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PubMed1996

Evolution of a persistent aphthovirus in cytolytic infections: partial reversion of phenotypic traits accompanied by genetic diversification.

Foot-and-mouth disease virus (FMDV) shows a dual potential to be cytolytic or to establish persistent infections in cell culture. FMDV R100, a virus rescued after 100 passages of carrier BHK-21 cells persistently infected with FMDV clone C-S8c1, showed multiple genetic and phenotypic alterations relative to the parental clone C-S8c1. Several FMDV R100 populations have been subjected to 100 serial cytolytic infections in BHK-21 cells, and the reversion of phenotypic and genetic alterations has been analyzed. An extreme temperature sensitivity of R100 reverted totally or partially in some passage series but not in others. The small-plaque morphology reverted to normal size in all cases. The hypervirulence for BHK-21 cells did not revert, and even showed an increase, upon cytolytic passage. Most of the mutations that had been fixed in the R100 genome during persistence did not revert in the course of cytolytic passages, but the extended polyribocytidylate tract of R100 (about 460 residues, versus 290 in C-S8c1) decreased dramatically in length, to the range of 220 to 260 residues in all passage series examined. In passages involving very large viral populations, a variant with two amino acid substitutions (L-144-->V and A-145-->P) next to the highly conserved Arg-Gly-Asp (RGD motif; positions 141 to 143) within the G-H loop of capsid protein VP1 became dominant. A clonal analysis allowed isolation of a mutant with the single replacement A-145-->P. Viral production and growth competition experiments showed the two variants to have a fitness very close to that of the parental virus. The results provide evidence that the repertoire of variants that could potentially become dominant in viral quasispecies may be influenced by the population size of the evolving virus. The net results of a series of persistent-infection passages followed by a series of cytolytic passages was progressive genomic diversification despite reversion or stasis of phenotypic traits. Implications for the evolution of RNA viruses are discussed.

Animals↗
PubMed1999

Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load.

Under an evolutionary perspective, antigens can be considered nothing else than chronic stressors that constituted the major selective pressure for immune system emergence and evolution. In this review, recent data are discussed under the hypothesis that human immunosenescence is the consequence of the continuous attrition caused by chronic antigenic overload/stress. The advantage of this theoretical approach is that a unifying hypothesis is proposed, which tries to fill in the current gap between the conceptualizations concerning the mechanisms which counteract aging and favor longevity in invertebrates and vertebrates. The hypothesis is that the immune system is, at a higher level of biological organization and complexity, the counterpart of the anti-stress response network identified in invertebrates as the major determinant of survival. We argue that some of the most important characteristics of immunosenescence, i.e. the accumulation and the clonal expansion of memory and effector T cells, the reduction/exhaustion of naive T cells, and the shrinkage of T cell repertoire, are compatible with this assumption. Thus, immunosenescence can be envisaged as a global reduction of the "immunological space." Concomitantly, immunosenescence results in the progressive generation of cellular mosaicism which is the consequence of the heterogeneous replicative histories and telomere shortening of T and B cell subsets, as well as hemopoietic stem cells. Most of the parameters affected by immunosenescence appear to be under genetic control, and future research on biomarkers should address this point. On the whole, immunosenescence can be taken as a proof that the beneficial effects of the immune system, devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in life, in a period largely not foreseen by evolution. This perspective fits with basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy.

Aging↗
PubMed2004

Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.

Cell Transformation, Neoplastic↗
PubMed2000

Sex, linkage disequilibrium and patterns of parasitism in three species of cyclically parthenogenetic Daphnia (Cladocera: Crustacea).

