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PubMed1994

Clonal deletion and clonal anergy in allogeneic bone marrow chimeras prepared with TBI or TLI.

The evolution of Vbeta6-expressing C3H (H2k, Thy 1.2, Mls a-) lymphocytes was investigated in C3H recipients mice pretreated with total body irradiation (TBI) or total lymphoid irradiation (TLI) and infusion of AKR (H2k, Thy 1.1, Mls a+) cells. After TBI (9.5 Gy) all Vbeta6+ Thy 1.2 (C3H) cells, which are capable of reacting against the Mls a antigen that like expressed by AKR mice, were deleted in the thymus and the periphery in stable bone marrow (BM) chimeras obtained by infusion of 5 x 10(6) T-cell-depleted (TCD) AKR BM cells. When, in the opposite combination, 30 x 10(6) C3H spleen cells were infused into TBI-treated AKR cells, all animals developed graft-versus-host disease (GVHD) with no clonal deletion and in contrast, showed an increase in Vbeta6+ C3H cells. After injection of 30 x 10(6) AKR BM cells into TLI-treated C3H mice no C3H cells were detected in the thymus and only a small percentage in the periphery. Within these C3H cells Vbeta6+ cells were only partially deleted and anergized as they did not respond in vitro after stimulation with Mls a+ AKR cells or anti-Vbeta6 mAb. Cells suppressing anti-Mls a-reacting C3H cells were not found. After injection of 15 x 10(6) AKR cells more C3H cells were found in the thymus, but only a minority of Vbeta6+ cells persisted in the periphery of these animals. In conclusion in TBI-prepared chimeras only clonal deletion occurred, whereas in TLI-prepared chimeras both clonal deletion and anergy occurred in maintaining tolerance.

Animals↗
PubMed1993

Congenital genetic instability in colorectal carcinomas.

INTRODUCTION: Oncogenic evolution is probably based on a progressive selection of clonal subpopulations from within a single clone. This selection is supposed to be based on enhanced genetic instability in the genome. In the vast majority of patients this increased lability is supposed to be the result of acquired alterations, and once established, it may contribute to the continuing, genetic instability within the neoplastic cells. It has been postulated, that inborn chromosomal instability is not limited to a few rare syndromes. Indeed, one of the common colorectal cancer (CRC) syndromes, familial adenomatous polyposis (FAP), is supposed to be a chromosomal instability syndrome. Also the hereditary nonpolyposis colorectal cancer syndrome (Lynch Syndrome (LS)) has shown genomic instability. Knudson (1971, 1985) has shown, that the same gene can be involved in both the hereditary form of a cancer and in the sporadic form of the same cancer. Due to the existence of such hereditary chromosomal instability syndromes, inherited genetic instability may be of some importance in the evolution of sporadic colorectal cancers. METHODS: In vitro research on dermal fibroblasts is based on the theory, that all studied cells of an individual carry the same genetic material, irrespective of their in vivo expression. Increased in vitro tetraploidy (IVT+) in skin fibroblast cultures is supposed to be a germinally transmitted expression of genomic instability, with special reference to LS. At the same time the chromosomal aberrations, which occur in neoplasms, can be measured by flow cytometric DNA analysis. The DNA content, thus measured, is supposed to be an expression of somatic acquired genetic instability. Finally, since occult mandibular osteomas have been shown to be associated with FAP, we have investigated a substantial part of our patients with this phenotypical marker. AIM OF STUDY: In CRC the adenoma-carcinoma sequence is widely accepted, and the purpose of our investigation was to find a correlation, if any, between: Changes in adenoma flow cytometric DNA content and histological grade and type of adenomas. Changes in dermal fibroblast IVT+ from adenoma patients and histological grade and type of adenomas. Changes in dermal fibroblast IVT+ and flow cytometrical DNA content in adenomas and carcinomas from the same patients. Furthermore, we wanted to investigate if: The occurrence of IVT+ in skin fibroblasts among patients with CRC was different from that of IVT+ among patients without colorectal neoplasies. The occurrence of IVT+ in skin fibroblasts among patients with CRC was associated with the occurrence of occult mandibular osteomas in the same patients. The occurrence of dermal fibroblast IVT+ conveyed any prognostic significance in CRC patients. RESULTS AND CONCLUSIONS: 1) A significant correlation was found between both the occurrence of skin fibroblast IVT+ and adenoma DNA aneuploidy in relation to the degree of dysplasia and histological type of adenomas. This signifies, that inborn and acquired genetic instability is correlated to the adenoma-carcinoma sequence. IVT+ was found to be correlated to the progression of adenomas to carcinomas and not to the development of adenomas. 2) A direct correlation between IVT+ and adenoma DNA aneuploidy could not be demonstrated. However, among those patients with diploid adenomas and IVT+ 57% showed villous adenomas. Among those patients with diploid adenomas and IVT- only 14% had villous adenomas. This further substantiates the correlation of IVT+ to the adenoma-carcinoma sequence. IVT+ was highly associated with DNA aneuploidy in carcinomas, and since IVT+ was found to be significantly associated with CRC's with a DNA index > or = 1.5, it is suggested that IVT+ mainly is correlated to the early steps in tumor progression. 3) IVT+ was found in 34% of sporadic CRC, and tumor DNA aneuploidy was demonstrated in 73%...

