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PubMed2002

Using cancer genetics to guide the selection of anticancer drug targets.

The genetic alterations that cause cancer are coming into view. Genes that are recurrently mutated in a particular form of human cancer flag the proteins (or molecular pathways) that are critical for the evolution of that malignancy. The first generation of anticancer agents prospectively guided by these principles, for which imatinib mesylate is a prototype, inhibit the biochemical activities that result from gain-of-function oncogenic mutations. Advances in somatic cell genetics and chemical biology should facilitate the development of a second generation of agents that will inhibit proteins that are selectively required for survival in the context of specific cancer-causing mutations, whether loss-of-function or gain-of-function.

Animals↗
PubMedDate not supplied

Regional assignment of ADA and ITPA to mouse chromosome 2 (C1----ter). A demonstration of the conserved linkage of enzyme and proto-oncogene loci.

Similarity of G-band patterns between the long arm of Chinese hamster chromosome 6 and mouse chromosome 2, combined with the assignments of AK1, ADA, and ITPA to hamster chromosome 6 and AK1 to mouse chromosome 2, suggested mouse chromosome 2 also might contain ADA and ITPA. Here, concordant segregation analysis of enzyme loci and chromosomes in mouse spleen X CHO as well as mouse microcell X CHO somatic cell hybrids established the assignments of ADA and ITPA onto mouse chromosome 2 in the region between the first G-band and the terminus (C1----ter). This assignment presents a demonstration of the conservation and evolution of enzyme and proto-oncogene loci linkage since two cellular homologs of viral oncogenes--c-src and c-abl--also map to mouse chromosome 2. In humans c-src, ADA, and ITPA remain conserved on chromosome 20, whereas AK1 and c-abl are together on chromosome 9. These observations and concepts are discussed with respect to the role of proto-oncogenes in chromosomal evolution and suggest the long arm of chromosome 6 as a fruitful place to look for c-src and c-abl in the Chinese hamster.

Adenosine Deaminase↗
PubMed2005

Mitogen induced activation, proliferation and surface antigen expression patterns in unmutated and hypermutated chronic lymphocytic leukemia cells.

OBJECTIVES: To determine whether the immunoglobulin V(H) gene mutational status has an effect on the activation, proliferation and surface antigen expression of chronic lymphocytic leukemia (CLL) cells when stimulated in vitro. METHODS: The proliferation and activation responses of CLL cells were studied in 22-immunoglobulin gene V(H) unmutated (UM-CLL) and 12 hypermutated (M-CLL) CLL cases in 4-day cultures. As the mitogen responses have been previously shown to be diverse in CLL, a case-specific strategy based on optimized mitogen combinations (OMCs) of interleukin-2 (IL-2), 12-O-tetradecanoylphorbol 13-acetate (TPA), Staphylococcus aureus Cowan 1 (SAC), and human recombinant tumor necrosis factor alpha (TNF) was applied in cell stimulation. The expression of 23 surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD27, CD38, CD40, CD45, CD45RA, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7, IgD, and IgM) was studied by flow cytometry at days 0 and 4. RESULTS: The proliferation and activation responses were similar in UM-CLL and M-CLL when OMCs contained IL-2, TPA or TNF. SAC induced faster proliferation in UM-CLL than in M-CLL. OMC stimulation induced preferential down-regulation of growth- promoting cell surface receptors CD5, CD21, and CD124 and preferential up-regulation of growth-inhibiting antigen CD80 in M-CLL. CONCLUSIONS: Difference in immunophenotypic evolution of UM-CLL and M-CLL can be demonstrated if appropriate matrix signals are provided. The pathways for CD5, CD21, CD124 (IL4R), and CD80 (B7-1) regulation should be further explored in relation with somatic hypermutation and outcome of CLL.

Antigens, CD↗
PubMed1998

Genomic imprinting and carcinogenesis.

The Mendelian inheritance is based on the fundamental rule in which mammalian genes are expressed equally from two homologous biparental alleles. Recently a small number of genes have been identified to show an exception to this rule in that homologous alleles can function differently in somatic cells depending on whether they come from the mother or the father. This intriguing biological phenomenon is called as genomic imprinting which does not conform classical Mendelian inheritance and has potentially far reaching implications for genetics, evolution, developmental biology and pathology including cancer. The gene encoding insulin-like growth factor 2 (IGF2) harbors at 11p15.5 and serves as paradigm for an imprinted gene. The IGF2 gene has been demonstrated to be imprinted with the paternal allele expressed and the maternal being silent which is evolutionally conserved between mice and human. Loss of imprinting (LOI) of IGF2 has been demonstrated in a dozen of tumor types including Wilms tumor (WT) with a promise of many more to come. The LOI of IGF2 may induce increased or deregulated IGF2 expression which could initiate the onset of WT. Thus the LOI of IGF2 may provide a novel mechanism of gene activation and play a role in the development of a wide range of tumors. This review also discusses other imprinted genes on 11p15 which may have a role in WT or other diseases. Finally molecular mechanisms of genomic imprinting are discussed.

