growth rate of foci. Foci with weak phenotypic expression predominated after N-nitrosomorpholine alone; in these, a high incidence of apoptosis counterbalanced cell replication. In contrast, during PB treatment foci with strong phenotypic expression predominated; in these, apoptotic activity was lower and the high replicative activity could manifest itself. Finally, all effects of PB on foci were largely although not completely reversible upon cessation of treatment; as a result phenotypic expression declined, and "remodeling" foci with high apoptotic activity predominated again.

Animals↗
PubMed1988

Leukemic cell maturation: phenotypic variability and oncogene expression in HL60 cells: a review.

Leukemic cells in vitro and in vivo demonstrate an unstable phenotype. We have observed in HL60 cells maintained in culture over long periods of time such phenomena as emergence of drug resistance, oncogene amplification, loss of granulocyte and monocyte lineage markers, and alteration in cell growth parameters. As summarized in this report, a comprehensive review of the literature on HL60 cells shows a wide diversity of phenotype for these cells. We have developed and acquired from other laboratories a series of HL60 sublines with varying phenotypic characteristics. The time in continuous log phase culture for HL60 cells (passage 13 ATCC, Rockville MD) to undergo phenotypic drift from a heavily granulated promyelocytic cell to a more undifferentiated agranular blast form on four occasions varied from 3 to 18 months. The actual loss of promyelocytic phenotype occurred rapidly (within less than 1 month) following a variable period of apparent stable phenotype, The change in morphology was invariably accompanied by decreased sensitivity to ARA-c (5- to 20-fold increase in LD50 and dose necessary to induce NSE positive cells). The c-myc gene is variably amplified in sublines of HL60 cells. The expression of c-myc primarily reflects alterations in cell cycle kinetics and was not found to be correlated with a switch between proliferation and maturation. These results suggest that phenotypic drift may be due to loss of response to regulatory signals that affect the expression of a number of cellular genes.

Cell Differentiation↗
PubMed1989

[Phenotypes of the alpha-1 proteinase inhibitor in septic diseases and leukemia in children].

Employment of isoelectrofocussing techniques for the determination of proteinase alpha 1-inhibitor (p alpha 1i) phenotypes helped detect original rare phenotypes. Their accurate identification should be performed with a set of standard sera. The findings of studies on the number of p alpha 1i by Mancini's immunoprecipitation test are analyzed, as are the data of phenotype studies by p alpha 1i isoelectrofocussing in children suffering from acute leukemia and sepsis. The findings evidence a drastic increase of p alpha 1i number, parallelled by the emergence of a manifest anode fraction of a common Pi MM phenotype; this may be regarded as a manifestation of a rare Pi MM anode phenotype in phenotyping. The possible reasons of this phenomenon are discussed; the authors emphasize the significance of analyzing rare p alpha 1i phenotypical variants with standard sera.

Bacterial Infections↗
PubMed1989

C4 and Bf phenotypes in black and Caucasian patients with childhood onset insulin dependent diabetes mellitus.

Certain alleles for the complement proteins, C4 and Bf, have been shown to be markers for insulin-dependent diabetes mellitus (IDDM) in samples of different racial and geographic composition. However, the same markers are not demonstrable in each group studied. Phenotyping for the complement alleles, C4 and Bf was performed on 168 Caucasian and 49 Black patients with IDDM. All of the patients were followed in Memphis, Tennessee and had onset of disease prior to age 18. The Bf*F1 allelic frequency was significantly increased for the Caucasian patients as compared to 93 healthy Caucasian controls (0.063 vs. 0.016) and for the Black IDDM patients as compared to 43 healthy Black controls (0.102 vs. 0.035). C4 phenotype frequencies showed a significant increase of the C4AQ0 (rr = 2.13) and C4A4 (rr = 2.91) phenotypes for the Caucasian IDDM patients as compared to controls, but the frequency of homozygous null C4A was not significantly increased. In addition significant negative associations of IDDM with C4A3 and C4A6 phenotypes and no association with any C4B phenotype were observed in our Caucasian patient population. Our data for Mild-South Blacks with IDDM suggest a similar positive association of IDDM with the BfF1 phenotype (rr = 3.4). However, there was no evidence among Black IDDM patients of the C4AQ0 and C4A4 associations observed in the Caucasian sample. The data support a possible association of IDDM with the C4A2 (rr = 5.86) and C4B2 (rr = 5.26) phenotypes. The hypothesis that racial admixture may account for the higher frequency of IDDM in US Blacks as compared with African Blacks has been forwarded by others.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1989

Protective HLA-DR phenotypes in rheumatoid arthritis.

