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PubMed1996

The construction of a stable starch-fermenting yeast strain using genetic engineering and rare-mating.

To develop a yeast strain that is able to produce ethanol directly from starch, alpha-amylase cDNA (originated from mouse salivary glands) was introduced into the hyploid Saccharomyces diastiticus cells secreting glucoamylase by using a linearized integrating vector. The integrating vector contains a LEU2 gene and the inside of the LEU2 gene was cut by KpnI to make the linearized vector. One of the transformants exhibited 100% mitotic stability after 100 generations of cell multiplication. To improve its ethanol-fermentability, the haploid transformant was rare-mated with a polyploid industrial strain having no amylase activity. The resulting hybrid RH51 produced 7.5 (w/v) ethanol directly from 20% (w/v) soluble starch and its mitotic stability was 100% at the end of fermentation.

Animals↗

PubMed1982

Development of tetraploidy in V79 spheroids.

Chinese hamster V-79-171 cells, when placed in suspension culture, spontaneously form multicell spheroids. As the spheroids enlarge the fraction of polyploid (predominantly tetraploid) cells increases and can approach 100% in very large spheroids. Spheroid size, rather than age, seems to be a major determinant for increased ploidy. When cell separation techniques were used to select enriched populations of diploid and tetraploid cells, the growth rate and plating efficiency of the diploid cells was always marginally higher, and they gradually became predominant in mixed monolayer cultures. Cloned tetraploid cells, however, generally remained quite stable, and no consistent ploidy dependent changes in radiosensitivity were observed relative to normal, diploid cell lines.

Animals↗

PubMed1978

Human hepatocytes and aging: a cytophotometrical analysis in 35 sudden-death cases.

Alterations in the nuclear and cellular size of human hepatocytes occurring with age, and particularly in senescence, were studied by microphotometry. The material studied was obtained in 35 cases of sudden death, involving 17 males and 18 females ranging in age from 16 to 100 years. Cells of the peripheral zones of hepatic lobules were analyzed. The following results were obtained: 1. The mean nuclear area of hepatocytes remained relatively constant in subjects under 60 years of age but showed an increase in those over 60, this increase being associated with a greater standard deviation. 2. Volumetric analysis showed that the modal value included between 61 and 100% (mean 86%) of the cell nuclei examined and did not increase with age. This cell population was presumed to consist of diploid cells, the size of which remained constant. 3. An increase in mean nuclear area was due to the appearance of cells with larger nuclei which probably were the result of polyploidization. 4. Hepatocyte size increased with age. Analysis of the nucleus-to-cell sizes showed that the increase in cell size with age was more significant than the increase in nuclear size. 5. Cellular enlargement was more closely correlated with decrease in gross liver weight than with nuclear enlargement.

Adolescent↗

PubMed1977

Nuclear DNA of myocardial cells in the periphery of infarctions and scars.

In 20 hearts the enlargement of muscle fibers and the increase in nuclear DNA is studied in the periphery of fresh and healed infarctions. The data of attack is verified by ECG records in most cases, five had passed undiagnosed. Selective cytophotometry is performed by measuring the largest nucleus in each of 50 fields of comparable density. Since significant differences in polyploidization exist between the control regions of hearts of similar weight primarily regions of the same heart are compared. No differences are observed in five hearts with infarctions about one week old. After five to six months the enlargement of the fibers is significaant (P less than 0.0005) while the increase in polyploidy is still slight (P less than 0.15). In all cases with scars one to nine years old the enlargement of fibers is significant (P less than 0.0005) while the increase in DNA is significant in most of them (5 X P less than 0.0005, 3 X P less than 0.005, 2 X P less than 0.01). In a case with two lesions, one posterior five (P less than 0.0005) and one anterior seven years old (P less than 0.0005), there is still slight increase in polyploidy with age (P less than 0.1). In the five undiagnosed cases only one has no significant increase in DNA. There is no correlation found between the enlargement of fibers and the increase in polyploidy in this limited number of cases.

Adult↗

PubMed1983

DNA ploidy-characteristics of human malignant melanoma analysed by flow cytometry and compared with histology and clinical course.

