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PubMed1988

[Cancer and therapy for it--from gynecological standpoints].

Life phenomena have been studied scientifically for more than 160 years. Meanwhile many excellent technology and methodology which human race created have been used in the field of medicine. Analytical research for the constitution of life and impediments to life has remarkably advanced. Pathophysiology of many diseases has been clarified and reasonable and effective treatment for disorders has been organized. Many disorders which showed high mortality in the past are now listed as one of minor diseases in the textbook. However, the disease which cause is unclear and which deprives human race of life still exists. That is "CANCER". The society of medicine devotes the greatest energies to abolish the cancer. I am going to talk about the physiological characteristics of "the cancer in human race" from the gynecological standpoints and to present some facts of studies about the therapy for cancer in our department. I. Evolution of human and cancer 1. Life of species and life of individuals In the development from uni-nuclear cell creature to multicellular entity, to give new generation sexual reproduction was out-lasted for the adaptation to environment advantageously after the spread out of mutant gene in this entity. With this evolution, a living creature divided its cells into two types. One is somatic cells which would die in certain period and the other is germ cells which would not die on principle in good environment. In short well evolved living entity clearly established individual life span for the first time and its constituent, that is somatic cells demonstrated "AGEING" phenomena regulating life span.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMedDate not supplied

Human longevity at the cost of reproductive success.

The disposable soma theory on the evolution of ageing states that longevity requires investments in somatic maintenance that reduce the resources available for reproduction. Experiments in Drosophila melanogaster indicate that trade-offs of this kind exist in non-human species. We have determined the interrelationship between longevity and reproductive success in Homo sapiens using a historical data set from the British aristocracy. The number of progeny was small when women died at an early age, increased with the age of death, reaching a plateau through the sixth, seventh and eighth decades of life, but decreased again in women who died at an age of 80 years or over. Age at first childbirth was lowest in women who died early and highest for women who died at the oldest ages. When account was taken only of women who had reached menopause, who were aged 60 years and over, female longevity was negatively correlated with number of progeny and positively correlated with age at first childbirth. The findings show that human life histories involve a trade-off between longevity and reproduction.

Adult↗
PubMedDate not supplied

On the evolution of X-chromosome inactivation in mammals and the clinical consequences to man--a hypothesis.

A clinical analysis of abnormal sex chromosome states in man suggests that Lyon's recent X-Y translocation hypothesis for the evolution of X-chromosome inactivation in mammals most likely would have lead to an evolutionary dead-end. Therefore, as an alternate I have hypothesized that: X-chromosome inactivation in somatic cells of mammals could have evolved by a complementary process of one by one heterozygous physical deletion in males and heterozygous inactivation in females of genes for "somatic" traits scattered throughout the genome whose effective output had become 50% excessive during prior evolution. However, this complementary process could occur safely only if the genes so deleted or inactivated first segregated by chance onto the evolving sex-chromosomes via a one by one reciprocal exchange for non-sex related genes already there. The complementary process thereby would allow slow evolution of the Y-chromosome in the male and X-chromosome inactivation in the female. Evolution of X-chromosome inactivation in this manner is compatible with Ohno's observation of "conservation" of the X-chromosome in mammals; and the occurrance of clinical "somatic" abnormalities in the abnormal X or Y chromosome states of man despite X-chromosome inactivation.

Aneuploidy↗
PubMed2001

Human natural chimerism: an acquired character or a vestige of evolution?

Analysis on five common classes of human natural chimeras (cytomictical, whole body, fetal-maternal, germ cell, and tumor chimeras) reveals that (1) they initiate only during pregnancy, (2) the most common class are chimeras which contain maternal cells, and (3) the primary mechanisms that are involved in their formation and establishment are still elusive. These classes of natural chimerism, are involved only with maladaptive phenomena such as malignancy and autoimmune diseases and without any documented benefit. A recent review has challenged the accepted dogma that the evolution of immunity is pathogen-directed and asserted that preserving individuality from littering the soma and the germline by conspecific alien cells might have been the original function of the innate immunity. Following this tenet, I propose here that human natural chimerism is a by-product of the new role evolved from primitive components of immunity to "educate" the developing embryo with the armamentarium of effector mechanisms, dedicated to purge the individual from pervasive somatic and germline variants, and is not a vestige of evolution.