Adenoma↗
PubMed2005

The evolution of male traits in social insects.

Pair formation in social insects mostly happens early in adult life and away from the social colony context, which precludes promiscuity in the usual sense. Termite males have continuous sperm production, but males of social Hymenoptera have fixed complements of sperm, except for a few species that mate before female dispersal and show male-fighting and lifelong sperm production. We develop an evolutionary framework for testing sexual selection and sperm competition theory across the advanced eusocial insects (ants, wasps, bees, termites) and highlight two areas related to premating sexual selection (sexual dimorphism and male mate number) that have remained understudied and in which considerable progress can be achieved with relatively simple approaches. We also infer that mating plugs may be relatively common, and we review further possibilities for postmating sexual selection, which gradually become less likely in termite evolution, but for which eusocial Hymenoptera provide unusual opportunities because they have clonal ejaculates and store viable sperm for up to several decades.

Animals↗
PubMed2005

Cytogenetic characteristics of patients with signs and symptoms of myelodysplastic syndromes in the State of Pará, Brazil.

The myelodysplastic syndromes (MDS) are clonal hematopoietic diseases characterized by medullary dysplasia, cytopenias, and frequent evolution to acute myeloid leukemia. In 1982, the French-American-British (FAB) group proposed a classification for the MDS, based on morphological characteristics of peripheral blood and of the bone marrow. Later, cytogenetics proved to be a useful tool for the refinement of prognosis, through the use of the International Prognosis Score System (IPSS), as well as through evidence of clonality. Recently, the World Health Organization (WHO) proposed a new classification for the MDS, based on significant modifications of the FAB proposal, with the inclusion of chromosome analysis. A cytogenetic analysis was made of 17 patients with symptoms of MDS in the State of Para, based on WHO recommendations, and application of the IPSS. Good metaphases were obtained for 13 patients; 12 had a normal karyotype and only one had a clonal abnormality, del(3)(p25). The genes related to neoplastic processes that have been mapped to 3p are: XPC in 3p25.1 and FANCD2 and VHL in 3p25-26. Four patients had classic symptoms of MDS; in the rest the possibility of MDS was excluded or several months of observation before diagnosis were recommended. Among those with MDS, it was not possible to apply IPSS and WHO recommendations, because fundamental data were lacking, specifically the medullary blast and ring sideroblast counts. We advocate the implementation of routine cytogenetic analyses for the study of MDS, especially in patients with moderate hematopoietic dysplasia.

Adolescent↗
PubMed2000

Molecular mechanisms in myelodysplastic syndromes and implications for evolution to acute leukemias.

This article reviews the molecular lesions that occur in the clonal hematopoietic disorders classified as myelodysplastic syndromes (MDS). A systematization of these molecular lesions is attempted based on the types of molecular abnormalities. Characteristically, these molecular lesions affect pluripotent hematopoietic progenitors and therefore affect myeloid, monocytic, erythroid, and megakaryocytic lineages. Progression of MDS to acute myelogenous leukemia is common; transformation is considered the final stage in the multi-step process of accumulation of molecular lesions over a prolonged latency period of MDS evolution. Although no molecular lesion is MDS specific, multiple combinations of molecular lesions are common and a systematic approach based on the type of molecular abnormality may offer a better understanding of MDS pathogenesis and the basis for new therapeutic strategies.

Acute Disease↗
PubMed1981

Tumourigenesis: the subterfuge of selection.