Flow cytometric analysis of nuclear DNA content is valuable for indicating ploidy- and proliferation abnormalities in surgically removed human malignant melanomas. In 35 primary cutaneous melanomas, 20 metastases of melanoma in skin and lymph nodes, and 16 nevi the DNA distribution was analyzed by flow cytometry and compared with a variety of histological parameters and the subsequent clinical course. Heteroploid DNA distributions with increased polyploid or aneuploid fractions were found in 26 primary melanomas (74%), 14 metastases (70%), and 4 nevi (25%) indicating tumor clones with an abnormal nuclear DNA content. Three or more cell clones in a single biopsy was found in 10 primary melanomas, 2 metastases, and 1 nevus. The frequency of heteroploidy was significantly higher in primary and secondary melanomas than in nevi (p less than 0.001) and was correlated significantly with a high mitotic activity (p less than 0.002), marked nuclear pleomorphism (p less than 0.01), large nucleoli (p less than 0.01) and a thickness of the primary melanoma of more than 2.25 mm (p less than 0.02). Such histologic findings in malignant melanomas have been shown previously to be correlated with a bad prognosis. No significant correlation was found between heteroploidy and the histologic type of melanoma or the level of invasion. A 2-year clinical follow-up showed that more patients died from melanoma if the DNA distribution in the primary or secondary melanoma was heteroploid (6/26; 23% and 8/13; 62% respectively) than if it was diploid (0/9; 0% and 2/5; 40% respectively). However, the differences were not statistically significant. It is concluded that heteroploidy 1) is not an absolute criterion of malignancy, 2) is significantly correlated with histologic features indicating marked cellular anaplasia, and 3) is apparently correlated with a bad prognosis.

Adolescent↗

PubMed1981

Effects of PUVA on a human skin epithelial cell line.

An established human epithelial cell line was exposed to photoactivated 8-methoxy psoralen (PUVA) during exponential growth. Effects of PUVA treatment on cell growth were measured by cell kinetic methods (counting of cell numbers, flow cytometric measurements (FCM) of DNA and calculations of labelling indices (LI)). Doses of 8-methoxy psoralen and UVA were comparable to those used in patients. The cell number in PUVA treated cultures remained almost constant, and very few mitoses were seen for 144 h. About 9 h after PUVA, both FCM and LI showed an increase in the fraction of cells in S-phase, reaching a maximum of 85-90% after 24 h. DNA synthesis took place at a low rate in these cells. FCM showed an increasing fraction of polyploid cells after PUVA treatment. The possibility that inhibition of cell proliferation is one of the main effects of PUVA, is discussed.

Cell Count↗

PubMed1982

Age-related alterations in the size of human hepatocytes. A study of mononuclear and binucleate cells.

Age-related alterations in the size of human hepatocytes (both mononuclear and binucleate forms), were studied in histological sections and in separated cells and nuclei using cytophotometrical and microspectrophotometrical methods. The following results were obtained: 1. The volume of nuclear DNA increased in proportion to nuclear size. The increase occurred in a group pattern reflecting nuclear polyploidization. 2. Cell size increased in proportion to nuclear size. Tetraploid cells (4C) were roughly two times greater than diploid cells (2C). 3. In most of the binucleate cells examined, the ploidy class of the two nuclei in a binucleate cell was observed to be equal. Heterogeneity of the ploidy class among the nuclei of a binucleate cell was present in less than 1% of total binucleate cells examined. The nuclear DNA volume of individual nuclei in binucleate cells appeared to be the same as that of mononuclear cells. 4. The cell size of binucleate cells corresponded with that of mononuclear cells whose ploidy class was the same as the sum of the ploidy classes of two nuclei of a binucleate cell. 5. The incidence of binucleate cells in the lobular periphery was about 4 to 6% in the third decade, and increased slightly with age up to 5 to 7% in the tenth decade. 6. The incidence of binucleate cells in the liver at different ages followed a similar pattern to that observed in mononuclear cells whose ploidy class was half of the sum of ploidy classes of the two nuclei of the binucleate cell.

Adult↗

PubMed1976

Karyometric and cytophotometric studies on nucleic acids in the culture of human lymphocytes with phytohemagglutinin.

Lymphocyte transformation with phytohemagglutinin (PHA) was analyzed by karyometry and cytophotometry of single cells. The former showed the distribution of various-sized transforming cells, and the latter the increase of DNA and RNA. Two different types of karyograms were obtained; one with three peaks corresponding to 2c, 4c, and 8c, and the other with only a 2c peak. Although small in number (8%), karyometry showed that DNA synthesis took place in the extremely early stage of transformation, 1 h after stimulation with PHA, which was proved by cytophotometry and ultrastructural findings. An increasing curve of DNA and RNA revealed that a lymphocyte continued to enlarge from 2c to 4c and divide again through the normal cell cycle in a suitable condition. The largest blast cell, a polyploid cell, may be induced by the lack of a sufficient amount of RNA and protein in need of cell division, and may be a degenerative cell in the strict sense. Among the large cells with blastlike appearance, there were a considerable number of so-called degenerative cells with a low amount of DNA. The ratio of RNA to DNA increased steeply in the actively DNA synthesizing S phase, which supports the morphologic findings of blast cell, the appearance of basophilic cytoplasm, and active-looking nucleoli.