Animals↗
PubMed1990

Limits to genetic intervention in humans: somatic and germline.

The promise of somatic cell gene therapy is likely to be limited to a narrow range of monogenic hereditary defects. This therapy raises few moral issues. However, extension to the 'improvement' of a normal trait might raise problems, similar to the use of hormones in sports. Another danger is uses that result, like heroic measures to save the premature newborn, in the prolongation of misery and in intolerable expense. The genetic alteration of germline cells, which can already be accomplished in animals, is in principle applicable to all monogenic diseases. Its use in humans is much less acceptable than somatic cell therapy. The objection that it tampers with human evolution is widely cited. However, more important may be the risk of producing a new defect, for risk is much less acceptable in a yet unborn person than in an already ill individual. In addition, the goal of germline therapy could almost always be accomplished more simply and safely by prenatal diagnosis and selective abortion. The highly polygenic nature of the most interesting traits, both behavioural and physical, makes it unlikely that we shall be able to modify them usefully in the foreseeable future by either somatic or germline intervention. Despite this delivery from temptation, public fear of future 'blueprinting' of humans no doubt contributes to a multi-faceted antiscience movement.

Ethics, Medical↗
PubMed1999

[Delirium and hallucinations in depression: cultural aspects].

Study of depression in North-Africa and Sub-Saharan Africa has shown that, since the seventies, the clinical expression of depression is markedly different from that of depression in the West. Several authors have noted the rareness of guilt themes and the frequency of persecution themes and somatic complaints in depressed Africans, even those living in the West. More recent studies have shown an evolution in depressive symptoms in North-Africa with an increase in guilt and a decrease in persecution and somatic complaints. This shift in symptoms brings the expression of depression closer to that observed in the West. Our study addresses delusional depression: in 73 cases of delusional depression, delusions of guilt were present in 31% of cases, persecution in 48% and hallucinations in 31.5%. A comparison of the sub-groups consulting in 1991 and a second sub-group consulting in 1998 shows a marked increase in guilt (23.5 versus 39%).

Adult↗
PubMed1999

Innate antibody catalysis.

Catalysis by antibodies is often assumed to require immunization with artificial haptens, which are proposed to stimulate adaptive immune processes and enable the development of catalytic sites with the ability to bind the transition state. Contrary to this assumption, we describe here a serine protease-like catalytic triad in an antibody light chain raised by immunization with vasoactive intestinal peptide (VIP), the structure and function of which is inherited via a germline V(L) gene. The serine protease mechanism was evident from loss of the catalytic activity by site directed mutagenesis at a framework region residue Asp1 (present study) and at two complementarity determining region residues Ser27a and His 93 (Gao, Q-S., Sun, M., Rees, A., Paul, S., 1995. Site-directed mutagenesis of proteolytic antibody light chain. J. Mol. Biol. 253, 658-664). All three catalytic residues (Ser27a, His93, Asp1) are also present in the germline counterpart of the mature V(L) gene, but the mature and germline sequences differ by four amino acids remote from the catalytic site. Reversion mutations were introduced at these amino acids in the mature light chain (His27 d:Asp, Thr28e:Ser, Ile34:Asn, Gln96:Trp; Kabat numbering, germline encoded residues shown second), generating the germline configuration of the protein. The germline light chain expressed peptidase activity, determined by assaying the cleavage of VIP and a synthetic protease substrate, Pro-Phe-Arg-Methylcoumarinamide. Differences between the kinetic constants for the mature and germline light chains were marginal. Diisopropylfluorophosphate, a serine protease inhibitor, blocked the peptidase activity of the germline light chain, suggesting the presence of the catalytic triad in a functional state. Like the mature light chain, the germline protein preferentially cleaves peptide bonds on the C-terminal side of basic residues. We conclude that the catalytic activity of certain antibodies is an innate function, originating over the course of phylogenetic evolution of the V(L) genes, as opposed to somatic processes.

Amino Acid Sequence↗
PubMedDate not supplied

Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma.