In a study of HLA-DR phenotypes in patients with rheumatoid arthritis (RA) and controls from the Saskatoon area and in Newfoundland, we found that certain phenotypes occurred more frequently in the patients than in healthy controls in both populations ("increased risk phenotypes"). The reverse was also true: certain phenotypes were reduced or excluded from patients with RA compared with controls. Three increased risk phenotypes with twice the expected frequencies or more were HLA-DR1,DR4; DR4 and DR4,DR5. Four "protective" phenotypes with half or less the expected frequencies were HLA-DR1, DR5; DR2; DR2,DR3 and DR3,DR7. We speculate that at least for the DR3,DR7 phenotype, the protective effect may be due to a hybrid DQw2 molecule.

Arthritis, Rheumatoid↗
PubMed1989

In vitro study of translocation t(4;11) acute leukemia. Sequential range of phenotype.

The nature of translocation t(4;11) acute leukemia cells has been widely discussed over the past few years. Many authors report their phenotypic heterogeneity, ranging from apparently common acute lymphoblastic leukemia antigen-positive to monoblastic leukemia, through "promiscuous" phenotype. We studied in vitro phenotypic modulation of three typical cases after induction by 12-O-tetradecanoyl phorbol 13 acetate. The initial phenotype was different in each case, but all of them exhibited changes in morphologic shape, cytochemistry, and immunophenotype; common features appeared after induction by 12-O-tetradecanoyl phorbol 13 acetate, including esterase activity, expression of CD-9, CD-15, and CD-18 surface antigens, and monocyte/macrophage morphology. In all cases a B-associated surface antigen, CD-19, persisted. During clinical evolution, some previously reported cases have shown a karyotypic and phenotypic transformation. In one of our cases this phenomenon correlated with in vitro phenotypic modulation of initial blast population. Furthermore, clinical relapses and in vitro modulation always seem to evolve toward a more "mature" phenotype. Those results support the "promiscuous lineage" hypothesis, and point out the usefulness of in vitro studies to express the myeloid potential of this category of acute leukemia, which can be regarded as a model of early hematopoietic differentiation.

Acute Disease↗
PubMed1988

Diagnosis and analysis of the clinical course of T-phenotype acute lymphoblastic leukemia.

We refer to the diagnostic possibilities in T-phenotype acute lymphoblastic leukemia. Immunophenotyping based on the proof of T-differentiation antigens by means of specific monoclonal antibodies and assessment of the E receptor, as well as examination of enzymatic activities of adenosine deaminase and purinenucleoside phosphorylase, were performed. Thirty patients with acute lymphoblastic leukemia of T-phenotype were examined. The monoclonal antibodies used demonstrated a heterogeneity in this type of leukemia reflecting the stage of thymocyte differentiation. The cells of some patients with T-phenotype acute lymphoblastic leukemia expressed simultaneously the common acute lymphoblastic leukemia antigen and Ia molecules. Examination of enzyme activities demonstrated a characteristic pattern with a significantly increased adenosine deaminase activity and simultaneously decreased purinenucleoside phosphorylase activity in T-phenotype acute lymphoblastic leukemia. The unfavorable course of disease in patients with T-phenotype acute lymphoblastic leukemia was demonstrated analyzing a group of 50 children with acute lymphoblastic leukemia. By means of statistical methods the cumulative rate of children surviving with acute lymphoblastic leukemia of common and T-phenotypes have been expressed. The results showed the need for a more effective treatment aimed at the T-phenotype of acute lymphoblastic leukemia.

Adenosine Deaminase↗
PubMed1985

[Genetic transformation of somatic cells. VII. The loss of the transformant phenotype is accompanied by both stable and unstable changes in DNA].