Adolescent↗

PubMed1993

Establishment, characterization and drug sensitivity of a new anaplastic thyroid carcinoma cell line (BHT-101).

A thyroid carcinoma cell line, BHT-101, has been established in vitro from a metastatic lymph node deposit in a female patient with a non-hormone producing anaplastic, partly thyroglobulin- and thyroxine (T4)-positive papillary thyroid cancer. The cell population is heterogeneous, containing epithelial-like and fibroblast-like cells, and has a doubling time of 24 h. The cell line is polyploid with hypertetraploid predominance and the karyotype showed trisomies, tetrasomies, pentasomies as well as many marker chromosomes. The majority of the cells are negative or weakly positive for thyroglobulin and thyroxine and estrogen and progesterone receptors are present in the cells. BHT-101 cells produce tumours when injected into immunosuppressed CBA/Ca mice. The cells are sensitive to adriamycin, methotrexate and tamoxifen but not to methimazole (Favistan). The epithelial-like clone 1 and the fibroblast-like clone 3, isolated from the parental line, differed in drug sensitivity. This new cell line is suitable for studying the biology of thyroid carcinoma and for parallel in vivo and in vitro studies of drug activity against thyroid cancer.

Animals↗

PubMed1985

Ploidity and cell cycle progression during treatment with gold chloride, auranofin and sodium aurothiomalate. Studies on a human epithelial cell line and its sub-strains made resistant to the antiproliferative effects of these gold compounds.

The possible influence of gold(III) chloride and the two gold(I)-containing anti-arthritic drugs, auranofin and sodium aurothiomalate, on cellular ploidity and cell cycle progression was investigated on cultured human epithelial cells. Four different cell lines were used: the parent line (HE) and three sub-strains which previously had acquired resistance to the antiproliferative effects of either 350 mumol gold chloride/l culture medium (HEAu350), 2 mumol auranofin/l (HEAF) or 300 mumol sodium aurothiomalate/l (HEMyo). DNA-histograms were obtained by flow cytometry examinations during a 9-days' exposure to either of these gold-containing compounds and concentrations. The HE, HEAF and HEMyo cells had similar ploidities, close to tetraploid. The HEAu350 cells had altered ploidity to distinct tetraploid. The distribution of the resistant cells with the cell cycle phases was not different from that of untreated HE cells. The HE cells, when treated with auranofin or sodium aurothiomalate, accumulated in the G2-phase of the cell cycle. In addition, a new cedecoploid peak appeared. No such changes were observed on gold chloride exposure or in HE controls grown without drug supplement. The effects of auranofin and sodium aurothiomalate on cell cycle progression of the HE cells possibly indicate a tendency to polyploidity, and furthermore that inhibition of cellular mitosis is one mechanism of the antiproliferative effect common to the two drugs.

Auranofin↗

PubMed1985

Cytogenetical changes during early stages of development of methotrexate resistance in HeLa cells.

HeLa cells cultured in ever-increasing doses of methotrexate (MTX) acquired resistance to this drug. Chromosomal changes occurring at early stages during the development of resistance to various doses (0.1, 0.3, 0.5, 1.0, 2.1, 3.0, 10.0 and 100.0 micrograms/ml) of MTX included: (a) an increase in the percentage of hypertetraploid cells (greater than 92 chromosomes) at all doses, and most profoundly at 1.0, 2.1 and 3.0 micrograms/ml; (b) an increase in the percentage of cells with structural abnormalities; (c) a remarkable increase in the percentage of hypertetraploid cells containing dicentrics, particularly at MTX dose levels 0.5-3.0 micrograms/ml and (d) emergence of increasing numbers of double minutes per cell with increasing MTX doses. At dose levels 2.1 and 3.0 micrograms/ml the modal chromosome number increased to 82, while at 0.1-1.0 microgram/ml it was similar to the mode of sensitive HeLa (64, 66) and at 10.0 and 100.0 micrograms/ml dropped to 62, 63. The results obtained suggest that polyploidization and formation of dicentrics are associated with the earlier stages of development of resistance to methotrexate.

Cells, Cultured↗

PubMed2002

Thrombopoietin: from theory to reality.