To gain insight into genetic variation for resistance to parasites, this study assayed clonal variation in cyclically parthenogenetic Daphnia magna with respect to parasitic infection. Samples were collected from natural populations, and the allozyme phenotypes of infected hosts were compared to those of uninfected hosts. Differences between the clonal composition of the infected and uninfected class were evident in only two of 16 populations examined. This result stands in contrast to a study of species in the D. pulex and D. longispina species complexes, where clonal variation for infection was found in 12 of 25 populations (Little & Ebert, 1999). Considering all populations from both studies, associations between host genotype and infection were typically evident only in populations that showed low genotypic diversity and evidence of genetic disequilibria, with D. magna showing the least amount of disequilibria. This pattern is compatible with at least two possibly overlapping hypotheses. First, it may be that those populations lacking clonal variation for infection experienced weaker parasite-mediated selection. We can not rule out variation in selection pressure as an explanation, but found no evidence that the prevalence or intensity of parasitism differed either among species, or between those populations which showed clonal variation for infection and those that did not. Second, it could be that some populations, especially those of D. magna, have more frequent sexual recruitment than others. Sexual recombination breaks up gene combinations which are in linkage disequilibrium, and our method to detect clonal variation for resistance relies on linkage between genetic markers (allozymes) and resistance loci. Past work on Daphnia has shown that the level of sexual recruitment (which is in turn mediated by habitat permanency) is indeed commonly linked to the occurrence of genetic disequilibria. Our results may thus underestimate the prevalence of clonal variation for infection (especially for D. magna), because most of the populations analysed appeared to have high levels of sexual recruitment and therefore lacked the linkage disequilibrium that underlies associations between allozymes and susceptibility.

Animals↗
PubMed2006

Clonal population structure and genetic diversity of Candida albicans in AIDS patients from Abidjan (Côte d'Ivoire).

We have investigated the genotype at 14 enzyme-encoding loci in 275 isolates of the pathogenic yeast Candida albicans sampled from 42 HIV-positive patients (all but one with AIDS) from Abidjan (Côte d'Ivoire). We separately analyzed the following variables: patient, residence, age, gender, T cell count, hospitalization (yes or no), drug treatment, date of sampling, multilocus genotype, and serotype. The most important factors contributing to the genetic variability of C. albicans are individual patient and gender. Our data manifest that the population size of the parasite is relatively small within each patient, although larger in women than in men, and that, at least for the patients involved in the study, the transmission rate of C. albicans between human adults is very low. Most important is the inference that the prevailing mode of reproduction of C. albicans in natural populations is clonal, so that sexual reproduction is extremely rare, if it occurs at all.

AIDS-Related Opportunistic Infections↗
PubMed1995

Colonizing populations of Candida albicans are clonal in origin but undergo microevolution through C1 fragment reorganization as demonstrated by DNA fingerprinting and C1 sequencing.

The genetic homogeneity of nine commensal and infecting populations of Candida albicans has been assessed by fingerprinting multiple isolates from each population by Southern blot hybridization first with the Ca3 probe and then with the 0.98-kb C1 fragment of the Ca3 probe. The isolates from each population were highly related, demonstrating the clonal origin of each population, but each population contained minor variants, demonstrating microevolution. Variation in each case was limited to bands of the Ca3 fingerprint pattern which hybridized with the 0.98-kb C1 fragment. The C1 fragment was therefore sequenced and demonstrated to contain an RPS repetitive element. The C1 fragment also contained part or all of a true end of the RPS element. These results, therefore, demonstrate that most colonizing C. albicans populations in nonimmuno-suppressed patients are clonal, that microevolution can be detected in every colonizing population by C1 hybridization, and that C1 contains the repeat RPS element.

Base Sequence↗
PubMed1985

Kinetic analysis of cloning patterns by human marrow cells in leukemia.

In leukemia and preleukemic disorders the progeny of a single cell proliferate and ultimately come to occupy the hemopoietic system. In the process normal stem cells are suppressed and in time may become extinct. This implies that neoplastic clones have a biological advantage. In this paper evidence is presented that the cloning of granulocytic colony forming cells in the clonal hemopathies is influenced by cell products that regulate cloning of normal colony forming cells. We have attempted to develop an approach to the study of clone-clone interactions in order to determine at what level(s) the battle between clones is fought. Future studies on relative responsiveness might help in understanding the mechanisms by which normal hemopoiesis is suppressed during the evolution of leukemia and re-established during remission induction.

Bone Marrow↗
PubMed2002

Application of information theory and extreme physical information to carcinogenesis.

