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At least 109 records · Page 6Linked to original sources
PubMed1994

In vivo phenotypic characteristics of AKR T-cell lymphomas with different leukemic potential: possible role of alpha 4 beta 7 integrin in the progression towards the leukemic phenotype.

The present study was undertaken in order to determine whether the expression of specific surface molecules which mediate immune recognition as well as cell-cell and cell-matrix interactions is associated with the leukemic evolution of T-cell lymphomas. To this end, we have investigated the in vivo phenotypic characteristics and the in vitro natural-killer(NK)-cell susceptibility of a group of MCF-247-induced AKR/J T-cell lymphomas with different leukemic potential. We found that in the AKR/J model, the biological aggressiveness of leukemic cells is not dependent upon an escape from host immune surveillance as a consequence of an in vivo down-regulation of H2-Kk determinants or a resistance to NK lysis. Moreover, NK susceptibility of AKR/J lymphomas does not seem to correlate with the level of H2-antigen expression. No obvious correlation was found between the leukemic phenotype and the amount of MEL-14, LFA-1, ICAM-1, Pgp-1/CD44 and THAM/CD26 antigen expression. An in vivo coordinated up-regulation of alpha 4 and beta 7 integrin chains, with the highest levels of expression detected in secondary sites of leukemic infiltration, was observed in the highly leukemic lymphoma NQ22 and, albeit to a lesser extent, in lymphomas with moderate leukemic potential. Conversely, non-leukemic lymphomas were repeatedly alpha 4- and beta 7-negative. These findings suggest that in the AKR/J system the expression of alpha 4 beta 7 integrin may contribute to leukemic spreading of T-cell lymphomas.

Animals↗
PubMed1995

Analysis of v-Ha-ras and v-fos oncogene transduction into a mouse epidermal cell line with "initiated" phenotype in culture but normal skin phenotype in vivo.

Cell line SCR722 was derived from adult SENCAR mouse epidermal cells initiated in culture by treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine and selection for foci proliferating in medium with calcium levels that induce terminal differentiation in normal cells. Expansion of one of these foci and two additional cell clonings produced cell line SCR722, which was near-tetraploid and formed normal skin when grafted to athymic nude mouse hosts. However, unlike normal keratinocytes, SCR722 cells fail to suppress papilloma formation when grafted along with papilloma cell line SP-1. For optimum growth in culture, SCR722 cells required fibroblast-conditioned medium and 0.5 mM Ca2+. SCR722 cells had a wild-type c-Ha-ras gene but had lost their requirement for conditioned medium in culture and produced dysplastic papillomas in grafts when transduced with the v-Ha-ras gene. SCR722 cells stably expressing the v-fos gene produced normal epidermis in grafts, but when these cells were transduced with the v-Ha-ras gene, they produced carcinomas. Clones with greater expression of the transfected v-fos gene had a more invasive phenotype in vivo. These results indicate that carcinogen treatment of epithelial cells can result in an altered but nontumorigenic phenotype that may be at risk for becoming a more advanced neoplastic state with additional genetic alterations.

Animals↗
PubMed1977

Classification of alpha1-antitrypsin (Pi) phenotypes by isoelectrofocusing. Distinction of six subtypes of the PiM phenotype.

Pi phenotypes have been determined by isoelectrofocusing in a sample of 538 healthy individuals from Southern Germany. Further subdivision of the common PiM phenotype is described. A procedure for the delineation of six common subtypes is presented. It is assumed that the six subtypes are determined by three alleles which are provisionally called PiMa, PiMb, and PiMc. Their frequencies in this sample were 0.75, 0.06, and 0.15, respectively.

Alleles↗
PubMed1985

Leu-7-positive cells with monocyte phenotype show different ultrastructural features in comparison to Leu-7-positive cells with T-cell phenotype.

The ultrastructural features of the Leu-7-positive - Leu-M3-positive cell subpopulation and the Leu-7-positive - Leu-4-positive cell subpopulation were characterized and compared using immunogold-immunoperoxidase double labelling with immunoelectron microscopy. The majority of Leu-7-positive cells coexpressed a monocyte phenotype and showed an ultrastructural pattern specific for functional natural killer (NK) cells, i.e. a low nuclear/cytoplasmic (N/C) ratio, an irregular outline, many cytoplasmic organelles and electron-dense granules. In contrast, only a minority of Leu-7-positive cells coexpressed a T phenotype, and these were characterized by a high N/C ratio, an even surface and the absence of electron-dense granules. Thus, Leu-7-positive - Leu-4-positive cells may by an immature form of NK cells, and Leu-7-positive - Leu-4-positive and Leu-7-positive - Leu-M3-positive cell subpopulations may represent different stages of Leu-7-positive cell differentiation.