Variation of rearrangement of regulatory genes is responsible for cellular malignant change. These types of chromosomal variations also produce heterochrony or paedomorphic evolution at the organismal level. Analogously, neoplasia represents a cellular 'macroevolutionary' event, and a tumour can be said to be an evolved population of cells. To understand this cellular evolution to malignancy, it may be necessary to go beyond a 'clonal selection' (adaptationist) explanation of neoplastic alteration. In the pericellular environment 'natural selection' consists of the organizational restraints of surrounding cells as well as the host's immunological surveillance and non-specific monocyte-macrophage systems. Indirect evidence suggests that success for the neoplasm depends not upon 'clonal selection', but solely upon a genetic methodology-the function of which is to elude selection. The author has coined the term 'cellular heterochrony' to illustrate analogic similarities in the molecular modes of speciation between anaplastic cancer cells and the heterochronic evolution of organisms. By reverting to juvenile (embryonic) repertoire of cellular behaviour a tumour secures its own tenure or niche by usurping the host's armamentarium of selection forces, employing many of the same or similar methods by which implanting and invading tissues of the mammalian embryo forestall maternal detection and rejection. A number of ways by which the tumour blocks, subverts or evades selection are discussed.

Biological Evolution↗
PubMed2002

When is a parasite species a species?

Regrettably, 140 years after the publication of Darwin's Origin of Species, we face the grotesque situation that we still do not know what is a species whose origin Darwin wanted to explain. A generally applicable species definition is not available. Is there a basic unit of biodiversity above the level of individuals? Do we try to define something that does not exist in reality? The strong potential for the evolution of genetic variability in parasites together with the importance of species diagnosis for applied fields of parasite research make biodiversity research a key role in parasitology. Frequent occurrence of sympatric speciation, clonal reproduction, selfing, sib mating or parthenogenesis imply exceptional conditions for the evolution of gene pool diversities in parasites.

Animals↗
PubMed1992

Expression of M-CSF and its receptor (C-FMS) during factor-independent cell line evolution from hematopoietic progenitor cells cocultivated with gamma irradiated marrow stromal cell lines.

Gamma irradiation of plateau-phase clonal bone marrow stromal cell lines produces factor-independent growth of cocultivated clonal interleukin-3/granulocyte-macrophage colony-stimulating factor-dependent hematopoietic progenitor cell lines. The process is associated with three biologic changes including: (i) adherence of hematopoietic cells to stromal cells forming 'cobblestone islands'; (ii) an intermediate stage [during which the cells show proliferation in suspension in the presence in leukemogenic stromal factor (LSF), a factor similar to macrophage colony-stimulating factor (M-CSF) released by irradiated stromal cells, and transient hematopoietic cell surface expression of MAC-1, and c-fms (M-CSF receptor)]; and (iii) a third stage of factor-independence. A monoclonal antibody to M-CSF receptor inhibited proliferation of intermediate stage but not all factor-independent cell subclones. In the present studies, a subclonal factor-independent malignant subline of FDC-P1JL26 derived by cocultivation with gamma-irradiated stromal cells as well as the parent clone and intermediate stage cells were shown to express significant levels of M-CSF polyA+ mRNA and M-CSF of at least two sizes (23 and 15 kDa) as detected by 35S-methionine labelling and immunoprecipitation with polyclonal anti-M-CSF antiserum. There was no significant difference in intracellular M-CSF protein size between cells at each of the three stages of biologic change. This M-CSF was not detected on the cell surface by fluorescence-activated cell sorting (FACS). In contrast, c-fms expression at the cell surface was detected by FACS analysis and c-fms polyA+ mRNA was only detected during the intermediate stage of induction of factor-independence. FDC-P1JL26 parent cells, the subclone stimulated by LSF, and the factor-independent subclone, showed little or no detectable autophosphorylation of the c-fms receptor at tyrosine. There was no detectable rearrangement of the M-CSF or c-fms genes by Southern analysis between clonal lines during the three stages. While we cannot rule out an autocrine mechanism or mutated c-fms receptor mechanism, the data also suggest that evolution of hemopoietic cell factor-independence during cocultivation with irradiated stromal cells may involve a mechanism distal to the c-fms receptor/M-CSF interaction.

Animals↗
PubMed2005

Intensity of malaria transmission and the evolution of drug resistance.

The intensity of malaria transmission varies both naturally and as a consequence of human public health intervention. The relationship between transmission intensity and the rate at which antimalarial drug resistance evolves affects the design of surveillance programmes, and the likely impact of malaria control programmes. Several theoretical studies have investigated this relationship and their key results are summarised and interpreted. The most important result is that transmission intensity does not directly affect the evolution of resistance. It exerts its influence through three clinical/epidemiological "mediators" (clonal multiplicity, the threat of infection, level of human immunity) which ultimately determine the dynamics of resistance via five "effector" variables: sexual recombination, intrahost dynamics, community drug use, proportion of malaria infections treated, and the number of parasites per host. We argue that the evolution of resistance is likely to be a two-stage process: mutations encoding drug tolerance preceding those encoding resistance. The evolution of drug tolerance is determined solely by the level of drug use in the community which is likely to have an extremely weak relationship with transmission intensity. The evolution of resistance is more complex and affected by all five effectors. The most likely scenarios are that resistance evolves faster in areas of high transmission if encoded by a single gene but if encoded by two or more genes it evolves fastest in areas of high or low transmission, with a minimum at intermediate levels of transmission.