Alleles↗
PubMedDate not supplied

[Ulcerative rectocolitis. Somatic aspects (author's transl)].

Regional enteritis (Crohn's disease) and ulcerative rectocolitis, both "non specific inflammatory diseases of the bowel", might be diseases with a common etiology but with clinical features corresponding to a different tissular response to a noxious factor. Both diseases are however characterized by distinct clinical, radiological, histological peculiarities; evolution also is different, as appears from the rarity of malignant degeneration in Crohn's disease and its frequence in ulcerative colitis; a psychological support seems to be classical in ulcerative colitis but is on the contrary unusual in regional ileitis. Besides the interference of psychological factors in the outbreak of an ulcerative colitis, besides the infectious and genetic theories, the immunological theory appears as one of the most interesting and promising. In a significant percentage of cases of ulcerative colitis, anticolon antibodies are evidenced, which exhibit a crossed reaction with bacterial antigens, especially with those of Escherichia coli 014. Besides this humoral immunity a cellular immunity exists also: lymphocytes of patients with ulcerative colitis behave as a toxic agent towards colic tissue cultures; this cytotoxicity parallels the course of the disease and provides an explanation for the sometimes dramatic therapeutic effects observed after administration of immunosuppressive drugs and antilymphocytic serum. Moreover, colic antigen can block this cytotoxicity; the immunologically active portion of this antigen may be isolated and its administration in patients with ulcerative colitis may perhaps induce a specific immunosuppression and influence the evolution of the disease.

Adrenal Cortex Hormones↗
PubMedDate not supplied

The fundamental prevalence of chronic myeloid leukemia-generating clonogenic cells in the light of the neutrality theory of evolution.

A variety of normal human tissues have been reported to harbor small cell populations carrying potentially oncogenic gene rearrangements. This backdrop of mutant cells may be present in the majority of healthy individuals and is apparently weakly selected against. This may provide empirical support for the concept of global neutrality, or near-neutrality (very weak selection), of many somatic mutations. Many healthy individuals, as well as patients with chronic myeloid leukemia, manifest the BCR-ABL fusion gene in blood cells. The presumed neutrality of the BCR-ABL rearrangement-carrying pluripotential hematopoietic stem cells and the relative uniformity of the incidence rate of CML worldwide were used to estimate the extent of the background of BCR-ABL-positive stem cells and the numerical size of the human pluripotential hematopoietic stem cell pool. Three different approaches (molecular-epidemiological, statistical, and population genetical) were employed. Each resulted in very similar estimates of the size of the stem cells carrying the BCR-ABL allele fusions (1.4 x 10(4) cells) and the size of the total human stem cell pool (1.6 x 10(9) cells per individual). The implication of these estimates in the context of the hierarchical nature of the stem cell pool is also considered. The presumptive smaller-sized population of CD34(-) stem cells could not be characterized by any of the approaches used as a "founding" population, representing an ultimate source of all hematopoietic progenitors, or as a subset of stem cells comprising a deeper "kinetic" segment of the total (10(9)-sized) stem cell compartment.

Cell Survival↗
PubMed1985

Feline glucose-6-phosphate dehydrogenase cellular mosaicism. Application to the study of retrovirus-induced pure red cell aplasia.

Neoplasms result from the uncontrolled proliferation of abnormal or transformed cells. The early stages of this process are difficult to study because of the lack of sensitive and specific markers of clonal evolution in an experimental system. We have developed a cat model using cellular mosaicism for glucose-6-phosphate dehydrogenase (G-6-PD). Our findings confirm that the structural locus for feline G-6-PD is on the X-chromosome and demonstrate that it is randomly inactivated in somatic cells. Heterozygous cats have balanced ratios of G-6-PD enzyme types in peripheral blood cells and hematopoietic progenitors that remain stable over time. In our initial studies, we used the model to analyze the events surrounding marrow failure experimentally induced by selected strains of feline leukemia virus (FeLV). Two G-6-PD heterozygous cats, one F1 male hybrid and one domestic cat were infected with FeLV (C or KT) and developed pure red cell aplasia (PRCA). Colonies arising from the more mature erythroid colony-forming cell were not detected in marrow culture of anemic animals although erythroid bursts persisted, suggesting that the differentiation of early erythroid progenitors (BFU-E) was inhibited in vivo. The ratio of G-6-PD types in hematopoietic progenitors and peripheral blood cells from the heterozygous cats did not change when the animals developed PRCA. Thus, the anemia did not result from the clonal expansion of a transformed myeloid stem cell. With this experimental approach, one may prospectively assess clonal evolution and cellular interactions in other FeLV-induced diseases.