From 6 clones of Chinese hamster cells varying in the rate of the loss of transformant phenotype and containing a thymidine kinase gene (tk-gene) of Herpes simplex virus type 1 (HSV1), 25 subclones negative in thymidine kinase (TK-) were isolated on a medium with 50 micrograms/ml 5-bromodeoxyuridine (BrdU). A study was made of the frequency of spontaneous reversions to the TK+ phenotype in cell populations of BrdU-resistant subclones, and of the transforming activity (upon transformation of TK- cells of A238 clone to the TK+ phenotype) of DNA preparations from a row BrdU-resistant subclones. In 7 of 11 BrdU-resistant subclones the TK- phenotype is associated with changes reducing significantly the transforming activity of DNA. Some of these alterations are stable and undergo no spontaneous reversion, while the other ones are unstable, being reversed or suppressed at a high frequency. BrdU-resistant subclones produced from clones more stable in transformant phenotype are on the whole more stable in the TK- phenotype than BrdU-resistant subclones from the clones with the high rate of the loss of the TK+ phenotype.

Animals↗
PubMed1988

Phenotyping of acute myelocytic leukemia (AML) progenitors: an approach for tracing minimal numbers of AML cells among normal bone marrow.

Previous studies have shown that the phenotypes of progenitors of human AML (AML-CFU) are variable, reflecting arrests at different stages of maturation. We were interested to seek discrepancies between the surface properties of AML precursors and normal bone marrow colony formers in order to detect minimal numbers of AML cells among normal bone marrow cells in remission bone marrow. Therefore, we selected two surface markers, the MoAb CD34, reactive with blast cells, and Vim-2, a surface marker reactive with mature myeloid cells, and determined the antigen density of these markers (relative fluorescence intensity using fluorescence-activated cell sorting) for normal marrow and AML progenitors. While these markers defined an identical phenotype (CD34++/Vim-2-/+) for a broad spectrum of normal progenitors, i.e., CFU-GEMM, BFU-e, day 15 CFU-GM, and day 7 CFU-GM, referred to as the "normal" progenitor phenotype, AML progenitors frequently exhibited different phenotypes. In 12 of 20 cases the phenotypes of the majority of AML progenitors were discrepant from the normal surface profile, i.e., according to one marker in 8 cases (CD34-/+/Vim-2-/+ or CD34++/Vim-2++) and two markers in 4 cases (CD34-/+/Vim-2++). Since these data indicate that AML and normal progenitors were frequently distinguishable, we then determined the potential utility of these phenotypic dissimilarities for detection of minimal disease. Artificial mixtures of normal bone marrow and minimal numbers (0.1-1%) of AML cells were prepared. Based upon the phenotypic discrepancies, AML metaphases were successfully demonstrated in these mixtures following cell sorting and culture. Thus, it appears that minimal numbers of AML mitoses can be identified with an approximate 10(-2) to 10(-3) sensitivity by taking advantage of differential coexpression of surface antigens.

Antibodies, Monoclonal↗
PubMed1987

Discordance between red cell and saliva Lewis phenotypes in patients with hydatid cysts.

Patients with hydatid cysts and controls of the same Tunisian area were typed for ABO, Lewis and secretor phenotypes. A high incidence of red cell Le(a-b-) phenotype (34-37%) was found among hydatid cyst patients as compared to normal controls (13-16%). However, a large proportion of the patients with Le(a-b-) red cell phenotype had discordant red cell and saliva Lewis phenotypes since they secreted Lea and/or Leb antigens in saliva. In addition, 1 patient with Le(a+b-) red cell phenotype secreted Leb antigen in saliva. The remaining patients and all the controls had concordant red cell and saliva Lewis phenotypes. The discordant results between the phenotypes obtained in serum and saliva of hydatid cyst patients are probably the consequence of a decrease in the concentration of the circulating Lewis glycosphingolipids, secondary to the disease.

ABO Blood-Group System↗
PubMed1987

Phenotype and localization of thymocytes expressing the homing receptor-associated antigen MEL-14: arguments for the view that most mature thymocytes are located in the medulla.