Antibodies, Monoclonal↗
PubMed1980

T-cell specificity for H-2 and Ir gene phenotype correlates with the phenotype of thymic antigen-presenting cells.

Experiments with chimaeric animals have demonstrated that the H-2 restriction specificity and immune response (Ir) gene phenotype of the T cell is acquired during development in the thymus. The mechanism by which this process occurs is unclear. One level of obligate expression of H-2 and Ir gene products is on the surface of antigen-presenting cells (APCs) which come from bone marrow precursors. We have now examined the turnover of APCs in the thymuses of F1 leads to parent (P) radiation-induced bone marrow chimaeras and found that APCs of donor phenotype appear at about 2 months after reconstitution. If the peripheral T-cell population is depleted after this time, new T cells emerging from the parental thymus (containing F1 APCs) behaving like F1 T cells, suggesting that cells from the bone marrow can influence thymic-directed T-cell differentiation. The thymic APC is an attractive condidate to play such a part in the development of the T-cell repertoire.

Animals↗
PubMedDate not supplied

Molecular basis for phenotypic heterogeneity in galactosaemia: prediction of clinical phenotype from genotype in Japanese patients.

We identified 14 mutations in 15 Japanese subjects from 13 families with galactose-1-phosphate uridyltransferase (GALT) deficiency using denaturing gradient gel electrophoresis (DGGE) and direct sequence analysis. These mutations accounted for 22 (96%) of 23 mutant alleles in 15 Japanese subjects. The mutational spectrum included nine missense mutations (M142V, G179D, A199T, R231H, W249R, N314D, P325L, R333Q, and R333W), two deletions (L275fsdelT and Q317fsdelC), a nonsense mutation (W249X), and two splicing mutations (V85-N97fsdel38bp and IVS4nt+1). Ten of the 14 mutations have not been reported in Caucasians. Differences in frequency and spectrum of GALT mutations suggest that the mutations may have occurred after racial divergence of Caucasians and Asians. The Duarte variant in Japanese was associated with the N314D mutation, g.1105G > C, g.1323G > A, and g.1391G > A (SacI -) polymorphisms, as in Caucasians. The Duarte variant may have occurred before racial divergence, and was an ancient mutation. In vitro GALT activities of nine missense mutations were determined by a COS cell expression system, and indicated between 1.3% and 35% of wild-type control. Patients with R333Q (29% in vitro GALT activity) or A199T (35%) showed mild clinical phenotypes, i.e. no ovarian failure or neurological deterioration. Genotype determination is useful for predicting biochemical and clinical phenotypes in classic galactosaemia, and can be of further help in managing patients with this disorder.

Adolescent↗
PubMed1998

The bcl-2 knockout mouse exhibits marked changes in osteoblast phenotype and collagen deposition in bone as well as a mild growth plate phenotype.

Histological examination of long bones from 1-day-old bcl-2 knockout and age-matched control mice revealed no obvious differences in length of bone, growth plate architecture or stage of endochondral ossification. In 35-day-old bcl-2 knockout mice that are growth retarded or 'dwarfed'. the proliferative zone of the growth plate appeared slightly thinner and the secondary centres of ossification less well developed than their age-matched wild-type controls. The most marked histological effects of bcl-2 ablation were on osteoblasts and bone. 35-day-old knockout mouse bones exhibited far greater numbers of osteoblasts than controls and the osteoblasts had a cuboidal phenotype in comparison with the normal flattened cell appearance. In addition, the collagen deposited by the osteoblasts in the bcl-2 knockout mouse bone was disorganized in comparison with control tissue and had a pseudo-woven appearance. The results suggest an important role for Bcl-2 in controlling osteoblast phenotype and bone deposition in vivo.

Animals↗
PubMedDate not supplied

Phenotypic and dynamical transitions in model genetic networks. I. Emergence of patterns and genotype-phenotype relationships.