Much is now known about the physiology of platelets and their role in primary hemostasis; however, until recently far less was understood about their immediate precursors, marrow megakaryocytes (MKs). With the cloning and characterization of thrombopoietin (TPO), the principle regulator of the growth and development of MKs, research has been rapid and broad-based. In several laboratories TPO was cloned based on it's binding to the product of the proto-oncogene c-mpl, at the time an orphan cytokine receptor, and was subsequently found to affect nearly all aspects of thrombopoiesis. Many of the molecular pathways that mediate TPO action have been explored. Like all other members of the hematopoietic cytokine receptor family upon hormone binding members of the JAK family of kinases are activated, which, in turn, phosphorylate the TPO receptor, generating docking sites for second messengers that affect multiple signaling pathways. Ultimately, cellular proliferative and anti-apoptotic mechanisms are initiated, increasing MK numbers, and a process termed endomitosis (EnM) begins, generating large, highly polyploid cells. The net result is the expansion of cells that give rise to mature platelets, a process that can be accentuated by the therapeutic administration of the hormone to thrombocytopenic patients.

Humans↗

PubMed1999

Phylogenies of developmentally important proteins do not support the hypothesis of two rounds of genome duplication early in vertebrate history.

It has been proposed that two rounds of duplication of the entire genome (polyploidization) occurred early in vertebrate history (the 2R hypothesis); and the observation that certain gene families important in regulating development have four members in vertebrates, as opposed to one in Drosophila, has been adduced as evidence in support of this hypothesis. However, such a pattern of relationship can be taken as support of the 2R hypothesis only if (1) the four vertebrate genes can be shown to have diverged after the origin of vertebrates, and (2) the phylogeny of the four vertebrate genes (A-D) exhibits a topology of the form (AB) (CD), rather than (A) (BCD). In order to test the 2R hypothesis, I constructed phylogenies for nine protein families important in development. Only one showed a topology of the form (AB) (CD), and that received weak statistical support. In contrast, four phylogenies showed topologies of the form (A) (BCD) with statistically significant support. Furthermore, in two cases there was significant support for duplication of the vertebrate genes prior to the divergence of deuterostomes and protostomes: in one case there was significant support for duplication of the vertebrate genes at least prior to the divergence of vertebrates and urochordates, and in one case there was weak support for duplication of the vertebrate genes prior to the divergence of deuterostomes and protostomes. Taken together with other recently published phylogenies of developmentally important genes, these results provide strong evidence against the 2R hypothesis.

Animals↗

PubMed1996

The KEULE gene is involved in cytokinesis in Arabidopsis.

We present evidence to show that the KEULE gene of Arabidopsis is involved in cytokinesis. Mutant keule embryos have large multinucleate cells with gapped or incomplete cross walls, as well as cell wall stubs that are very similar to those observed upon caffeine inhibition of cytokinesis in plants. These defects are observed in all populations of dividing cells in the mutant, including calli, but less frequently in mature cells. Cell division appears to be slowed down, and the planes of cell division are often misoriented. In late embryos and seedlings, cross-wall formation usually appears complete, suggesting that the requirement for KEULE during cytokinesis is not absolute. Nonetheless, keule mutants die as seedlings with large polyploid cells. The bloated surface layer of keule seedlings does not uniformly behave like wild-type epidermis, and patches of this layer assume characteristics of the underlying ground tissue. The cytokinesis defect of keule mutants may influence aspects of cellular differentiation.

Arabidopsis↗

PubMed2003

Chromosomal territory segmentation in apoptotic cells.

The nuclear architecture of selected chromosomes in apoptotic nuclei of human leukemic cells K-562 and HL-60 was investigated. Etoposide and prolonged confluence were used for the induction of apoptosis. DAPI as well as TUNEL labeling of apoptotic nuclear bodies was combined with visualization of chromosomal territories by the FISH technique. Simultaneous vital staining by annexin V, propidium iodide, and Hoechst 33342 was applied to distinguish apoptotic, necrotic, and intact cell fraction of tested populations. Our FISH analyses revealed that the three-dimensional (3D) structure of apoptotic nuclei as well as the 3D structure of apoptotic bodies is preserved in formaldehyde-fixed cells. High-molecular-weight DNA fragmentation was determined in apoptotic K-562 cells in contrast to oligonucleosomal cleavage observed in apoptotic HL-60 cells. In K-562 populations, chromosomal territories were located separately either in one apoptotic body or underwent disassembly into chromosomal segments dispersed into single and/or several apoptotic bodies. The apoptotic disorganization of chromosomal territories was irregular, leading mainly to chromosomal segments of different sizes and, consequently, chromosomal disassembly was not observed at specific sites. In comparison with the control, an increased number of centromeric FISH signals were observed in prolonged confluence-treated K-562 cells induced to apoptosis. This finding can be explained either as a consequence of apoptosis or by polyploidization. Sequential staining of the same apoptotic nuclei by the FISH and TUNEL techniques revealed that chromosomal territory segmentation precedes the formation of nuclear apoptotic bodies.