Animals↗
PubMedDate not supplied

Myasthenia gravis: An embryologic and phylogenetic perspective.

Myasthenia gravis is a rare disease with unique clinical features. These include (1) progressive fatigue on exertion, most evident clinically in the muscles of the head and neck (2) a definite relationship of the disease to the thyroid, parathyroid and thymus glands. A hypothesis is advanced with correlates these facts on the basis of a common embryologic origin of these glands and the branchial arch muscles. A corollary is that the muscles of the head and neck differ from the somatic musculature in some as-yet-unidentified manner, for example, pharmacologically. A plea is made for comparative studies between the two.

Biological Evolution↗
PubMed1993

Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes.

The tre oncogenic locus was identified in transformants receiving human DNA from Ewing's sarcoma cells EW1. Genetic elements of tre originate from chromosomes 5, 18, and 17. The TRE17 oncogene is consistently transcribed in various human cancer cells and proves oncogenic (onc) in expression vector-based assays. Here, the nucleotide sequence of TRE17 with defined noncoding and two coding exons (4,426 nucleotides) was compared with sequences cloned from placental DNA library or generated by polymerase chain reaction (PCR) from EW1 and independent healthy individuals. Cloned sequences displayed restriction site polymorphism, with different patterns for EW1 and normal tissues. Sequence analysis revealed that they originate from a family of homologous sequences alpha, beta, and gamma. TRE17 alpha and less frequent TRE17 beta (similarity score approximately equal to 88%) were found in both normal and EW1 cells. oncTRE17, classified as TRE17 beta, differed from the wild-type TRE17 beta, besides a few intronic changes, by a single-base frameshift insertion in one of the coding exons. TRE17 gamma, so far identified in EW1 but not in normal somatic cells, diverged from oncTRE17 by 6% nucleotide substitutions and by stop codons in each reading frame. The results are consistent with the possibility that TRE17 sequences other than oncTRE17 are translated if alternatively spliced. Expression of TRE17 in normal somatic cells was, however, not yet reported.

Amino Acid Sequence↗
PubMed2003

Evidence on the evolution of polymorphism of microsatellite markers in varieties of Vitis vinifera L.

This paper contributes a description of four mutations in microsatellite allele-length found within strains of each of the varieties known as Muscat d'Alsace, Greco di Tufo, Primitivo and Corvina veronese: the comparison of microsatellite sequences of wild and mutated strains showed in all cases an increase of one or more repeats of the core GA sequence. Whereas studies on animals reported mutations which originated in gametes, in grapevines somatic cell-mutations take place and are eventually fixed and transmitted to new individuals through vegetative propagation. The mutations detected in 1998 were found again 3 years later in seven out of eight plants. A chimeric situation was clearly noted and resolved in three of the four cases described. Considerations about the genesis of microsatellite alleles and the reliability of fingerprinting with these markers are provided.

DNA, Plant↗
PubMed1984

Tetrahymena H4 genes: structure, evolution and organization in macro- and micronuclei.

The ciliated protozoan Tetrahymena thermophila contains two types of H4 histone genes (H4-I and H4-II). Southern blotting and analysis of DNA from nullisomic strains indicate that H4-I and H4-II are on different chromosomes and that only H4-II is closely linked to an H3 gene. No DNA sequence rearrangements are observed for either of the H4 genes when the transcriptionally inert, germ line, micronucleus is compared to the transcriptionally active, somatic macronucleus. Comparison of the H4-I gene and its flanking sequences to H4 gene sequences of other organisms indicates that there are evolutionary constraints on coding nucleotides that are unrelated to their protein coding function and that these evolutionary pressures operate at the level of translation.

Amino Acid Sequence↗
PubMed2004

Human birthweight evolution across contrasting environments.

