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Results for “somatic evolution”

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PubMed1996

[Criteria for somatization studied in an outpatient clinic for general internal medicine].

OBJECTIVE: To compare the evolution of bodily symptoms and the frequency of medical consultation using three different operational definitions of 'somatization'. DESIGN: Descriptive follow-up study. SETTING: General Internal Medicine Outpatient Clinic of Leiden University Hospital, the Netherlands. METHOD: Information about physical and psychic symptoms and about the somatic-medical diagnosis was collected in a group of 158 newly referred patients. The concept of 'somatization' was operationalized in three ways: a) seeking medical consultation for somatically unexplained symptoms; b) seeking medical consultation for somatically unexplained symptoms combined with an anxiety disorder or a depressive disorder according to the 'present state examination'; c) seeking medical consultation for somatically unexplained symptoms combined with a somatization disorder or hypochondria according to the Diagnostic and statistical manual of mental disorders (DSM) III R criteria. After a follow-up period of 1.2 years, information was collected from the entire study group about the evolution of the physical symptoms and the frequency of medical consultation. RESULTS: Patients with somatically unexplained symptoms combined with a somatization disorder or hypochondria were characterized in the follow-up by numerous physical symptoms and a high frequency of medical consultation. Compared with the other patients with unexplained symptoms, they visited the general practitioner during the follow-up period 2.5 times as often, saw specialists twice as often and were admitted to a 'somatic' hospital, 6 times as often. CONCLUSION: Using criteria of low restrictiveness for somatization, a large group of patients were identified with a relatively normal (average) illness behaviour. Using more restrictive criteria led to identification of a smaller group with more extreme illness behaviour.

Adult↗
PubMed1997

p53 mutations in breast cancer: incidence and relations to tumor aggressiveness and evolution of the disease.

Breast cancer is a polymorphic disease and, until now, nodal invasion and steroid receptor levels remain the most powerful and widely used prognostic indicators. Molecular oncology has proven the importance of somatic genetic events in cancer genesis and evolution. In breast cancer a number of genetic aberrations have been proposed to bear impact on disease outcome. Greatest significance has been associated to ERBB2 amplification and overexpression. More recently p53 mutations have been suggested to bear meaning in terms of cancer evolution. We discuss here the molecular epidemiology of p53 mutations in human breast tumors and the clinico-pathological significance that can be associated to them.

Breast Neoplasms↗
PubMed1986

Mechanisms of DNA sequence amplification and their evolutionary consequences.

DNA sequence amplification is a phenomenon that occurs predictably at defined stages during normal development in some organisms and has been shown to occur spontaneously, but sporadically, in a variety of cells, including mammalian cells, selected for overproduction of a gene product. Developmentally programmed gene amplification includes rDNA amplification during oögenesis in amphibia, chorion protein gene amplification in Drosophila and the chromosomal changes accompanying macronuclear formation in ciliates. Selected gene amplification is illustrated by mutant mammalian cells which have been selected in vitro or in vivo for the overproduction of a gene product. In these cells the unit of DNA that is amplified is much larger than the gene under selection, and appears to be formed by multiple recombination events, which bring together sequences not normally adjacent to each other. Often the product of amplification can be seen microscopically as aberrant chromosome forms. The vast majority of DNA amplification events occur in somatic nuclei, and thus would not have any direct effect on the evolution of a genome. However, the ability to amplify DNA in somatic cells does have consequences for the composition of the genomes of the organisms in which it can occur, and should DNA amplification occur, even sporadically, in germ-line cells the potential effect on evolution would be great.

Amphibians↗
PubMed1992

Evolutionary somatic cell changes in cervical tumour progression quantitatively evaluated with morphological, histochemical and kinetic parameters.

The somatic cell changes which characterise malignancy evolution in human cervical preneoplastic and neoplastic lesions have been assessed on histological sections by means of a computerised image analyser. Many features have been simultaneously measured on each cell of the lesions studied, and the following results have been obtained: Some features, mainly kinetic, show continuously increasing values which express changes correlated to the increasing malignancy; other features, especially related to nuclear atypia, cellular heterogeneity and the degree of aneuploidy, have values dropping at the level of early stromal infiltration, which can be morphometrically characterised as composed of relatively homogeneous phenotypes; these features seem to express the degree of genetic instability and relate to the evolutionary somatic cell changes; tumour progression evolves through sequential discontinuous steps, each of them characterised by specific phenotypical features of the neoplastic cell population; the neoplastic cells in the foci of early stromal infiltration and vascular invasion, phenotypically more homogeneous than the parent cell populations of carcinoma in situ and infiltrating carcinoma, seem to possess a greater genetic stability.

Aneuploidy↗
PubMedDate not supplied

[Comparative double-blind study of bromazepam versus prazepam in non-psychotic anxiety].