Cellular information dynamics during somatic evolution of the malignant phenotypes are complex and poorly understood. Accumulating, random genetic mutations and, therefore, loss of genomic information appears necessary for carcinogenesis. However, additional control parameters can be inferred because unconstrained mutagenesis would ultimately produce cellular information degradation incompatible with life. Similarly, the stability of some genomic segments, such as those controlling proliferation and metabolism, indicates the presence of selective mutational constraints. By applying Information Theory and Extreme Physical Information (EPI) analysis, we demonstrate that the phenotypic characteristics and growth pattern of cancer populations are emergent properties resulting from the nonlinear dynamics of accumulating, random genetic mutations and tissue selection factors. Maximum quantitative loss of transgenerational information is demonstrated in genomic segments encoding negative or neutral evolutionary properties. This is most evident in the progressive dedifferentiation observed during carcinogenesis and may terminate in a differentiation "information catastrophe" producing decoherent cellular morphology and function. In contrast, microenvironmental selection pressures preserve genomic information controlling properties that confer selective growth advantages even in the presence of a high background mutation rate. Thus, phenotypic traits characteristically retained by tumor populations can be identified as critical selection parameters favoring clonal proliferation. The information model of carcinogenesis is tested by applying EPI analysis to predict tumor growth dynamics. We found that cellular proliferation attributable to information degradation will produce power law tumor growth with an exponent of 1.62. Data from six published studies that use sequential mammograms to measure the volume of small, untreated human breast cancers demonstrate power law tumor growth with a mean exponent value of 1.73 +/- 0.23. Other predictions including exponential growth of tumor cells in vitro are also supported by experimental observations. The nonlinear dynamics of stochastic information loss constrained by somatic evolution indicate that carcinogenesis will not be associated with any predictable, fixed sequence of genomic alterations. Rather, sporadic clinical cancers are emergent structures produced by multiple, fundamentally nondeterministic genetic pathways.

Animals↗
PubMed2003

Recombination activity of a distinctive integron-gene cassette system associated with Pseudomonas stutzeri populations in soil.

Class 1 integrons have strongly influenced the evolution of multiple antibiotic resistance. Diverse integrons have recently been detected directly in a range of natural environments. In order to characterize the properties of these environmental integrons, we sought to isolate organisms containing integrons from soils, which resulted in the isolation of Pseudomonas stutzeri strain Q. Further isolation efforts targeted at this species resulted in recovery of two other strains (P and BAM). 16S rRNA sequences and chromosome mapping showed that these three strains are very closely related clonal variants in a single genomovar of P. stutzeri. Only strains Q and BAM were found to contain an integron and an associated gene cassette array. The intI and attI components of these strains showed 99 and 90% identity, respectively. The structure of these integrons and their associated gene cassettes was similar to that reported previously for other integron classes. The two integrons contained nonoverlapping sets of cassette-associated genes. In contrast, many of the cassette-associated recombination sites in the two integrons were similar and were considered to constitute a distinct subfamily consisting of 59-base element (59-be) recombination sites (the Pseudomonas subfamily). The recombination activity of P. stutzeri integron components was tested in cointegrate assays. IntIPstQ was shown to catalyze site-specific recombination between its cognate attI site and 59-be sites from antibiotic resistance gene cassettes. While IntIPstQ did not efficiently mediate recombination between members of the Pseudomonas 59-be subfamily and other 59-be types, the former sites were functional when they were tested with IntI1. We concluded that integrons present in P. stutzeri possess recombination activity and represent a hot spot for genomic diversity in this species.

Amino Acid Sequence↗
PubMed2003

Extended lifespan of Barrett's esophagus epithelium transduced with the human telomerase catalytic subunit: a useful in vitro model.

