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PubMed2003

Monitoring cell cycle distributions in living cells by videomicrofluorometry and discriminant factorial analysis.

BACKGROUND: The study of the cell cycle of living cells is often based on quantification of nuclear DNA. These studies may be improved by multifactorial analysis evaluating several parameters for each cell. METHODS: Single lymphoblastoid living cells were labeled with three fluorescent markers: Hoechst 33342 for nuclear DNA, Rhodamine 123 for mitochondria, and Nile Red for plasma membrane. Numerical image analysis allowed us to obtain, for each cell, morphological parameters (e.g., cell size, nuclear size, and shape) and functional information (e.g., nuclear DNA content, level of mitochondria energetic state, and the amount and properties of the plasma membrane) by fluorescence intensity. These parameters were used in a typological analysis that separated control cells into four groups. RESULTS: A discriminant factorial analysis (DFA) confirmed the four groups: G0-G1, S, G2+M, and polyploid cells called Gn. These groups were significantly different, with a classification probability of 0.9999; these control cells defined a learning population. Different populations of untreated and adriamycin-treated cells were analyzed as additional individuals within a DFA and were classified into the G0-G1, S, G2+M, and Gn groups by their probability of belonging to each of the groups. CONCLUSIONS: This approach is particularly efficient when it is used to determine variations in cellular properties and to objectively study cellular populations.

Cell Cycle↗
PubMed1994

Morphologic and morphometric features of low grade serous tumours of the ovary.

Peritoneal washings from twelve patients with serous tumours of the ovary were studied. Six patients had borderline serous tumours (BSTs), and six had grade one adenocarcinomas. Papanicolaou stained slides were assessed for nine morphologic parameters; background, single cells, size of papillary fragments, contour of papillary fragments, psamomma bodies, cytoplasmic vacuoles, nuclear pleomorphism, nuclear membrane contour, and nucleoli. The slides were destained and restained by the Feulgen method for assessment, with a computer based image analysis system (CAS100, Cell Analysis Systems, Inc., Elmhurst, IL), of DNA content, nuclear size, and nuclear roundness. The contour of the papillary fragments (P = 0.004) and the presence of nuclear pleomorphism (0.019) were distinguishing characteristics. All six BSTs were diploid while three of the six adenocarcinomas had aneuploidy. Two exhibited polyploid DNA distribution and one exhibited diploid DNA distribution. The pooled data for the nuclear size and roundness showed little difference in the modal values, although the nuclei of the adenocarcinoma cells were slightly larger than those of the borderline cells (54 sq. microns vs. 46 sw. microns). However, the coefficients of variation (CVs) for each of these parameters were larger in the adenocarcinoma group than in the borderline group (59.7 vs. 36.4% for size and 33.5 vs. 17.8% for roundness). Although the sample size is small, the data suggest that aneuploidy is rare in borderline tumours. In addition, the presence of papillary groups with irregular contours and nuclear pleomorphism (reflected in higher CVs for nuclear size and roundness) both occur more commonly in adenocarcinomas than in borderline tumours and may be of predictive value in distinguishing the two groups.

Cystadenocarcinoma, Papillary↗
PubMed1997

Conservation of a master hematopoietic switch gene during vertebrate evolution: isolation and characterization of Ikaros from teleost and amphibian species.

The generation of T, B and NK lymphocyte lineages from pluripotent hematopoietic stem cells is dependent upon the early expression of the Ikaros locus which by means of alternative splicing produces a variety of zinc finger DNA binding transcription factors. We assessed the general biological importance of Ikaros by studying its conservation and expression in teleost fish and amphibians. Portions of Ikaros cDNA from rainbow trout and Xenopus were amplified by reverse transcription-polymerase chain reaction (RT-PCR). They show roughly 75% conservation of the amino acid sequence with mammalian Ikaros. The trout fragment was then used to isolate full-length Ikaros clones from a trout thymocyte cDNA library. In mice and humans, Ikaros produces six alternatively spliced isoforms, but in trout two additional novel splice variants designated Ik-7 and Ik-8 were also found. Ik-7 is expressed in a similar fashion to Ik-1 and Ik-2, the predominant isoforms expressed in mammalian lymphocytes. In trout and zebrafish, as in mammals, Ikaros is a single-copy gene, but in Xenopus segregation analysis demonstrates that Ikaros has been duplicated, most likely a result of polyploidization. We then examined the expression of Ikaros in trout and Xenopus tumor T cell lines via Northern blot, RT-PCR, immunofluorescence and Western blot analysis. Overall, Ikaros is expressed in a lymphoid-specific fashion similar to that found in mice and humans. In addition Ikaros is expressed early in trout ontogeny, beginning roughly at days 3-4 in the yolk sac and at day 5-6 in the embryo proper. The conservation of Ikaros structure and expression confirms it as a master switch of hematopoiesis.

Alternative Splicing↗
PubMed1995

Application of DNA fingerprinting to the taxonomy of European blackberry species.

Thousands of blackberry species (Rubus subgenus Rubus) have been described from Central and Northern Europe. These species are usually polyploid and pseudogamous. Since apomixis is only facultative, the species have retained the possibility to produce some offspring by sexual recombination. Hybridization of restriction-enzyme-digested DNA samples to the M13, (AC)/(TG) and 33.15 probes has yield valuable information on the occurrence and distribution of genetic variation in Rubus. Intraspecific variation proved to be very restricted, with identical DNA fingerprints sometimes being exhibited by Swedish, Danish and German populations of the same species. By comparison, interspecific variation was usually pronounced, suggesting that most species have been derived through genetic recombination. Speciation through interspecific hybridization was demonstrated in one case. Several critical taxa were investigated; some of these proved to have unique DNA fingerprints, whereas others appear to be identical with previously described species. Evaluation of raspberry cultivars, obtained through several generations of vegetative propagation or with various in vitro techniques, failed to detect any DNA fingerprint variation, suggesting that the fingerprints are somatically stable. Blackberry seedlings, obtained by pollinating various species as well as interspecific hybrids with pollen from yet other species, were successfully evaluated with DNA fingerprinting to determine the relative proportions of the apomictic and sexual seed set.