Loss of genes at specific chromosomal loci is a characteristic of retinoblastoma, Wilms' tumour, transitional cell carcinoma of the bladder, embryonal tumours and small cell carcinoma of the lung. The significance of nonrandom gene loss in these neoplasms is that gene loss on one chromosome may uncover null mutations at corresponding loci of the homologous chromosome. Loss of specific gene products from somatic cells may be critical in the origin or evolution of certain human tumours. Clues to identification of new loci of gene loss in common adult solid tumours may be found in literature that describes chromosomal abnormalities in rare heritable cancers. Karyotypes of tumours in two families with hereditary renal carcinoma showed translocations involving the short arm of chromosome 3 (refs 10 and 11). We have examined tumours from 18 patients with non-hereditary renal cell carcinomas and found loss of alleles at loci on the short arm of chromosome 3 in all eleven of the patients who could be evaluated.

Adult↗
PubMed1990

The phosphocreatine shuttle of sea urchin sperm: flagellar creatine kinase resulted from a gene triplication.

TCK, the creatine kinase (ATP:creatine N-phosphotransferase) from sperm flagella of the sea urchin Strongylocentrotus purpuratus, is a Mr 145,000 axonemal protein that is employed in energy transport. Its amino acid sequence was obtained by analysis of fragments from cyanogen bromide digestion and by sequencing cDNA clones from two sea urchin testis libraries. TCK contains three complete but nonidentical creatine kinase segments joined by regions of sequence that are not creatine kinase-like and flanked by unique amino and carboxyl termini. Each creatine kinase segment is homologous to vertebrate creatine kinases of both muscle and brain types, and all three repeats contain the essential active-site cysteine. The sequence differences among repeats suggest an ancient gene triplication, around the time of the chordate-echinoderm divergence. The echinoderm, with a unique creatine kinase in sperm, arginine kinase in eggs, and both phosphagen kinases in somatic cells, may represent a preserved branch point in evolution, and TCK may be a relic of this event.

Amino Acid Sequence↗
PubMed2000

Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma.

Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL.

Adult↗
PubMed1991

[Paradoxical sleep: is it the guardian of psychological individualism].

The brain is the sole organ of homeotherms that do not undergo cell division. We thus have to explain how certain aspects of psychological heredity (found in homozygotes twins raised in different surroundings) may persist for a whole life (psychological individuation). A definitive genetic programming during development (by neurogenesis) is unlikely due to the plasticity of the nervous system. That's why we have to consider the possibility of an iterative genetic programming. The internal mechanisms (synchronous) of paradoxical sleep (SP) are particularly adapted to such programming. This would activate an endogenous system of stimulation that would stimulate and stabilize receptors genetically programmed by DNA in some neuronal circuits. The excitation of these neurons during SP leads to oniric behaviours that could be experimentally revealed--the lists of these behaviours are specific to each individual and indirect data suggest a genetic component of this programming. Amongst the mechanisms allowing the iterative programming of SP, sleep is particularly important. Security--and hence the inhibition of the arousal system--is a sine qua non condition for genetic programming to take place. In that sense, sleep could very well be the guardian of dreaming. On the other hand, sleep seems to be necessary for the accumulation of energetic resources used by the cholinergic mechanisms of SP. The temporal modalities of SP (diachronic organization) are also discussed in relation to phylogenesis. Thus, the absence of SP in poikilotherms is explained by a continual neurogenesis in the adult. During ontogenesis in mammals, a stage of programming by neurogenesis (seismic sleep) precedes the appearance of SP so long as the programming system isn't functional. The presence, or absence, of rebound after SP deprivation is interpreted in terms of the existence, or non existence, of stress during SP suppression. An explanation is proposed to account for the absence of specific effects of SP deprivation in humans. In the same way somatic intraspecific variability is one of the conditions of evolution, it is proposed that one of the functions of SP is to maintain psychological variability in a given population.

Animals↗
PubMed2000

Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load.