The efficacy of bromazepam and prazepam for the different components of anxiety: inhibition, asthenia and somatisation is evaluated in a multi-centric, comparative and randomised study, conducted as double blind and in parallel groups in 159 adult patients showing a manifest anxiety according to the F.D.A. criteria. After a 7 day wash-out period, the patients receive either bromazepam in a 12 mg/d dose or prazepam in a 40 mg/d dose, over 4 weeks (D0-D28), then in a decreasing dose from D28 to D43; follow-up is carried out using the anxious inhibition scale W.P.2, auto-questionnaire A.D.A., the Hamilton anxiety scale and the Tyrer questionnaire (benzodiazepine withdrawal symptoms questionnaire). Patients are evaluated seven times during the study: at day 7 for inclusion, day 0 for randomisation, then day 7 and day 14 for following visits, at day 28 for efficacy and tolerance evaluation, and at day 50 for utilisation and withdrawal evaluation. The major efficacy criteria are the evolution of inhibition, asthenia and somatisation as compounds of anxiety respectively evaluated by W.P.2 scale, asthenic partial score of autoquestionnaire A.D.A. and somatic partial score of Hamilton anxiety scale. The analysis of results don't show any significant difference between the two groups on the evolution of the components asthenia and inhibition. However the evolution of the somatic component clearly makes a significant difference in favour of bromazepam. There is also a significant difference in terms of global anxiolytic action efficacy, in favour of bromazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Peripheral neurotoxicity of taxol in patients previously treated with cisplatin.

BACKGROUND: Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum-resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. METHODS: Twenty-two patients affected by a relapse of cisplatin-treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol-induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). RESULTS: No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. CONCLUSIONS: Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose-limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin.

Adult↗
PubMed1992

Transcription factors, translocations and haematological malignancies.

Haematological malignancies arise as a consequence of clonal evolution driven by an accumulation of somatic mutations. Many haematological malignancies are associated with chromosome translocations that have provided powerful tools for the identification of proto-oncogenes implicated in the pathogenesis of leukaemia/lymphoma. The recent characterisation of several translocation breakpoints associated with human haematological tumours has demonstrated that genes encoding transcription factors are frequently involved. Direct alteration of transcription factor activity by somatic mutation may represent a particularly powerful leukaemogenic event.

Gene Expression Regulation, Leukemic↗
PubMed1983

Acquired alpha-thalassemia in preleukemia is due to decreased expression of all four alpha-globin genes.

A somatic mutation(s), acquired during the evolution of preleukemia in a 75-year-old Caucasian male of North European origin, resulted in a marked decrease in alpha-globin mRNA. The small amount of alpha-globin mRNA present in bone marrow cells was normally processed, had a normal (alpha 1/alpha 2)-globin mRNA ratio, and was translated normally. No detectable zeta-globin mRNA was found. The alpha- and zeta-globin genes were both hypomethylated and restriction endonuclease maps of the alpha- and zeta-globin genes were comparable in the patient's marrow and fibroblast DNA. The data are most consistent with the acquisition of a mutation(s) that resulted in decreased expression of all four alpha-globin genes.

Aged↗
PubMed1984

Transformation of the Hprt gene with DNA from spermatogenic cells. Implications for the evolution of X chromosome inactivation.

DNA-mediated transformation of hypoxanthine guanine phosphoribosyl transferase (HPRT)-deficient cells was used to assess the state of the chromosome Hprt gene in spermatogenic cells. It had been shown previously that DNA from the inactive X chromosome of somatic cells functions poorly or not at all in HPRT transformation, indicating that DNA modification is involved in somatic cell X chromosome inactivation (XCI). In contrast, DNA from mature sperm does function in HPRT transformation suggesting that DNA modification may not be the basis of XCI in mature sperm. In this paper, transformation of HPRT- mouse and hamster cells has been performed to test the nature of XCI during earlier stages of spermatogenesis. DNA from these developing murine germ cells was shown to be capable of HPRT transformation, extending the observation that XCI in sperm does not appear to involve a DNA modification. We also show here that DNA from mature sperm of marsupials functions in HPRT transformation, a result consistent with a role for sperm XCI in the evolution of somatic X inactivation.

Animals↗
PubMed1997

Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.

Stationary-phase mutation in microbes can produce selected ('adaptive') mutants preferentially. In one system, this occurs via a distinct, recombination-dependent mechanism. Two points of controversy have surrounded these adaptive reversions of an Escherichia coli lac mutation. First, are the mutations directed preferentially to the selected gene in a Lamarckian manner? Second, is the adaptive mutation mechanism specific to the F plasmid replicon carrying lac? We report that lac adaptive mutations are associated with hypermutation in unselected genes, in all replicons in the cell. The associated mutations have a similar sequence spectrum to the adaptive reversions. Thus, the adaptive mutagenesis mechanism is not directed to the lac genes, in a Lamarckian manner, nor to the F' replicon carrying lac. Hypermutation was not found in non-revertants exposed to selection. Therefore, the genome-wide hypermutation underlying adaptive mutation occurs in a differentiated subpopulation. The existence of mutable subpopulations in non-growing cells is important in bacterial evolution and could be relevant to the somatic mutations that give rise to cancers in multicellular organisms.