As there has been no previous information on the consequences of telomerase expression in genetically altered, mortal cells derived from pre-malignant tissue, we sought to determine the effect of hTERT (human catalytic subunit of telomerase reverse transcriptase) transduction of pre-malignant cell strains from Barrett's esophagus that do not contain telomerase activity and possess a finite lifespan. Primary cultures of Barrett's esophageal epithelium transduced with a retrovirus containing hTERT were characterized by growth factor requirements, cytogenetics and flow cytometry. Expression of telomerase lengthened telomeres and greatly extended the lifespan of hTERT transduced (hTERT+) Barrett's esophagus cells. Growth factor dependency of the hTERT+ cultures remained largely similar to the parental cultures, although there was a modest increase in the ability to grow in agar. Chromosomal instability, measured by both karyotypic and FISH (fluorescence in situ hybridization) analyses, was reduced but not abrogated by hTERT transduction, suggesting that telomerase expression can enhance genomic stability. However, the persistence of residual instability gave rise to new clonal and non-clonal genetic variants, and in one hTERT+ culture a new DNA aneuploid population was observed, the only time such a ploidy shift has been seen in Barrett's cell strains in vitro. These in vitro observations are analogous to the clinical progression to aneuploidy that often precedes cancer in Barrett's esophagus, and suggest that reactivation of telomerase may be permissive for continued genetic evolution to cancer. Long-lived Barrett's esophagus epithelial cultures should provide a useful in vitro model for studies of neoplastic evolution and chemopreventive therapies.

Barrett Esophagus↗
PubMed2001

Diversity of SHV and TEM beta-lactamases in Klebsiella pneumoniae: gene evolution in Northern Taiwan and two novel beta-lactamases, SHV-25 and SHV-26.

A total of 113 blood culture isolates of Klebsiella pneumoniae from 10 hospitals in northern Taiwan were studied for SHV and TEM beta-lactamase production. bla(SHV) was amplified from all isolates by PCR. TEM-type resistance, was found in 32 of the isolates and was of the TEM-1 type in all isolates. SHV-1, -2, -5, -11, and -12 and two novel enzymes were identified. These novel enzymes were designated SHV-25 and SHV-26 and had pIs of 7.5 and 7.6, respectively. Amino acid differences in comparison to the amino acid sequence of bla(SHV-1) were found at positions T18A (ThrACC-->AlaGCC), L35Q (LeuCTA-->GluCAA), and M129V (MetATG-->ValGTG) for SHV-25 and at position A187T (AlaGCC-->ThrACC) for SHV-26. The results of substrate profiles and MIC determinations showed that the novel enzymes did not hydrolyze extended-spectrum cephalosporins, rendering the isolates susceptible to these agents. Inhibition profiles revealed that the 50% inhibitory concentration for SHV-26 was higher than those for SHV-1 and SHV-25, resulting in an intermediate resistance to amoxicillin-clavulanic acid. Forty-nine ribotypes were identified, suggesting that major clonal spread had not occurred in any of the hospitals. According to the amino acid sequence, SHV beta-lactamases in Taiwan may basically be derived through stepwise mutation from SHV-1 or SHV-11 and further subdivided by four routes. The stepwise mutations initiated from SHV-1 or SHV-11 to SHV-2, SHV-5, and SHV-12 comprise the evolutionary change responsible for extended-spectrum beta-lactamase (ESBL) production in Taiwan. The stepwise mutations that lead to a non-ESBL (SHV-25) and the beta-lactamase (SHV-26) with reduced susceptibility to clavulanic acid are possibly derived from SHV-11 and SHV-1, respectively. The results suggest a stepwise evolution of SHV beta-lactamases in Taiwan.

Automation↗
PubMed1989

Unusual karyotypic evolution in subacute myelomonocytic leukemia in two monozygotic twins.

A subacute myelomonocytic leukemia was diagnosed in 28-month-old cotwins. At this age, their spontaneously dividing cells had a normal karyotype. A few months later, after treatment with 6-mercaptopurine, the following karyotypes were observed: 50,XX, +X, +13, +19, +21 in one and 51,XX, +X, +X, +10, +19, +21 in the other. After bone marrow transplantation, both relapsed although they had received high doses of chemo- and radiotherapy. One developed a clone 46,XX,del(20q), which acquired other clonal rearrangements. The other child developed two different abnormal clones, both with unbalanced rearrangement of chromosome 13. Some of these clones may correspond to immature erythroblasts. The gain of chromosomes, especially for #13, which occurred independently in the cotwins by various mechanisms and at different periods during the disease, is very striking. It may indicate the existence of a strong selective advantage for trisomic 13 cells and may be related to the genetic constitution of the patients.