The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between somatic mutation and heavy chain isotype expression, we analyzed the variable heavy (V(H)) chain genes of 30 FL samples of different isotypes. The V(H) genes of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype-switched lymphomas contained more somatic mutations than immunoglobulin M-positive lymphomas (33.8 mutations per V(H) gene versus 23.0, respectively). In all but one of the FLs, the ratios of replacement versus silent mutations in the framework regions were low, independent of the absolute number of somatic mutations and the level of intraclonal variation. Analysis of relapse samples of 4 FLs showed no obvious increase in somatic mutation load in most FLs and a decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence for selection of certain subclones, rather than clonal evolution. Our findings question if intraclonal variation is always a reflection of ongoing somatic hypermutation. This may have implications for the concept of antigen-driven lymphomagenesis. (Blood. 2000;95:2922-2929)

Adult↗
PubMed1999

High genome-wide mutation rates in vegetatively propagated bermudagrass.

A cascade DNA amplification strategy that generates arbitrary signatures from amplification profiles (ASAP) was used to measure genome-wide mutation rates in bermudagrass (Cynodon). ASAP quantified nucleotide changes that were induced by irradiation, genetic instabilities and normal vegetative growth of cultivars and accessions of sterile interspecific hybrids. DNA sequence divergence between cultivar 'Tifway' and its gamma radiation-induced mutant 'Tifway II' (0.70 +/- 0.66%) was comparable to estimates in radiation-induced mutants and spontaneous sports of chrysanthemum (Chrysanthemum morifolium Ramat.). A similar divergence in sequence (0.95 +/- 0.20%) was observed in the pairwise comparison of 17 nondisjunctive 'Tifgreen' and 'Tifdwarf' accessions. Mutation during normal Tifdwarf vegetative growth was evaluated by planting sprigs and sampling their offspring. Somatic sequence divergence levels (0.004 +/- 0.007%) resulted in a mutation rate of 1.05 x 10-8 per nucleotide per generation, assuming that a bermudagrass sprig constitutes a generation of growth. These rates were comparable to those found in germinal cells and individuals of either human or Drosophila melanogaster, supporting the notion that eukaryotic evolution is generation rather than time dependent. The high accumulation of somatic mutations (10 per triploid genome) is consistent with a model whereby mutation load in a population exhibiting obligate vegetative reproduction is substantially higher than in a population under sexual or asexual reproduction. These constraints could be the cause of reported genetic instabilities in the Tifgreen-Tifdwarf complex. Finally, a long-term rate measured across accessions and indicative of the accumulation of mutations in 17 Tifgreen-Tifdwarf populations (µ = 1.02 x 10-8 per nucleotide per generation) was strikingly congruent with the bermudagrass vegetative mutation rate, suggesting absence of evolutionary constraints in the sampled genomic regions. Mutation rates calculated from across-accesions divergence estimates (5.18 +/- 0.53%) indicated that plant material was evolving 100 times faster (3.8 x 10-7 changes per nucleotide per year) than a molecular clock rate estimate for grasses, probably resulting from the compound effect of clonal growth and life span of the hybrid plant material.

Journal Article↗
PubMed1991

Effects of visceral distension on the activities of neurones receiving cutaneous inputs in the rat lumbar dorsal horn; comparison with effects of remote noxious somatic stimuli.

(1) Unitary extracellular recordings were made from 92 lumbar dorsal horn neurones in urethane-anaesthetised rats. These neurones were classed as 'noxious-only' (4), 'non-noxious-only' (33) or 'convergent' (55) by their responses to stimulation of their cutaneous receptive fields on the ipsilateral hindpaw. (2) Distension of abdominal viscera (colon, urinary bladder) depressed the activities of the vast majority (93%) of the convergent neurones but of only one other cell (a non-noxious-only neurone). Similarly, noxious stimulation of widespread somatic structures depressed activity in all but one of the convergent neurones but in only 3 other cells (one non-noxious- and two noxious-only neurones). One or other of these procedures also excited 3 cells--one convergent neurone responding to distension of the colon, another to stimulation of widespread somatic structures and one non-noxious-only neurone being excited by stimulation on the contralateral hindpaw. (3) The inhibitory effects of the noxious somatic stimuli were very like those described previously and termed 'diffuse noxious inhibitory controls' (DNIC) and it seems likely that the effects of the visceral stimuli were also manifestations of DNIC, particularly in view of their similar, nearly total, specificity to convergent neurones. There were however, some small differences in the extent and temporal evolution of the inhibitory effects of the visceral and of the somatic stimuli--the visceral stimuli generally producing weaker inhibitions with slower rates of onset and recovery. It is proposed that these differences may have reflected different amounts and patterns of activity in the relevant primary afferent fibres rather than being due to different central neural mechanisms. (4) These results and the likely explanation that the effects of the visceral stimuli were mediated by a diffuse mechanism should be taken into account when interpreting the results of other studies in which inhibitory effects are produced by visceral stimulation.

