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PubMed2001

Dynamic restoration of dystrophin to dystrophin-deficient myotubes.

Dystrophin domains are observed in myoblast transplantation experiments and in muscle fibers after somatic reversion in human Duchenne and mdx mouse muscular dystrophy. However, the formation and evolution of dystrophin-positive domains are not well established. Using a muscle satellite cell coculture system, we examined the dynamic restoration of dystrophin expression in dystrophin-deficient myotubes. The dystrophin-positive domains around source nuclei were clearly identified in hybrid myotubes. The occurrence of dystrophin domains was higher in myotubes differentiated from cocultures with a low concentration of normal wild-type satellite cells in relation to dystrophin-deficient satellite cells. At higher seeding ratios, the domain feature of dystrophin expression was more transitory and decreased as myotubes differentiated over time in culture. The average domain size initially increased with the addition of new nuclei by fusion early after differentiation of cocultures. However, separating dystrophin-positive domains according to their number of dystrophin-expressing contributory nuclei showed that diffusion of dystrophin contributed to domain elongation, even in early myotubes and later without fusion of additional nuclei. Diffusion occurred for all domains of one to six wild-type nuclei, and the diffusion rate was higher in domains with larger numbers of nuclei. This dynamic domain feature of dystrophin expression was also related to restoring the organization of dystrophin-associated proteins and acetylcholine receptors to hybrid myotubes. Factors regulating domain formation and diffusion therefore are important considerations in the design of strategies for both myoblast transplantation and gene therapy of Duchenne muscular dystrophy.

Animals↗
PubMed1998

A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization.

Reactivation of telomerase and stabilization of telomeres occur simultaneously during human cell immortalization in vitro and the vast majority of human cancers possess high levels of telomerase activity. Telomerase repression in human somatic cells may therefore have evolved as a powerful resistance mechanism against immortalization, clonal evolution and malignant progression. The comparative ease with which rodent cells immortalize in vitro suggests that they have less stringent controls over replicative senescence than human cells. Here, we report that Syrian hamster dermal fibroblasts possess substantial levels of telomerase activity throughout their culture life-span, even after growth arrest in senescence. In our studies, telomerase was also detected in uncultured newborn hamster skin, in several adult tissues, and in cultured fibroblasts induced to enter the post-mitotic state irreversibly by serum withdrawal. Transfection of near-senescent dermal fibroblasts with a selectable plasmid vector expressing the SV40 T-antigen gene resulted in high-frequency single-step immortalization without the crisis typically observed during the immortalization of human cells. Collectively, these data provide an explanation for the increased susceptibility of rodent cells to immortalization (and malignant transformation) compared with their human equivalents, and provide evidence for a novel, growth factor-sensitive, mammalian senescence mechanism unrelated to telomere maintenance.

Animals↗
PubMed2003

Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants.

Deciding whether a missense allelic variant affects protein function is important in many contexts. We previously demonstrated that a detailed analysis of p53 intragenic conservation correlates with somatic mutation hotspots. Here we refine these evolutionary studies and expand them to the p16/Ink4a gene. We calculated that in order for 'absolute conservation' of a codon across multiple species to achieve P<0.05, the evolutionary substitution database must contain at least 3(M) variants, where M equals the number of codons in the gene. Codons in p53 were divided into high (73% of codons), intermediate (29% of codons), and low (0 codons) likelihood of being mutation hotspots. From a database of 263 somatic missense p16 mutations, we identified only four codons that are mutational hotspots at P<0.05 (8 mutations). However, data on function, structure, and disease association support the conclusion that 11 other codons with > or =5 somatic mutations also likely indicate functionally critical residues, even though P0.05. We calculated p16 evolution using amino acid substitution matrices and nucleotide substitution distances. We looked for evolutionary parameters at each codon that would predict whether missense mutations were disease associated or disrupted function. The current p16 evolutionary substitution database is too small to determine whether observations of 'absolute conservation' are statistically significant. Increasing the number of sequences from three to seven significantly improved the predictive value of evolutionary computations. The sensitivity and specificity for conservation scores in predicting disease association of p16 codons is 70-80%. Despite the small p16 sequence database, our calculations of high conservation correctly predicted loss of cell cycle arrest function in 75% of tested codons, and low conservation correctly predicted wild-type function in 80-90% of codons. These data validate our hypothesis that detailed evolutionary analyses help predict the consequences of missense amino-acid variants.