Genotype-phenotype interactions during the evolution of form in multicellular organisms is a complex problem but one that can be aided by computational approaches. We present here a framework within which developmental patterns and their underlying genetic networks can be simulated. Gene networks were chosen to reflect realistic regulatory circuits, including positive and negative feedback control, and the exchange of a subset of gene products between cells, or within a syncytium. Some of these networks generate stable spatial patterns of a subset of their molecular constituents, and can be assigned to categories (e.g., "emergent" or "hierarchic") based on the topology of molecular circuitry. These categories roughly correspond to what has been discussed in the literature as "self-organizing" and "programmed" processes of development. The capability of such networks to form patterns of repeating stripes was studied in network ensembles in which parameters of gene-gene interaction were caused to vary in a manner analogous to genetic mutation. The evolution under mutational change of individual representative networks of each category was also simulated. We have found that patterns with few stripes (< or =3) are most likely to originate in the form of a hierarchic network, whereas those with greater numbers of stripes (> or =4) originate most readily as emergent networks. However, regardless of how many stripes it contains, once a pattern is established, there appears to be an evolutionary tendency for emergent mechanisms to be replaced by hierarchic mechanisms. These results have potential significance for the understanding of genotype-phenotype relationships in the evolution of metazoan form.

Biological Evolution↗
PubMed2003

Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3.

Neuronopathic Gaucher disease, classically divided into two types, can have a continuum of phenotypes, often defying categorization. Nine children had an intermediate phenotype characterized by a delayed age of onset but rapidly progressive neurological disease, including refractory seizures and oculomotor abnormalities. There was genotypic heterogeneity among these patients.

Age of Onset↗
PubMed1991

The effects of cAMP on differentiation of cultured Schwann cells: progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP-, N-CAM-, NGF-receptor-) depends on growth inhibition.

The present experiments were designed to clarify the relationship between cAMP elevation, proliferation and differentiation in Schwann cells. They were carried out on short-term cultures of cells obtained from neonatal rat sciatic nerves. It was found that the myelin-related phenotype was expressed in response to agents that elevate or mimic intracellular cAMP (forskolin, cholera toxin, cAMP analogues), provided cell division was absent. This phenotype included upregulation of the major myelin protein P0 and downregulation of GFAP, N-CAM, A5E3, and NGF receptor. In contrast, when cells were cultured in conditions where cell division occurred, elevation of intracellular cAMP produced an alternative response, characterized by DNA synthesis and absence of myelin-related differentiation. The cAMP mediated induction of an early Schwann cell antigen, 04, followed a different pattern since it was induced equally in dividing and nondividing cells. These observations are consistent with the proposal that during development of the rat sciatic nerve: (a) cAMP elevation, possibly induced by axon-associated factors, is a primary signal responsible for the induction of 04 expression in proliferating Schwann cells during the premyelination period; (b) subsequent withdrawal of cells associated with the larger axons from the cell cycle acts as a permissive secondary signal for induction of myelination, since in quiescent cells the ongoing cAMP elevation will trigger myelination.

1-Methyl-3-isobutylxanthine↗
PubMed2002

A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.

Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo. The infant was shown to have a PBD, on the basis of elevated plasma levels of very-long- and branched-chain fatty acids (VLCFAs and BCFAs), deficiency of multiple peroxisomal functions in fibroblasts, and complete absence of peroxisomes in fibroblasts and liver. Surprisingly, both parents had elevated plasma levels of VLCFAs and BCFAs. Fibroblast studies confirmed that both parents had a PBD. The parents' milder phenotypes correlated with relatively mild peroxisomal biochemical dysfunction and with catalase immunofluorescence microscopy demonstrating mosaicism and temperature sensitivity in fibroblasts. The infant and both of his parents belonged to complementation group C. PEX6 gene sequencing revealed mutations on both alleles, in the infant and in his parents. This unique family is the first report of a PBD with which the parents are themselves affected individuals rather than asymptomatic carriers. Because of considerable overlap between USH and milder PBD phenotypes, individuals suspected to have USH should be screened for peroxisomal dysfunction.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2002

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

Buffers↗
PubMed1993

Immortalization phenotype dissociated from the preneoplastic phenotype in mouse mammary epithelial outgrowths in vivo.