We explore from both theoretical and empirical perspectives the hypothesis that a significant part of the worldwide variability in human birthweight results from adaptive responses to local selective pressures. We first developed an agent-based model to simulate the process of evolutionary selection on life history strategy, and then we performed a comparative analysis across 89 countries worldwide. The model illustrates that optimal birthweight depends on which fitness-reducing risk locally predominates (somatic diseases, parasitic diseases or adverse environmental conditions). When fitness variations between individuals mainly result from somatic diseases (e.g. industrialized countries), or conversely from infectious and parasitic diseases (e.g. developing countries), selection is expected to favour individuals producing larger children. Conversely, when environmental risks increase in relative importance, selective pressures for producing children with high birthweight are reduced. The comparative analysis supports these theoretical expectations, in particular the finding that birthweight is higher than predicted in highly parasitized countries.

Adaptation, Physiological↗
PubMedDate not supplied

[The problem of the stability of living systems and its evolutionary and morphofunctional bases].

Stability of the living matter is not only a morphological problem, but also a physiological-behavioral problem. Analysis of data accumulated in this field is the topic of this study. Contradicting the existing assumptions, it has shown that the taxonomic stability is not a casuistic phenomenon, but an important independent and widespread law of evolution providing for conservation without modification of the structures and functions for sometimes tens and hundreds millions of years. This is the first publication of the concept of the material substratum of this phenomenon. The study has established that the stability of the orders of mammals persisting despite the variability of the somatic organs in many representatives, and conservation of this separation even in case of transition into the aquatic habitat are due to the regulating mechanism represented by the nervous system of animals and man. This is, in particular, reflected in the specific structural and physiological mechanisms on the subcortical and cortical levels (visual system and neocortex). The study questions the concept of the origin of mammals from a single root of primary insectivorous ancestors on the basis of the discovered cytoarchitectural differences in the visual system and neocortex, and also the most recent paleontological data. In view of that the author emphasizes the independent principle of cytoarchitectural organization of the above brain formations in each order, and their stable separation during the established paleontological history. This phenomenon is interpreted as a major evidence of the principle of stability in the evolution process.

Animals↗
PubMedDate not supplied

[Post-traumatic stress, post-traumatic depression and major depressive episode: literature].

Although they are likely to add their effects, physical and psychic traumata (or traumas) can provoke in different ways the appearance of depressive symptoms sometimes common. Post-traumatic depression, reactional depression, major depressive disorder and post-traumatic stress disorder represent different clinical and nosographic disorders in despite of their occasionally common symptomatic core. Historically, it is interesting to note during the XXth century the true semantic change of the terms of trauma from the somatic field to the psychic sphere. Physical traumatism is often represented by a material shock for the subject and by its organic consequences. It is defined as an event that leaves its mark which itself inflicts and handicaps the vital trajectory of the subject. It primarily comprises brain and rachis injuries, whose evolution is frequently characterized by the occurrence/appearance of a depressive disorder, whose genesis rests on psychological but also neurobiologic and physical arguments. Thus major depressive disorders are often present in the course of various physical traumatisms mainly related to nervous system. In accordance with several studies, the prevalence of major depressive disorders ranges from 25% to 50%. These mood disorders occur in the year which follows the accidental event. Their average time of revelation is estimated at four months and their average duration lies between three and six months. Lastly, although these depressive illnesses present clinical symptoms comparable with those observed in other contexts, some nuances can be raised. Nonetheless, they confine sometimes with true clinical forms depending on the intensity, the form, the circumstances or the consequences of the trauma. Psychic traumatism doesn't have the same profile and rests for much dedicated with the reexperiencing. Thus for some authors, depression illness represents a disorder that occurs after a traumatic event whereas others see a differential diagnosis which exludes or which represents a comorbidity with post-traumatic stress disorder. The review of the literature allows us to emphasize the complexity of the links as well as the clinical and epidemiologic differences between stress disorder and major depressive disorder. From the clinical point of view, the major features of PTSD are articulated around a triad of symptoms. They include the reexperiencing symptoms of the traumatic event such as intrusive memories and recurrent nightmares, the protective reactions such as avoidance of the stimuli associated with the trauma and emotional numbing, and the arousal symptoms such as the startled response and hypervigilance. The complexity of this syndrom is due to the frequent combination of these symptoms with other nonspecific ones. As far as the mood is concerned (the mood symptoms are concerned), the regrouping of some of these symptoms allows the clinician to sometimes releave a depressive symptomatology without being able to assess the DSM diagnosis of major depressive disorder. Epidemiologic studies dealing with the risk of installation of a PTSD after a traumatic event reveal differences in the prevalence depending on the nature of the traumatic events: ranging from 1% in general population to 80% following some situations of extreme and durable psychic suffering. Between both poles, one finds a prevalence ranging between 20 and 50% following other events such as serious accidents, natural disasters or criminal assaults. The clinical features of depressive episodes comorbid or associated with PTSD have some characteristics making it possible to individualize various clinical forms as a function of traumatic event type: asthenic, characterial or with somatic symptoms. According to the majority of authors, the co-occurrence of post-traumatic stress disorder and major depressive disorder is high although differential diagnosis is sometimes difficult. However, conceptual differences remain and two conceptions are distinguished. For some authors, like Bleich and Shalev, there would not be true chronological evolution from PTSD to MDD. Moreover the presence of symptoms considered as pertaining to the mood register within the criteria of PTSD would be clearly predictive of the occurrence and the severity of the diagnosis but not of the chronicity. For others, there would be a continuity between post-traumatic stress disorder and major depressive disorder. It is the case in many studies of veterans but also for civilian traumatic events. It is also the case for the American national study of comorbidity in which Kessler concludes that for 78% of the subjects who present a comorbidity PTSD/MDD (comorbidity raised for 48% of the 5,877 subjects included), the mood disorder is secondary to PTSD. (ABSTRACT TRUNCATED)