Amino Acid Sequence↗
PubMed1997

Receptor-associated protein in an oviparous species is correlated with the expression of a receptor variant.

The biosynthesis of proteins containing cysteine-rich domains requires chaperones for their correct folding. For instance, the 39-kDa receptor-associated protein (RAP) aides in the cell-surface targeting of newly synthesized members of the mammalian low density lipoprotein receptor (LDLR) gene family, which contains tandemly arranged clusters of hexacysteine repeats. In the chicken, an LDLR relative with eight such repeats is expressed as two different splice variant forms in cell type-specific fashion (Bujo, H., Lindstedt, K. A., Hermann, M., Mola Dalmau, L., Nimpf, J., and Schneider, W. J. (1995) J. Biol. Chem. 270, 23546-23551). To learn more about evolutionary aspects of RAP, its role in escorting of these different receptor splice variants, and other potential functions, we have extended our studies on the avian LDLR family to RAP. cDNA cloning, determination of tissue expression at both the transcript and the protein level, stable expression in COS cells, and binding studies with chicken RAP revealed that mammalian RAPs have retained many features of the non-amniotic proteins. However, structural details, e.g. the well defined internal triplicate repeats in the chicken protein, have been somewhat diluted during evolution. Interestingly, chicken RAP was found to correlate positively with the expression levels in somatic cells of the larger splice variant of the eight-cysteine repeat receptor, but not with those of the smaller variant, expressed only in germ cells. This is compatible with the possibility that RAP may play a role in receptor biology that could be complementing its function in assisting folding. Chicken RAP in crude extracts of the stable expressor COS cells is able to bind to LDLR relatives in ligand blots without requirement for prior purification of the ligand. Thus, in conjunction with the avian model of massive lipid transport to germ cells, these cells provide a novel comparative system amenable to investigation of the biological functions of RAP.

Amino Acid Sequence↗
PubMedDate not supplied

A regional model (Northeastern Brazil) of induced mal-nutrition delays ontogeny of reflexes and locomotor activity in rats.

The aim of this study was to investigate the effects of malnutrition, induced by a regional basic diet (RBD), on motor development. RBD is a 7.87%-protein diet based on aliments typical of Northeastern Brazil, elaborated after nutritional investigation by Teodosio et al. (1979). Female rats were treated with RBD during lactation. The reflex ontogenesis and the development of locomotor activity in their offspring were assessed. Malnourished (MN) rats showed a delay in reflex maturation and in locomotor activity evolution. The decreased locomotor activity may be related to the reduced movement experiences induced by the delay in the reflex maturation. Occurring during the critical period of brain development, this fact could jeopardize all the steps in future locomotion evolution. The present results confirm deleterious effects of RDB-induced malnutrition on the somatic development and maturation of the nervous system (NS).

Aging↗
PubMed2002

Marked intratumoral heterogeneity of c-myc and cyclinD1 but not of c-erbB2 amplification in breast cancer.

Intratumoral heterogeneity mirrors subclonal diversity and might affect treatment response. To investigate molecular heterogeneity of primary breast cancer specimens, we determined the amplification status of growth regulatory genes (c-erbB2, topoisomerase IIalpha, c-myc, and cyclinD1) in macroscopically and microscopically separate areas of individual tumors (n = 21). Using laser-assisted microdissection and quantitative PCR, we found marked intratumoral heterogeneity with different patterns for each gene. Molecular heterogeneity in amplification pattern could be demonstrated between both macroscopically (0.5 to several centimeters) and microscopically (10 to several hundred micrometers) distant tumor areas. C-erbB2 amplification proved to be the most stable amplification in individual tumors, with heterogeneity occurring in only 36% of amplified cases. By contrast, amplification of c-myc and cyclinD1 revealed varying patterns in the vast majority of amplified cases (100% and 83%). The constancy of c-erbB2 amplification underlines its presumed importance in breast cancer biology. We conclude that the molecular heterogeneity of breast cancer as evidenced in this study requires thorough and representative sampling of different tumor areas when the biologic significance of somatic mutations is considered. Patterns of heterogeneity can be used to trace the clonal evolution within different compartments of an individual tumor.