Mouse mammary epithelial cells (MMEC) isolated from normal virgin BALB/c female mice and grown in cell culture for various lengths of time were injected into the mammary fat pads of syngenic mice. Of the ductal outgrowths which resulted from the injected MMEC, four gave rise to outgrowths that were serially transplanted beyond the lifetime of normal ductal outgrowths. The lifetime of normal ducts is five or six transplant generations. The four ductal outgrowth lines, termed EL for 'extended life', have been serially transplanted for 7, 9, 13 and 14 transplant generations. The outgrowths are predominantly ductal in morphology, do not exhibit intraductal epitheliosis characteristic of ductal hyperplasias, are ovarian dependent for growth and are responsive to prolactin-mediated alveolar differentiation. Three of the EL lines, EL5, 7 and 11 have not produced any tumors spontaneously (0/64) and only one tumor after dimethylbenz[a]anthracene (DMBA) treatment (1/30). The fourth line, EL12, differs from the other three in the presence of a limited degree of alveolar differentiation. The EL12 line has not produced any spontaneous tumors (0/23) but is somewhat more responsive to DMBA (3/10). We interpret the EL lines (at least EL11 and EL12) to represent cell populations where the immortalized phenotype is dissociated from the hyperplastic phenotype which is characteristic of mouse mammary preneoplastic populations. The tumor suppressor gene, p53, is not overexpressed in the EL ductal outgrowths. To our knowledge, this is the first example of cell populations in vivo that are immortalized but otherwise normal. As such, they may represent the earliest stage observable in the genesis of mouse mammary tumors and provide unique cell populations to examine molecular alterations associated with the property of immortality.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Stable phenotypic expression of glutathione S-transferase placental type and unstable phenotypic expression of gamma-glutamyltransferase in rat liver preneoplastic and neoplastic lesions.

Using immunohistochemical demonstration of glutathione S-transferase placental type (GST-P) and histochemical demonstration of gamma-glutamyltransferase (gamma-GT), the long-term development of preneoplastic and neoplastic lesions was followed in rats over a 50-week period. Rats were given a single i.p. injection of 200 mg/kg body weight of diethylnitrosamine (DEN), and then 2 weeks later were administered 0.02% 2-acetylaminofluorene (2-AAF) (group 1), 0.05% phenobarbital (PB) (group 2), 2.0% butylated hydroxyanisole (BHA) (group 3) or no supplement (group 4) in their diet for 6 weeks, all rats being subjected to partial hepatectomy at week 3. Hepatocellular proliferated lesions were classified as foci, nodules and hepatocellular carcinomas. Development of foci, nodules and hepatocellular carcinomas was enhanced strongly by 2-AAF and weakly by PB, and inhibited by BHA. Almost all foci and nodules were GST-P positive, although 5-10% of the GST-P-positive foci were gamma-GT negative. The areas of GST-P-positive foci and nodules increased with time in all groups. In contrast, while the areas of gamma-GT-positive lesions also increased with time in groups 2-4, they decreased from week 12 in group 1. As the percentage gamma-GT-positive area in GST-P-positive foci significantly decreased with time in all groups, the rate of phenotypic reversion of gamma-GT in foci in group 1 was revealed to be larger than the focus growing rate, whereas that in groups 2-4 was smaller. Gamma-GT-negative and GST-P-positive micro-nodules of altered morphology appeared within gamma-GT- and GST-P-positive nodules in later stages. All hepatocellular carcinomas found in this experiment consisted of GST-P-positive cells. In contrast, 37% (13/35) of the hepatocellular carcinomas were negative for gamma-GT. The results indicate GST-P to be the most accurate marker enzyme for detection of initiated cells during liver carcinogenesis and gamma-GT to be more appropriate for indicating changes of phenotypic expression in each lesion type.

Animals↗
PubMed1994

Monoallelic expression of normal mRNA in the PIT1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype.

The combined deficiency of thyrotropin, growth hormone and prolactin, caused by PIT1 abnormality manifests in the homozygous or heterozygous state. We studied a patient having an allele with Arg271Trp mutation, which produces clinical symptoms in heterozygotes by a dominant-negative effect. However, in the family, her father, grandmother and aunts had the same mutation without clinical symptoms, although the proband had typical phenotypic expression. We analyzed the PIT1 transcript in peripheral lymphocytes by reverse transcription-polymerase chain reaction and found monoallelic expression of normal allele in the father and grandmother and skewed pattern of biallelic expression in the proband. The phenotypic expression of PIT1 abnormality may depend on different transcription of the PIT1 gene.