Adaptation, Biological↗
PubMed1988

Evolution of cancer genes as a mutation-driven process.

Cancer is primarily a somatic genetic disease resulting from the accumulation of several precancerous mutations in a cell lineage. The evolution of highly oncogenic retroviruses has been used as a model for the evolution of a cancer cell. The properties of intermediates between one set of replication-competent retrovirus and protooncogene progenitors and the homologous highly oncogenic retrovirus were analyzed to differentiate between selection-driven and mutation-driven models of this evolution. In this case and in some other cases where sufficient data are available, it appears that the intermediates in the evolution of highly oncogenic retroviruses are not transforming, indicating that they were not formed in a purely selection-driven process. Furthermore, analysis of retrovirus mutation rates indicates that there is a high rate of mutation in retrovirus replication such that the evolution of highly oncogenic retroviruses could be mutation-driven. Other evidence is mentioned suggesting that oncogenesis in general is at least partially mutation-driven, although mutational mechanisms are involved that are different from those involved in the evolution of highly oncogenic retroviruses.

Biological Evolution↗
PubMed1999

Retention of polysomy at 9p23-24 during karyotypic evolution in human breast cancer cell line COLO 824.

Somatic genetic alterations of 9p have been seen in a wide range of human cancers, including breast cancer. Loss of heterozygosity analysis of primary breast cancer tumors has revealed a high frequency of deletion of DNA from 9p21-22 encompassing the MTSI (P16/CDKN2A) gene. We report the approximately tenfold increase in copy number of DNA from 9p23-24, which is far distal to P16/CDKN2A in female breast cancer cell line COLO 824, as revealed by fluorescence in situ hybridization, comparative genomic hybridization, and microsatellite analysis. Amplification of DNA has been reported previously to encompass multiple sites of the genome of the breast cancer cell, but increase in DNA copy number has not been seen in distal 9p.

Aneuploidy↗
PubMed1997

Human ageing and telomeres.

Telomerase expression is repressed early in development in all normal somatic human tissues investigated to date, whereas activity and the expression of the RNA component for this enzyme are upregulated in almost all cases of malignant transformation and late-stage cancer. The telomere hypothesis of ageing and immortalization postulates that sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalization. Measurements of telomere length and telomerase activity in cancer and during normal and accelerated human ageing in skin, blood, haemopoietic, skeletal muscle, vascular and CNS tissues support this model. Tissue culture studies of cell ageing and transformation have added to our understanding of telomere dynamics in these processes. Evolution of telomerase repression and mortality in somatic cells of long-lived organisms is consistent with antagonistic pleiotropy models in which cell senescence is a tumour suppressor mechanism: stringent repression of telomerase has a beneficial early effect in reducing the probability of cancer, but a deleterious, unselected late effect in its contributions to age-related disease.

Aging↗
PubMed2026

Late acquisition of BCR::ABL1 during clonal evolution of SAMD9-associated MDS with phenotypic shift from AML to B-ALL.

We describe a unique case of SAMD9-associated myelodysplastic syndrome (MDS) with monosomy 7 that evolved over 16 years into BCR::ABL1-positive acute myeloid leukemia (AML) and subsequently manifested as B-cell acute lymphoblastic leukemia (B-ALL). Genomic analysis at AML diagnosis revealed a germline SAMD9 mutation together with somatic RUNX1 and PPM1D mutations, supporting stepwise clonal evolution, with BCR::ABL1 emerging as a late leukemogenic event. The dominant leukemic population at AML onset showed myeloid morphology and immunophenotype, whereas a minor CD19+CD10+ population was already detectable. Following venetoclax and azacitidine therapy, the dominant leukemic phenotype shifted to B-ALL while retaining BCR::ABL1 positivity. Detection of the Philadelphia chromosome in mature neutrophils at both AML onset and ALL relapse supported multilineage involvement of a multipotent BCR::ABL1-positive clone. Ponatinib achieved disease control. This case highlights late acquisition of BCR::ABL1 during SAMD9-associated clonal evolution and therapy-driven phenotypic shift within a shared Ph-positive leukemic stem-cell hierarchy.

Humans↗
PubMed1976

Sequences of 5S ribosomal RNA from Xenopus mulleri and the evolution of 5S gene-coding sequences.