The monoclonal antibody MEL-14 recognizes a lymphocyte surface structure (the MEL-14 antigen) involved in migration of lymphocytes into lymph nodes. Its use as a maturation marker for T cells within the thymus led to the view that a small population (1 to 2%) of MEL-14high thymocytes located in the inner cortex represented fully mature cells about to exit as thymus emigrants. The medulla, in this view, contained only the phenotypically mature but MEL-14low cells, and was not the source of thymus emigrants. The data we present, derived from flow-cytometric analysis of suspension-stained CBA mouse thymocytes, is not in accordance with this view. A high proportion (approximately 20%) of thymocytes express relatively high levels of MEL-14; these include some immature Ly-2- L3T4- and nonmature Ly-2+ L3T4+ thymocytes. Among the 12 to 14% thymocytes of mature phenotype (PNAlow or H-2Khigh or Ly-2+ L3T4- and Ly-2- L3T4+), more than half express relatively high levels of MEL-14. The mature phenotype and MEL-14moderate-to-high cells (8% of thymocytes) appear too numerous to account for the few percent MEL-14high cells seen in the cortex in frozen sections, and the mature phenotype but MEL-14low cells (2 to 3% of thymocytes) too few to fill the medulla; however, both together account numerically for the medullary population. By section staining, the medulla contains Ly-2- L3T4+ and Ly-2+ L3T4- cells in a characteristic 2:1 ratio; by suspension staining this ratio agrees with that of the total mature phenotype population, but not with that of the MEL-14low subset previously claimed to represent medullary cells. Another paradox is apparent when suspension staining and section staining are compared: suspension staining reveals that many mature phenotype cells coexpress high levels of both MEL-14 and H-2K, yet section staining reveals H-2Khigh cells in the medulla but not in the inner cortex, and reveals scattered MEL-14high cells throughout the cortex but not in the medulla. We suggest that section staining for MEL-14 fails to locate the mature cells that stain for MEL-14 in suspension; the few MEL-14high cells localized in both the inner and the outer cortex on section staining are predominantly immature Ly-2- L3T4- and nonmature Ly-2+ L3T4+ thymocytes; the majority of thymocytes of mature phenotype, whether MEL-14high or MEL-14low on suspension staining, are of medullary location; the medulla is the most likely immediate source of thymic emigrants.

Animals↗
PubMed1987

Drug acetylator phenotypes in newborn infants.

The distribution of drug acetylator phenotypes in 100 healthy newborn infants was studied and compared with the acetylator phenotypes frequency in different age groups. Phenotyping was performed by assaying total and free sulphadimidine in the urine after single oral test dose of the drug/100 mg. As in elderly subjects, slow acetylator phenotype was predominant also in healthy newborns (83%), which was the highest frequency of all age groups observed. Acetylator phenotype in the newborn infants may be influenced by genetic, environmental (e.g., nutritive), as well as by developmental factors (e.g., postnatal enzyme deficiency, age-specific changes in organ functions, etc.). In this connection, slow acetylator phenotype of the neonate may be related to a negative pantothenic acid balance causing insufficient Coenzyme-A synthesis, too. The predominance of the slow acetylator phenotype resulting in higher drug sensitivity can be regarded clinically as a special risk factor in human neonates.

Acetyl Coenzyme A↗
PubMed1995

LDL subclass phenotypes and the risk factors of the insulin resistance syndrome.

The insulin resistance syndrome is characterized by a constellation of risk factors including obesity, central body fat distribution, hypertension, glucose intolerance, elevated plasma insulin levels, increased triglyceride and decreased high-density lipoprotein (HDL) cholesterol. Similarly, low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, is associated with increased triglyceride and lower HDL cholesterol levels. Both the insulin resistance syndrome and phenotype B have also been related to increased risk of coronary heart disease. Using a sample of nearly 700 women who participated in the Kaiser Permanente Women Twins Study, we investigated the associations of LDL subclass phenotype B with the risk factors that characterize the insulin resistance syndrome. The results demonstrate that LDL subclass phenotype B was strongly associated with both age and diabetes status. Among nondiabetic women, phenotype B was more prevalent in those with higher body mass index and in those with higher waist-hip ratio. In addition to the expected associations with triglyceride and HDL cholesterol, mean values of both systolic and diastolic blood pressure were higher in women with phenotype B. Finally, fasting and post-load insulin levels and post-load glucose levels were higher in those with phenotype B. In general, these relationships persisted in multivariate statistical analyses. Therefore, a predominance of small, dense LDL particles appears to be an integral feature of the risk factors that characterize the insulin resistance syndrome.