Apoptosis↗

PubMed1998

[Retrospective analysis of selected tumor markers (p53, PCNA, Ki67; DNA ploidy) and ultrastructure in patients with larynx carcinomas].

A comparison was made of the staining intensities of selected immunohistochemical proliferating antigens (p53, PCNA, Ki67), DNA flow-cytometry and ultrastructures of neoplastic cells from 120 cases of laryngeal cancers. Clinically very advanced tumors were in the majority (T3, 43%; T4, 18%). A 5-grade scale was adopted to evaluate the level of immunohistochemical staining of the carcinoma cell nuclei. Positive staining was obtained in 70% for p53, 57% for Ki67 and 80% for PCNA. Sixty-two percent of the cases were DNA-diploid and 38% DNA-aneuploid. The DNA-diploid carcinomas were accompanied by enlargement of the cell nuclei, preservation of wide margins of nuclear heterochromatin, enlargements of the nuclear areas and increases in the number of nuclei. In the aneuploid-polyploid cancers the nuclei had a substantial polymorphism, with large cleaved nuclei showing significant variations in size and having a nuclear envelope. A frequent finding was euchromatization of chromatin. Dense chromatin appeared in the form of small clumps spread over the whole area of these irregular nuclei. Enlargement and activation of nucleoli were found. There was a positive (chi-square) correlation between T- and N-stage and immunohistochemical staining. There was also a positive correlation in staining intensity between p53, Ki67 and PCNA markers and strong correlation between these markers for proliferative activity and the degree of aggressiveness of a tumor.

Biomarkers, Tumor↗

PubMed2002

Studies on the origin and evolution of tetraploid wheats based on the internal transcribed spacer (ITS) sequences of nuclear ribosomal DNA.

In this study, the internal transcribed spacer (ITS) sequences of nuclear ribosomal DNA in the tetraploid wheats, Triticum turgidum (AABB) and Triticum timopheevii (AAGG), their possible diploid donors, i.e., Triticum monococcum (AA), Triticum urartu (AA), and five species in Aegilops sect. Sitopsis (SS genome), and a related species Aegilops tauschii were cloned and sequenced. ITS1 and ITS2 regions of 24 clones from the above species were compared. Phylogenetic analysis demonstrated that Aegilops speltoides was distinct from other species in Aegilops sect. Sitopsis and was the most-likely donor of the B and G genomes to tetraploid wheats. Two types of ITS repeats were cloned from Triticum turgidum ssp. dicoccoides, one markedly similar to that from T. monococcum ssp. boeoticum (AA), and the other to that from Ae. speltoides (SS). The former might have resulted from a recent integression event. The results also indicated that T. turgidum and T. timopheevii might have simultaneously originated from a common ancestral tetraploid species or be derived from two hybridization events but within a very short interval time. ITS paralogues in tetraploid wheats have not been uniformly homogenized by concerted evolution, and high heterogeneity has been found among repeats within individuals of tetraploid wheats. In some tetraploid wheats, the observed heterogeneity originated from the same genome (B or G). Three kinds of ITS repeats from the G genome of an individual of T. timopheevii ssp. araraticum were more divergent than that from inter-specific taxa. This study also demonstrated that hybridization and polyploidization might accelerate the evolution rate of ITS repeats in tetraploid wheats.

Journal Article↗

PubMed2002

Pitfalls of genetic analysis using a doubled-haploid backcrossed to its parent.

A population derived from a doubled-haploid backcrossed to its parent has a unique genetic structure, which affects the mapping and genetic analysis of molecular-marker data. In such a cross: (1) repulsion linkages are reduced dramatically and can be detected only in restricted chromosome sections; each repulsion-linkage group represents a section of a chromosome carrying a crossover that occurred in the meiosis that produced the gamete from which the doubled-haploid was derived; (2) the number of coupling-linkage groups observed depends on how many crossovers occurred during the meiosis; the observed size of a linkage group will be only a fraction of a total chromosome if the chromosome carried in the doubled-haploid resulted from crossover exchanges; (3) the size covered by all the observed linkages is only equivalent to the haploid genome; and (4) the ratio of single-dose to multi-dose markers is inflated. These features have not been recognized in previous reports, resulting in misinterpretations in genetic mapping and analysis of the molecular-marker data. The ratio of single- to multi-dose markers has been used inappropriately to distinguish polyploid type.

Journal Article↗