Sequences for 5S RNA from somatic cells and oocytes of Xenopus mulleri are presented. Comparison with sequences previously given for Xenopus laevis indicates that the somatic 5S RNA genes of each species are more closely related to each other than either is to its own set of oocyte genes, suggesting that somatic and oocyte genes within each species are evolving independently. However, detailed analysis of sequence variants in each species suggests that there is a mechanism which allows occasional genetic exchanges between somatic and oocyte-specific genes. Possible genetic mechanisms which allows such an exchange are discussed.

Animals↗
PubMed1990

Floral homeotic mutations produced by transposon-mutagenesis in Antirrhinum majus.

To isolate and study genes controlling floral development, we have carried out a large-scale transposon-mutagenesis experiment in Antirrhinum majus. Ten independent floral homeotic mutations were obtained that could be divided into three classes, depending on whether they affect (1) the identity of organs within the same whorl; (2) the identity and sometimes also the number of whorls; and (3) the fate of the axillary meristem that normally gives rise to the flower. The classes of floral phenotypes suggest a model for the genetic control of primordium fate in which class 2 genes are proposed to act in overlapping pairs of adjacent whorls so that their combinations at different positions along the radius of the flower can specify the fate and number of whorls. These could interact with class 1 genes, which vary in their action along the vertical axis of the flower to generate bilateral symmetry. Both of these classes may be ultimately regulated by class 3 genes required for flower initiation. The similarity between some of the homeotic phenotypes with those of other species suggests that the mechanisms controlling whorl identity and number have been highly conserved in plant evolution. Many of the mutations obtained show somatic and germinal instability characteristic of transposon insertions, allowing the cell-autonomy of floral homeotic genes to be tested for the first time. In addition, we show that the deficiens (def) gene (class 2) acts throughout organ development, but its action may be different at various developmental stages, accounting for the intermediate phenotypes conferred by certain def alleles. Expression of def early in development is not necessary for its later expression, indicating that other genes act throughout the development of specific organs to maintain def expression. Direct evidence that the mutations obtained were caused by transposons came from molecular analysis of leaf or flower pigmentation mutants, indicating that isolation of the homeotic genes should now be possible.

DNA Transposable Elements↗
PubMed1997

Neurophysiological evaluation of sexual dysfunction in familial amyloidotic polyneuropathy--Portuguese type.

Familial amyloidotic polyneuropathy (FAP)--Portuguese type, is an autosomal dominant polyneuropathy related with an abnormal transthyrretin (TTR Met 30). In males, the first complaint can be sexual dysfunction. Fifteen FAP patients, mean age 37 +/- 7.7 years, mean disease duration 5.2 +/- 2.2 years, all males, complaining of sexual dysfunction were studied with pudendal evoked potentials (PEP), bulbocavernous reflex (BCR) and sympathetic skin response (SSR). PEP and BCR reflect the central somatosensory pathways and sacral arch functioning; SSR relates with autonomic pathways. The aims of this study were: to correlate clinical and EMG scores with somatic and autonomic fibres involvement; to evaluate the timing of somatic and autonomic nerves lesion in disease evolution. Results showed: that PEP and BCR abnormalities have a statistically significant correlation with clinical and EMG scores; abnormal SSR in the plant precede other clinical or EMG abnormalities in the present study.

Adult↗
PubMed2026

Induced pluripotent stem cell reprogramming: methodological evolution and challenges in clinical translation.

Cell reprogramming can transform somatic cells into induced pluripotent stem cells providing a platform for patient-specific disease modeling, drug screening and regenerative medicine research. Since the advent of OKSM-mediated reprogramming, the system of technical approaches has evolved continuously - from integrated viral vectors to non-integrated episomal systems and, more recently, chemical reprogramming and CRISPR approaches. The simultaneous advances in single-cell multi-omics, biomaterials engineering, and artificial intelligence have further refined the controllability and precision of the reprogramming process. Despite these innovations, problems persist that hinder clinical translation: incomplete epigenetic resetting, ongoing clonal heterogeneity, genomic instability in long-term culture, and the lack of standardized Good Manufacturing Practice protocols for large-scale manufacturing. This review summarizes the trajectory of iPSC reprogramming technologies, with special emphasis on the translational applicability of each modality. We evaluated viral and nonviral delivery systems, chemical reprogramming, strategies that aid gene editing, and emerging engineering platforms, including microfluidics, smart biomaterials, and artificial-intelligence-driven process optimization. We further identify the core "translational triltrilas", namely, the inherent tradeoffs between security, homogeneity, and scalability, and propose a comprehensive strategy to overcome these bottlenecks. By linking basic mechanistic understandings with industrial and regulatory considerations, this review aims to provide a route for transitioning iPSC technology from a laboratory tool to a clinically viable manufacturing platform.

clinical translation↗