Afferent Pathways↗
PubMed1997

Evolution of the structural repertoire of the human V(H) and Vkappa germline genes.

Variable genes of human Ig are classified in families and clans which reflect the early events of gene duplication in the evolution of the locus. This organization in multiple copies of variable genes plus the somatic processes of recombination and hypermutation allows the immune system to generate an antibody repertoire of great diversity. At present the role that somatic processes play in the generation of that diversity is understood with some detail. It is a matter of hard controversy, however, which selective pressures have shaped the evolution of the germline genes of Ig and, consequently, what the role of this germline component in the generation of the antibody diversity actually is. Previous studies of our group have showed that the structural repertoire of Ig-determined by the canonical structures-is an important factor to determine the recognition properties of the antibodies. Complete knowledge of the sequences of the human V(H) and Vkappa loci is available to analyze the evolution of the structural repertoire of these loci. Two phylogenetic gene trees were built from the functional germline genes and the evolution of the structural repertoire was studied. We report that for both loci the canonical structures are not randomly distributed within the tree. Conversely, it is shown that the evolution of the structural repertoire follows a gradual process of diversification. This indicates a correlation between the evolution of genes and the structural repertoire, although important differences are found in the patterns of evolution of the structural repertoire between V(H) and Vkappa. Based on those results we propose a primordial structural repertoire for V(H) and Vkappa. The general properties and an outline of the three-dimensional structure of this primordial repertoire are given.

Amino Acid Sequence↗
PubMed1994

Short introns interrupting the Oct-2 POU domain may prevent recombination between POU family genes without interfering with potential POU domain 'shuffling' in evolution.

Transcription factors are often encoded by gene families that share the same type of DNA binding domain. The POU domain genes are one such paradigm. We compared the genomic DNA encoding the POU domain of the Oct-2 genes in human and mouse. In both species this domain is split into a cluster of four exons by short, highly diverged introns. We postulate that the main role of these introns is to prevent ectopic homologous recombination with other members of the POU gene family, with its potentially deleterious effects in somatic and germline cells. Such rapidly diverging introns may generally promote evolution by facilitating the maintenance of duplicated genes. The use of different codons for the same protein domain among members of a gene family may be a slower process that serves a similar purpose. Introns that split conserved domains such as the POU domain do not conform to the exon shuffling hypothesis originally put forward by W. Gilbert (1978). However, we note that the introns flanking the POU domain are in the same phase, i.e. interrupt codons in the same reading frame. Thus we propose that the entire POU domain, which is encoded by a tight cluster of exons, has been shuffled together during evolution as a functional unit, or 'shufflon'.

Animals↗
PubMed2002

Consequences of hierarchical allocation for the evolution of life-history traits.

Resource allocation within individuals may often be hierarchical, and this may have important effects on genetic correlations and on trait evolution. For example, organisms may divide energy between reproduction and somatic growth and then subdivide reproductive resources. Genetic variation in allocation to pathways early in such hierarchies (e.g., reproduction) can cause positive genetic correlations between traits that trade off (e.g., offspring size and number) because some individuals invest more resources in reproduction than others. We used quantitative-genetic models to explore the evolutionary implications of allocation hierarchies. Our results showed that when variation in allocation early in the hierarchy exceeds subsequent variation in allocation, genetic covariances and initial responses to selection do not reflect trade-offs occurring at later levels in the hierarchy. This general pattern was evident for many starting allocations and optima and for whether traits contributed multiplicatively or additively to fitness. Finally, artificial selection on a single trait revealed masked trade-offs when variation in early allocation was comparable to subsequent variation in allocation. This result confirms artificial selection as a powerful, but not foolproof, method of detecting trade-offs. Thus, allocation hierarchies can profoundly affect life-history evolution by causing traits to evolve in the opposite direction to that predicted by trade-offs.

Animal Population Groups↗