Animals↗
PubMed2006

Evolution of multi-drug resistant hepatitis B virus during sequential therapy.

Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine+adefovir, lamivudine+hepatitis B immunoglobulin (HBIG), or lamivudine+entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudine-resistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents co-locate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants.

Adult↗
PubMed2006

Clonal and non-clonal chromosome aberrations and genome variation and aberration.

The theoretical view that genome aberrations rather than gene mutations cause a majority of cancers has gained increasing support from recent experimental data. Genetic aberration at the chromosome level is a key aspect of genome aberration and the systematic definition of chromosomal aberrations with their impact on genome variation and cancer genome evolution is of great importance. However, traditionally, efforts have focused on recurrent clonal chromosome aberrations (CCAs). The significance of stochastic non-clonal chromosome aberrations (NCCAs) is discussed in this paper with emphasis on the simple types of NCCAs that have until recently been considered "non-significant background". Comparison of various subtypes of transitional and late-stage CCAs with simple and complex types of NCCAs has uncovered a dynamic relationship among NCCAs, CCAs, overall genomic instability, and karyotypic evolution, as well as the stochastic nature of cancer evolution. Here, we review concepts and methodologies to measure NCCAs and discuss the possible causative mechanism and consequences of NCCAs. This study raises challenging questions regarding the concept of cancer evolution driven by stochastic chromosomal aberration mediated genome irregularities that could have repercussions reaching far beyond cancer and organismal genomes.

Chromosome Aberrations↗
PubMed1986

Multiple chromosomally distinct cell populations in myelodysplastic syndromes and their possible significance in the evolution of the disease.

Serial chromosome investigations performed in untreated myelodysplastic syndromes (MDS) revealed that: multiple chromosomally unrelated cell populations may emerge during the course of the disease; chromosome changes of the clonal type may disappear or become undetectable, and may or may not reappear during further evolution. The former of these phenomena was found in four cases and was consistently associated with clinical-haematological progression of the disease to a more malignant form, including acute leukaemia. The second was apparently unrelated to clinical and haematological changes in the evolution pattern. These observations are in favour of the hypothesis that MDS evolve as a multistep process in which several events, including the acquisition of sometimes unrelated chromosome changes determine the progression of the disease.

Adult↗
PubMed1999

Generation of CD28- cells from long-term-stimulated CD8+CD28+ T cells: a possible mechanism accounting for the increased number of CD8+CD28- T cells in HIV-1-infected patients.

According to CD28 molecule expression, CD8+ T cells can be classed as CD28bright, CD28dim, and CD28-. The CD28dim T cells were found to derive from mitogenic stimulated CD28-T cells but also from CD28bright T cells through a mechanism of CD28 down-modulation. Moreover, after prolonged in vitro interleukin-2 stimulation, clonal CD28bright, cells showed a CD28dim expression before further evolution to a stable CD28-phenotype. This loss was concomitant with the disappearance of CD28 mRNA. A study of the cytokine production pattern revealed that CD28dim and CD28- T cell clones produced similar levels of type 1 and type 2 cytokines, which differed from those produced by the CD28bright T cell clones. A high percentage of CD28dim and CD28- cells, with similarities in their cytokine production pattern, were found in the blood samples of HIV-infected patients, as compared to healthy donors. The CD28 down-modulation may account for the increased number of CD8+CD28- T cells in HIV-infected patients.

Adult↗
PubMed2004

Genomic changes following host restriction in bacteria.

Many genomic sequences have been recently published for bacteria that can replicate only within eukaryotic hosts. Comparisons of genomic features with those of closely related bacteria retaining free-living stages indicate that rapid evolutionary change often occurs immediately after host restriction. Typical changes include a large increase in the frequency of mobile elements in the genome, chromosomal rearrangements mediated by recombination among these elements, pseudogene formation, and deletions of varying size. In anciently host-restricted lineages, the frequency of insertion sequence elements decreases as genomes become extremely small and strictly clonal. These changes represent a general syndrome of genome evolution, which is observed repeatedly in host-restricted lineages from numerous phylogenetic groups. Considerable variation also exists, however, in part reflecting unstudied aspects of the population structure and ecology of host-restricted bacterial lineages.