Alleles↗
PubMed1995

The CD45RA+ (quiescent) cellular phenotype is overabundant relative to the CD45RA- phenotype within the involuted splenic T cell population of weanling mice subjected to wasting protein-energy malnutrition.

The objective of this investigation was to determine whether an imbalance between naive- and memory-phenotype cells occurs within CD4+ and/or CD8+ splenic T cell subsets in models of protein-energy malnutrition (PEM) which produce wasting disease (loss of approximately 1.6% of body weight per day for 14 d) and profound depression in thymus-dependent immunity. Male and female weanling mice of disparate inbred strains, CBA/J and C57BL/6J, were allocated to the following groups: zero-time control (23 d old and 19 d old, respectively), ad libitum intake of a complete purified diet (19% crude protein, 17 kJ/g gross energy), restricted intake of the complete diet, and (C57BL/6J, only) ad libitum intake of an isocaloric low protein diet (0.6% crude protein). Surface expression of isoforms of CD45, a component of the T cell receptor complex, as well as of the accessory molecule, CD2, were assessed by flow cytometry of splenic mononuclear cell suspensions. Both major T cell subsets in the malnourished groups contained a significantly higher proportion of cells expressing the surface marker, CD45RA, than was found in the spleen cells of the control groups. CD45RA+ (naive-phenotype) T cells represent the extreme of quiescence and stringent activation requirements among thymic lymphocytes. The results provide the first clear evidence of a T cell subset imbalance in PEM which is consistent with depression in acquired immunity and which occurs, apart from antigenic challenge, in a site wherein immune responses take place. The T cell receptor complex may emerge as a focal point of the depressive influence of PEM on the competence of thymic lymphocytes.

Aging↗
PubMed1999

Restoration to a quiescent and contractile phenotype from a proliferative phenotype of myofibroblast-like human aortic smooth muscle cells by culture on type IV collagen gels.

Aortic smooth muscle cells (A-SMC) undergo phenotypic transition to a synthetic and proliferative state and become fibroblast-like cells upon serial passage with culture on plastic dishes, especially in the presence of serum. Such fibroblast-like cells (M-SMC) derived from A-SMC may correspond to the cells identified pathologically as myofibroblasts. We examined the effects of type IV collagen gels used as a culture substrate on the morphology and proliferation of M-SMC. The M-SMC underwent extreme elongation in shape when cultured on rigid type IV collagen gels, and eventually formed cell-to-cell junctions with the elongated processes. In contrast, M-SMC showed a spindle-like cell shape on dishes coated with a type IV collagen solution or type I collagen solution, or on type I collagen gels or fragile type IV collagen gels. Cell proliferation was totally repressed by culture on rigid type IV collagen gels for over 10 days, while the highest proliferative activity was seen for cells grown on dishes coated with type IV collagen solution. The expression of smooth muscle myosin heavy chains, specific markers for contractile A-SMC, was acquired by M-SMC cultured on rigid type IV collagen gels for 3 days, while M-SMC cultured on type IV collagen-coated dishes continued to show no expression. These results suggest that the quiescent and contractile phenotype of A-SMC might be restored in M-SMC by culture on rigid type IV collagen gels, even after they have become myofibroblastic.

Animals↗
PubMed2000

Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes.

Among 14 limb-girdle muscular dystrophy genes that have been mapped, 10 (three autosomal dominant and seven autosomal recessive) have so far had their product identified. This review will focus on the most recent data in the field and on our own experience of more than 200 patients studied with autosomal recessive-limb-girdle muscular dystrophy, classified from calpainopathy to telethoninopathy. Genotype: phenotype correlations in this highly heterogeneous group show a similar clinical course among patients with different forms, whereas a discordant phenotype may be seen in unrelated patients or in affected sibs carrying the same mutation. Understanding such similarities or differences remains a major challenge. It will depend on future knowledge of gene-protein functions, on protein interactions and on identifying modifying genes and other factors underlying clinical variability.

Genes, Dominant↗