Bone Marrow Transplantation↗
PubMed2006

Paired-end sequence mapping detects extensive genomic rearrangement and translocation during divergence of Francisella tularensis subsp. tularensis and Francisella tularensis subsp. holarctica populations.

Comparative genome hybridization of the Francisella tularensis subsp. tularensis and F. tularensis subsp. holarctica populations have shown that genome content is highly conserved, with relatively few genes in the F. tularensis subsp. tularensis genome being absent in other F. tularensis subspecies. To determine if organization of the genome differs between global populations of F. tularensis subsp. tularensis and F. tularensis subsp. holarctica, we have used paired-end sequence mapping (PESM) to identify regions of the genome where synteny is broken. The PESM approach compares the physical distances between paired-end sequencing reads of a library of a wild-type reference F. tularensis subsp. holarctica strain to the predicted lengths between the reads based on map coordinates of two different F. tularensis genome sequences. A total of 17 different continuous regions were identified in the F. tularensis subsp. holarctica genome (CR(holar)(c)(tica)) which are noncontiguous in the F. tularensis subsp. tularensis genome. Six of the 17 different CR(holarctica) are positioned as adjacent pairs in the F. tularensis subsp. tularensis genome sequence but are translocated in F. tularensis subsp. holarctica, implying that their arrangements are ancestral in F. tularensis subsp. tularensis and derived in F. tularensis subsp. holarctica. PCR analysis of the CR(holarctica) in 88 additional F. tularensis subsp. tularensis and F. tularensis subsp. holarctica isolates showed that the arrangements of the CR(holarctica) are highly conserved, particularly in F. tularensis subsp. holarctica, consistent with the hypothesis that global populations of F. tularensis subsp. holarctica have recently experienced a periodic selection event or they have emerged from a recent clonal expansion. Two unique F. tularensis subsp. tularensis-like strains were also observed which likely are derived from evolutionary intermediates and may represent a new taxonomic unit.

Biological Evolution↗
PubMed1999

Restricted diversification of T-cells in chronic active Epstein-Barr virus infection: potential inclination to T-lymphoproliferative disease.

To assess the abnormal T-cell expansion in chronic active Epstein-Barr virus infection (CAEBV), T-cell antigen receptor (TCR) repertoire was analyzed in four patients with the disease. All fulfilled the diagnostic criteria of CAEBV, presenting with fever, hepatosplenomegaly, cytopenia, abnormal high titers of anti EBV-antibodies, and positive EBV genome of unknown cause. Southern blotting probed with EBV-terminal repeats and TCR Cbeta gene indicated clonal expansion of the infected cells in 3 and 2 patients, respectively. The number of CD4+ HLA-DR+ cells appreciably increased in patients 1 (59%) and 2 (24%), who had a coronary aneurysm and central nervous system involvement, respectively. TCR gene expression examined by the inverse polymerase chain reaction methods revealed that Vbeta gene usages were preferential in all patients (Vbeta7 and Vbeta12: patient 1, Vbeta4: patient 2, Vbeta13: patients 3 and 4), compared with those in healthy controls. Valpha18 gene expression was remarkably high in patients 1 and 2. Moreover, Jbeta gene expression was skewing in the reigning Vbeta clones in all patients. Vbeta4-Jbeta1.5 and Vbeta13-Jbeta1.5 genes were clonally expressed in patients 2 and 4, respectively. These results suggest that CAEBV is associated with the restricted diversity of T-cells, which may stem from the sustained expansion of oligoclonal T-cells possibly driven by conventional viral antigens, but not, superantigens. Although the study is limited by the small number of patients, the unbalanced T-cell repertoire might contribute to the evolution of T-lymphoproliferative disease, otherwise, imply the innate defective immunity to EBV in CAEBV patients.

Adolescent↗
PubMed2002

Multivariate analysis of chromosomal imbalances in breast cancer delineates cytogenetic pathways and reveals complex relationships among imbalances.