Bacteria↗
PubMed1997

Molecular analysis of the cyclin-dependent kinase inhibitor genes, p15, p16, p18 and p19 in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal blood disorders characterized by dyshematopoiesis with a frequent evolution to acute leukemia. Chromosomal deletions rather than translocations are the predominant karyotypic abnormalities in MDS, suggesting a recessive mechanism in the pathogenesis of MDS, such as inactivation of tumor suppressor genes. A group of cyclin-dependent kinase inhibitors, p15 (INK4B), p16 (INK4A), p18 (INK4C) and p19 (INK4D), are candidate tumor suppressor genes. To determine whether genetic alterations of these genes play an important role in the development and/or progression of MDS, we examined 46 samples from MDS patients by Southern blotting, single-strand-conformation polymorphism (SSCP) using polymerase chain reaction (PCR) and sequencing of DNA. These samples included 13 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 16 refractory anemias with an excess of blasts (RAEB), eight refractory anemias with an excess of blasts in transformation (RAEB-T) and five chronic myelomonocytic leukemia (CMMoL) samples. Except for allelic polymorphisms or silent point mutations, no alterations of coding regions of these four CDKI genes were identified. In summary, genetic abnormalities of the p15, p16, p18 and p19 genes are rare events in the development and/or progression of MDS.

Blotting, Southern↗
PubMed1997

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.

Induction of the adaptive immune response depends on the expression of co-stimulatory molecules and cytokines by antigen-presenting cells. The mechanisms that control the initial induction of these signals upon infection are poorly understood. It has been proposed that their expression is controlled by the non-clonal, or innate, component of immunity that preceded in evolution the development of an adaptive immune system in vertebrates. We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila. Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kappaB pathway. We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kappaB and the expression of NF-kappaB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimulatory molecule B7.1, which is required for the activation of naive T cells.

Amino Acid Sequence↗
PubMed2004

A 1.7-kilobase single-stranded DNA that folds into a nanoscale octahedron.

Molecular self-assembly offers a means of spontaneously forming complex and well-defined structures from simple components. The specific bonding between DNA base pairs has been used in this way to create DNA-based nanostructures and to direct the assembly of material on the subnanometre to micrometre scale. In principle, large-scale clonal production of suitable DNA sequences and the directed evolution of sequence lineages towards optimized behaviour can be realized through exponential DNA amplification by polymerases. But known examples of three-dimensional geometric DNA objects are not amenable to cloning because they contain topologies that prevent copying by polymerases. Here we report the design and synthesis of a 1,669-nucleotide, single-stranded DNA molecule that is readily amplified by polymerases and that, in the presence of five 40-mer synthetic oligodeoxynucleotides, folds into an octahedron structure by a simple denaturation-renaturation procedure. We use cryo-electron microscopy to show that the DNA strands fold successfully, with 12 struts or edges joined at six four-way junctions to form hollow octahedra approximately 22 nanometres in diameter. Because the base-pair sequence of individual struts is not repeated in a given octahedron, each strut is uniquely addressable by the appropriate sequence-specific DNA binder.

Base Pairing↗
PubMed1996

Cystic smooth-muscle tumor of the liver and spleen associated with Epstein-Barr virus after renal transplantation.

Immunosuppression is known to favor the development of various types of tumors. After organ transplantation, the risk of lymphoproliferative disease, whether clonal or not, is particularly increased and clearly associated with Epstein-Barr virus infection. We report a case of an unusual large cystic tumor of the liver with satellite hepatic and splenic nodules occurring 4 years after renal transplantation. Radiologic examination showed a rich vascularization of the tumor. Light and electron microscopy of a surgical liver biopsy, completed by an immunohistochemical study, demonstrated a well-differentiated tumor of smooth-muscle origin. Using in situ hybridization, we showed large amounts of Epstein-Barr virus messenger RNAs within the tumor cells. In addition, Southern blot analysis revealed that viral DNA was present in the form of a single monoclonal episome within the tumor. The polymerase chain reaction analysis of the genomic DNA of tumoral cells also indicated a monoclonal pattern. At last, the tumor was shown to be of host origin. Six months later, and despite three courses of chemotherapy, the tumoral lesions were unchanged. This case underlines the role of Epstein-Barr virus infection in the development of unusual and clonal smooth-muscle tumors after organ transplantation. The evolution of these rare tumors is uncertain.

Female↗