Comorbidity↗
PubMed1995

Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes.

About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution.

Adult↗
PubMed2001

"Bar-coding" primate chromosomes: molecular cytogenetic screening for the ancestral hominoid karyotype.

Two recently introduced multicolor FISH approaches, cross-species color banding (also termed Rx-FISH) and multiplex FISH using painting probes derived from somatic cell hybrids retaining fragments of human chromosomes, were applied in a comparative molecular cytogenetic study of higher primates. We analyzed these "chromosome bar code" patterns to obtain an overview of chromosomal rearrangements that occurred during higher primate evolution. The objective was to reconstruct the ancestral genome organization of hominoids using the macaque as outgroup species. Approximately 160 individual and discernible molecular cytogenetic markers were assigned in these species. Resulting comparative maps allowed us to identify numerous intra-chromosomal rearrangements, to discriminate them from previous contradicting chromosome banding interpretations and to propose an ancestral karyotype for hominoids. From 25 different chromosome forms in an ancestral karyotype for all hominoids of 2N=48 we propose 21. Probes for chromosomes 2p, 4, 9 and Y were not informative in the present experiments. The orangutan karyotype was very similar to the proposed ancestral organization and conserved 19 of the 21 ancestral forms; thus most chromosomes were already present in early hominoid evolution, while African apes and human show various derived changes.

Animals↗
PubMed1990

Myogenin is in an evolutionarily conserved linkage group on human chromosome 1q31-q41 and unlinked to other mapped muscle regulatory factor genes.

Myogenin is a member of a family of muscle-specific regulatory factors which includes MyoD1, Myf-5, and Myf-6 (also called MRF4 and herculin). Extensive regions of sequence homology in genes for these three factors suggest duplication events associated with their evolution. In the present study, the chromosomal location of the myogenin gene in humans (MYOG), mice (Myog), and Chinese hamsters (MYOG) was determined using in situ hybridization to human metaphase chromosomes as well as segregation analysis among interspecific somatic cell hybrid panels and interspecific backcrossed mice. We localize the gene encoding myogenin to human chromosome 1q31-q41 within a linkage group homologous with a region on mouse chromosome 1 and Chinese hamster chromosome 5. The results verify the nonlinkage of MYOG to MYOD1, MYF5, and MYF6 genes and indicate that events associated with the duplication of MYOG with respect to MYOD1, MYF5, or MYF6 loci were not chromosome-wide.

Animals↗
PubMed2004

Chromatin diminution leads to rapid evolutionary changes in the organization of the germ line genomes of the parasitic nematodes A. suum and P. univalens.

Chromatin diminution in the parasitic nematodes Ascaris suum and Parascaris univalens represents a rather complex molecular phenomenon that includes chromosomal breakage, DNA degradation and new telomere formation. At a given elimination site, DNA breakage and new telomere addition does not take place at a single chromosomal locus but at many different places within a several kilobase long chromosomal region, referred to as chromosomal breakage region (CBR). Here we describe the cloning and the characterisation of seven CBRs from A. suum and P. univalens and we show that the process has been conserved between the two species. A detailed sequence comparison provides evidence that the sequences of the CBRs and their flanking regions are not directly important for the specification of the elimination sites. Six out of the seven CBRs are conserved between the two nematode species, suggesting that they have already existed in a common ancestor. We present a hypothesis stating that the elimination process ensures the maintenance of a functional somatic genome and concomitantly allows extremely rapid and profound changes in the germ line genome, thereby allowing the development of new germ line specific functions and thus providing a selective advantage for the chromatin eliminating nematodes during further evolution.

Animals↗