Adult↗
PubMed1994

[Role of sun exposure on benign melanocytic nevi. A first study in populations controlled for age, sex and phenotype].

BACKGROUND: These studies were designed to assess the influence of sun exposure on nevi in white people. In order to eliminate the confounding effect of age, sex and phenotype, two parallel studies were conducted in people of the same age (17 to 24 years), sex (males) and phenotype: one in people with "red" phenotype and one in people with "dark" phenotype. RESULTS: In both groups, comparison of nevus counts on the inner and outer side of the upper extremities and comparison of mean density of nevi (number per square meter) in always-exposed and never-exposed skin show that number of nevi is higher in sun exposed areas. In both groups the density of large and atypical nevi was maximal on intermittently sun-exposed skin while the density of small nevi was maximal on always-exposed skin. The number of large nevi on intermittently-exposed skin correlated with cumulative intensive exposure during beach recreation in the red phenotype group. The number of large nevi was significantly higher in red phenotypes who repeatedly experienced severe sunburns in their first 20 years of life. CONCLUSIONS: The number of nevi at the end of the second decade is influenced by cumulative sun exposure from birth. "Traumatizing" sun exposure, which is more frequent in "red" phenotype than in "dark" one, has an influence on the number of large nevi and is therefore likely to make small nevi grow.

Adult↗
PubMed1994

[Application of ORM1 phenotyping in forensic science].

ORM1 is an important genetic marker for both parentage testing and personal identification in forensic science. We have examined the ORM1 phenotypes in the human serum and dried bloodstains using the ULPAGIF method. ORM1 phenotypes were successfully demonstrated from dried bloodstains stored at 4 degrees C and room temperature for up to twenty-four weeks. In bloodstains stored at 37 degrees C, the 100% of ORM1 phenotyping was no longer possible after 12 weeks. We examined 9 bloodstains stored at room temperature for one, two and three years, respectively. For the one-year-old bloodstains, all of the samples could be phenotyped correctly, for the two-year-old bloodstains 8 out of the 9 and for the three-year-old bloodstains 7 out of the 9 samples could be phenotyped correctly. The results have indicated that ORM1 is relatively stable, for it is tolerable toward high temperature and long duration. It was suggested that the bloodstains should be ultrasonicated before ULPAGIF, because the ultrasonication could elevate the detectable rate of ORM1 phenotypes from bloodstains. ORM1 phenotypes was performed in five disputed parentage cases. One of the alleged fathers was excluded.

Blood Stains↗
PubMed1993

Zidovudine resistance, syncytium-inducing phenotype, and HIV disease progression in a case-control study. The VA Cooperative Study Group.

A case-control study of patients with progressive (cases) or nonprogressive (controls) disease was designed to determine the association among disease progression, zidovudine sensitivity, and syncytium-inducing phenotype. Viral isolates were screened for sensitivity to zidovudine using a peripheral blood mononuclear cell-based assay and for syncytium-inducing (SI) phenotype in MT2 cell culture. Thirty-four patients, whose disease progressed to AIDS or whose CD4 cell numbers fell < 200 cells/mm3, were matched with 34 patients whose conditions had not progressed or whose CD4 cell numbers remained > 200 cells/mm3. Virus was successfully cultured from both the progressor and the nonprogressor in 17 of these 34 matched case-control pairs. In six of the 17 pairs, virus isolated from the progressor had an IC50 (50% inhibitory concentration) for zidovudine > 1 microM and at least threefold greater than the IC50 of virus isolated from the matched nonprogressor (p = 0.04). In 16 of these 17 pairs the virus isolated from the progressor had the SI phenotype, indicative of high cytopathogenicity, while the virus from the matched nonprogressor had a non-syncytium-inducing phenotype (p < 0.0001). Zidovudine therapy did not appear to select for the SI phenotype in this patient population. A statistically significant association between high-level zidovudine resistance and clinical disease progression was demonstrated. A statistically significant association between the SI phenotype and disease progression was demonstrated. The results suggest that disease progression while being treated with zidovudine therapy may be more closely associated with the SI phenotype than with zidovudine resistance.

Acquired Immunodeficiency Syndrome↗