More than 550 breast adenocarcinomas with clonal chromosomal abnormalities have been reported. Although the aberration pattern is clearly nonrandom, no specific primary or secondary karyotypic abnormality has been identified, and furthermore the chronological order in which the aberrations appear during disease progression is not well known. The high degree of karyotypic complexity in epithelial tumors such as breast cancer is one reason why our understanding of the sequential order of cytogenetic evolution is unclear. To overcome some of these difficulties, we have used several statistical methods that allow identification and interpretation of karyotypic pathways. These methods were applied on 538 breast cancer karyotypes. The distribution of the number of imbalances/tumor showed a monomodal appearance, indicating that one single mode of karyotypic evolution is operating in this tumor type. We show that there exists a temporal order with respect to the appearance of chromosomal imbalances. The imbalances +1pq, 1q-, 3p-, and +7 appear earlier than expected from random events, and two cytogenetic pathways, one initiated by +1q and followed by 11q- and -22, the other initiated by either 3p- or 1q- and followed by 1p-, 3q-, and 6q-, can be discerned. We also show that +7 and +8q behave independently of the other imbalances and cannot, by simple means, be incorporated in the identified pathway scheme. Although the cytogenetic pathways are well separated at earlier stages, they later converge and include a common set of late imbalances.

Adenocarcinoma↗
PubMed2002

Genomic abnormalities in monoclonal gammopathy of undetermined significance.

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Delta 13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain-lambda (IgL-lambda, and Delta 13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-lambda translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Delta 13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Delta 13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.

Aneuploidy↗
PubMed1992

Mechanisms of human carcinogens.

Mutational mechanisms can be proposed as contributing to the activity of most human carcinogens. Many of these chemicals are electrophilic or are metabolically activated to reactive molecules that can alter DNA. Even human carcinogens that do not exhibit direct chemical interaction with DNA, e.g., hormones and asbestos, have been shown to induce genetic effects when in vitro assays for chromosomal mutations are employed. Since these chemicals are usually inactive in the Salmonella assay and other gene mutational assays, more emphasis has been placed on their nonmutational mechanisms. Evidence exists that these carcinogens alter gene expression and stimulate cell proliferation by epigenetic mechanisms; such properties almost certainly contribute to the carcinogenic activity of these chemicals. Although less well studied, DNA reactive, genotoxic carcinogens also alter gene expression and cell proliferation by epigenetic mechanisms. These findings are consistent with the current understanding of the molecular basis of multistep carcinogenesis. The neoplastic evolution of most common human cancers occurs as the result of multiple mutational events. The molecular basis for these mutations is varied and includes point mutations, deletion mutations, chromosome rearrangements, gene amplification, and chromosome losses and gains. Therefore, different mutational activities of carcinogens may influence the carcinogenic process at different steps. In addition, chemical influences on gene expression and cell proliferation are important in allowing clonal expansion of preneoplastic cells and in disrupting the suppressive effects of surrounding normal cells on preneoplastic cells (Dotto et al., 1988). Therefore, the mechanisms of action of human carcinogens, and very likely many rodent carcinogens, will include both genetic and epigenetic processes.

Animals↗
PubMed2004

Assessment of evolution of pandemic Vibrio parahaemolyticus by multilocus sequence typing.

The genetic relatedness of 81 isolates of Vibrio parahaemolyticus was assessed by multilocus sequence typing. The strain with serotype O3:K6 emerged as a pandemic pathogen in 1996, with subsequent expansion to include strains having serotypes O1:KUT, O4:K68, and O1:K25. Sequence data from gyrB, recA, dnaE, and gnd revealed that 16 distinct serogroups isolated prior to the pandemic were highly variable and only isolates of serogroup O3:K6 shared two alleles with the pandemic strains. The pandemic strains regardless of serotype were clonal, with 51 of 54 isolates having the identical allelic profile (AP). Serotype alone did not adequately define a pandemic strain: among O1:KUT strains tested, seven strains with the identical pandemic AP carried previously described pandemic markers, while five nonpandemic strains had five distinct APs. Our sequence data provide strong molecular support for the clonal origin of pandemic V. parahaemolyticus O3:K6 and suggest that strains within such a clonal group may acquire previously identified serotypes.

Genes, Bacterial↗