Breast Neoplasms↗
PubMed1990

[Liaison psychiatry in oncology].

The goal of 'liaison' in medicine is the integration of biomedical, psychological and social aspects in the diagnosis and treatment of patients. The notion of 'liaison psychiatry' implicates an addition of the psychiatric aspect from outside. In my view, liaison has to grow within somatic medicine. In oncology an internal integration is in the making. Based on the evolution of psychosocial oncology in Switzerland in the last ten years, the beginning process of integration is explained. The explanation with the biopsychosocial paradigm takes place mainly on two levels, the practical everyday experience and the scientific discussion. As an example of the scientific level, the integration of psychological and social parameters in the evaluation of oncological treatments in the IBCSG (International Breast Cancer Study Group) studies is presented: as an example of the everyday practical level, the authors group-work with physicians and nurses in the oncological outpatient clinic of the University of Bern is described.

Combined Modality Therapy↗
PubMed1998

[Habitual abortions: psychogenic and/or induced psychopathology].

Infertility is felt nowadays as a personal affront, quite intolerable, and RSA are an emblematic example of that personal and social failure, failure of the woman and of the couple, failure of the doctor too, failure of their common project. No wonder if those recurrences open the way to the problem of cause and/or consequences for those women whose pregnancy regularly begins and as regularly sees its evolution thwarted. The hypothesis of a psychological factor not excluding but rather potentialising a somatic one, should work as an incentive to important predictive studies, the best means for prevention. Whatever our present medical possibilities, the emphasis should always be on attentive listening and counselling, so as to mingle in judicious harmony "hightech" science and "tender love and care".

Abortion, Habitual↗
PubMed1996

Somatic and germ cell parasitism in a colonial ascidian: possible role for a highly polymorphic allorecognition system.

A colonial protochordate, Botryllus schlosseri, undergoes a natural transplantation reaction in the wild that results alternatively in colony fusion (chimera formation) or inflammatory rejection. A single, highly polymorphic histocompatibility locus (called Fu/HC) is responsible for rejection versus fusion. Gonads are seeded and gametogenesis can occur in colonies well after fusion, and involves circulating germ-line progenitors. Buss proposed that colonial organisms might develop self/non-self histocompatibility systems to limit the possibility of interindividual germ cell "parasitism" (GCP) to histocompatible kin [Buss, L. W. (1982) Proc. Natl. Acad. Sci. USA 79, 5337-5341 and Buss, L. W. (1987) The Evolution of Individuality (Princeton Univ. Press, Princeton]. Here we demonstrate in laboratory and field experiments that both somatic cell and (more importantly) germ-line parasitism are a common occurrence in fused chimeras. These experiments support the tenet in Buss's hypothesis that germ cell and somatic cell parasitism can occur in fused chimeras and that a somatic appearance may mask the winner of a gametic war. They also provide an interesting challenge to develop formulas that describe the inheritance of competing germ lines rather than competing individuals. The fact that fused B. schlosseri have higher rates of GCP than unfused colonies additionally provides a rational explanation for the generation and maintenance of a high degree of Fu/HC polymorphism, largely limiting GCP to sibling offspring.

Animals↗
PubMed1980

Chromosome evolution of near-haploid clones in an established human acute lymphoblastic leukemia cell line (NALM-16).

A cell line has been established from blood lymphoblasts of a female patient with acute lymphoblastic leukemia (ALL) shown to have near-haploid (27 chromosomes) cells in the bone marrow. The findings about the cell line were: 1) The frequency of near-haploid cells in culture decreased with time from 98.2% when the culture was started to 5.4% 15 months later. 2) Most of the other cells except the near-haploid ones were hyperdiploid, i.e., duplicates of the cells with near-haploid chromosome constitutions. 3) Chromosome evolution was seen in the near-haploid clones. The possible ancestor clone (clone A) had 27 chromosomes, one of each pair except no.10, 14, 18, and 21, which were disomic. A suggested evolution process is: clone A yields clone B (26 chromosomes: clone A, -no.10) yields clone C (27 chromosomes: clone B, +X) yields clone D (26 chromosomes: clone C, -no.21), clone E (28 chromosomes: clone C, +NO.20). Clone B and D, each with 26 chromosomes, appeared to contain the lowest number of chromosomes, appeared to contain the lowest number of chromosomes ever described for human somatic cell clones in vitro. 4) Changes in the constitutions of the hyperdiploid cell clones were preceded by evolution and changes in the near-haploid clones. 5) In near-haploid cells with 2 X-chromosomes, 1 exhibited late DNA replication; in hyperdiploid cells with 3-5 X-chromosomes, 2 were non-late DNA-replicating. 6) Fresh (uncultured) and cultured leukemia cells were antigenically typical non-T, non-B or common type ALL cells (positive for la-like and null-type ALL antigens and negative for surface membrane immunoglobulin).

Cell Membrane↗
PubMed2001

In vitro abzyme evolution to optimize antibody recognition for catalysis.

Enzymes have evolved their ability to use binding energies for catalysis by increasing the affinity for the transition state of a reaction and decreasing the affinity for the ground state. To evolve abzymes toward higher catalytic activity, we have reconstructed an enzyme-evolutionary process in vitro. Thus, a phage-displayed combinatorial library from a hydrolytic abzyme, 6D9, generated by the conventional in vivo method with immunization of the transition-state analog (TSA), was screened against a newly devised TSA to optimize the differential affinity for the transition state relative to the ground state. The library format successfully afforded evolved variants with 6- to 20-fold increases in activity (kcat) as compared with 6D9. Structural analysis revealed an advantage of the in vitro evolution over the in vivo evolution: an induced catalytic residue in the evolved abzyme arises from double mutations in one codon, which rarely occur in somatic hypermutation in the immune response.

Amino Acid Sequence↗
PubMed2001

Sex and ageing.

Sex and ageing are often linked, particularly in the context of the evolutionary theories of ageing, which suggest that senescence may be the price for investing in offspring at the expense of somatic maintenance and repair. Considerable evidence supports this concept although, strictly, it is not sex per se but the existence of the soma/germ-line distinction that appears to hold the key. Other aspects of the sex-ageing axis seeing exciting new developments are the evolution of the human life history, particularly with respect to menopause, and the molecular mechanisms that sustain the immortality of the germ-line in contrast to the cumulative damage that appears to underlie the ageing of somatic cells.

Aging↗
PubMed1996

Clonal evolution of lung tumors.

Lung tumors, particularly squamous cell carcinomas, are believed to develop through a series of morphological abnormalities, driven by underlying somatic genetic changes. One way of studying this process is to analyze candidate somatic genetic changes in samples of squamous metaplasia and bronchial dysplasia of varying degrees of severity as well as tumor from the same patient. This assumes a clonal relationship between these lesions. In this article, we provide evidence that adjacent, physically distinct bronchial abnormalities are clonally related. This has been achieved using a plaque assay technique to detect the same p53 mutation, present throughout a tumor specimen, in a small proportion of cells in an adjacent squamous metaplasia. In addition, we have obtained two dysplasia samples from a tumor-free patient over a 9-month interval. The earlier sample had one p53 mutation, whereas the later sample has to p53 mutations on different alleles. Thus, the pattern of clonal evolution detected in the parallel samples mimics the pattern seen in longitudinal samples and supports the analysis of synchronously collected samples for the study of tumor progression.

Base Sequence↗
PubMed2000

Time evolution of the Partridge-Barton model.

The time evolution of the Partridge-Barton model in the presence of the pleiotropic constraint and deleterious somatic mutations is exactly solved for arbitrary fecundity in the context of a matricial formalism. Analytical expressions for the time dependence of the mean survival probabilities are derived. Using the fact that the asymptotic behavior for large time t is controlled by the largest matrix eigenvalue, we obtain the steady state values for the mean survival probabilities and the Malthusian growth exponent. The mean age of the population exhibits a t-1 power law decayment. Some Monte Carlo simulations were also performed and they corroborated our theoretical results.

Biological Evolution↗