DNA Fingerprinting↗
PubMed1983

A comparative cytogenetic study on cases of induced abortions in TCDD-exposed and nonexposed women.

In order to evaluate the cytogenetic findings previously obtained on induced abortions in women exposed to 2,3,7,8 tetrachlorodibenzo-p-Dioxim (TCDD) after the Seveso accident, chromosome analyses were carried out on a comparable control sample. The frequencies of aberrant cells, the relative proportions of individual types of chromosome aberration, the average number of lesions per damaged cell, and the frequencies of polyploids do not differ significantly in maternal blood and placenta in the two samples. A highly significant increase in the frequencies of aberrant cells and in the average number of aberrations per damaged cell was found in the fetal tissues in the group of exposed pregnancies. A noticeable feature of the data on the frequencies of cells with aberrations is the marked variability among individuals within tissues and within samples. On the basis of these results, the authors point to the need to continue cytogenetic investigations on interrupted pregnancies in TCDD-exposed and nonexposed women.

Abortion, Induced↗
PubMed2003

Distinct chromosomal aberrations in sinonasal mucosal melanoma as detected by comparative genomic hybridization.

Sinonasal mucosal melanomas are the most frequent mucosal melanomas and arise from melanocytes located in the nasal cavity and the paranasal sinuses. The melanoma types, cutaneous melanoma, uveal melanoma, and mucosal melanoma, differ in etiology, geographic distribution, and clinical behavior. Genetic alterations have been previously studied in cutaneous and uveal melanomas but, to the best of our knowledge, not in mucosal melanomas. Comparative genomic hybridization (CGH) was performed on 14 routinely processed sinonasal mucosal melanomas. Furthermore, ploidy analysis was performed on 11 tumors to provide complementary data on the DNA index. The CGH profiles of sinonasal mucosal melanomas show remarkably consistent alterations: chromosome arm 1q is gained in all tumors and gains of 6p and 8q are present in 93 and 57%, respectively. Comparison of CGH data with both the common variants of cutaneous melanoma and uveal melanoma revealed that sinonasal mucosal melanomas harbor a distinct pattern of chromosomal abnormalities. Ploidy analysis also showed that diploid tumors exhibit gains of 1q and alterations of chromosome 6 (3 of 3 cases tested), whereas clear-copy gains and high-copy gains were seen only in triploid and tetraploid tumors (6 of 8 cases tested). This indicates that alteration of chromosomes 1 and 6 may precede polyploidization and formation of clear-copy gains and high-copy gains.

Aged↗
PubMed1989

Molecular studies of the sex chromosomes in human testicular cancer: pronounced changes in X and Y chromosome dosage in some tumors.

Nine males with testicular germ cell tumors were studied by Southern blotting using probes recognizing different regions of the X and Y chromosomes. In the tumors of three patients, an imbalance was noted with a relative deficiency of DNA of Y-chromosomal and a concurrent excess of that of X-chromosomal origin. The X:Y signal ratios were 4, 4, and 2, respectively, in tumor DNA relative to normal DNA, and the ratios of Y to an autosomal locus were 0.4, 0.6, and 0.7, respectively, in the same tumors. Several loci on both arms of the Y chromosome were similarly involved. No structural abnormalities of Y chromosome DNA could be demonstrated. The X/Y change occurred in two of the three patients with nonseminomatous tumors and in two of the three patients with metastatic disease. To account for the results, two alternative models are discussed: first, loss of the Y chromosome and increase in X chromosome number in some but not all tumor cells; second, polyploidization with one Y chromosome and several X chromosomes.

Adult↗
PubMed1989

Complex karyotypic anomalies in a bizarre leiomyoma of the uterus.

Cytogenetic investigation of short-term cultures from a bizarre leiomyoma of the uterus, a tumor type not hitherto karyotypically characterized, revealed two abnormal clones with multiple complex rearrangements. Three-fourths of the aberrant cells were hypodiploid with the composite karyotype 38-44,XX,-6,-7,-10, -11,+20,-22,r(1),der(2)(:2p23----cen----2q13::1q21---- 1qter),der(2)t(2; 9)(p21;q13),t(5;?)(q35;?), t(5;?),(q35;?),+der(5)t(5;15)(q11;q15), der(8)t(8;11)(q24;q13),t(15;?)(p12;?),der(16)t(12;16)(q13;p13),+r,+mar. The remaining abnormal mitoses were hypotetraploid, with chromosome numbers ranging from 74 to 86. These massively rearranged cells showed the same markers that were found in the hypodiploid clone, but in duplicate, indicating that this clone had arisen through polyploidization of hypodiploid cells. Flow cytometry revealed a DNA index of 1.03.

Female↗
PubMed1995

Physiology of transformed glial cells.

Much of our present knowledge of glial cell function stems from studies of glioma cell lines, both rodent (C6, C6 polyploid, and TR33B) and human (1321N1, 138MG, D384, R-111, T67, Tp-276MG, Tp-301MG, Tp-483MG, Tp-387MG, U-118MG, U-251MG, U-373MG, U-787MG, U-1242MG, and UC-11MG). New methods such as patch clamp and Ca2+ imaging have lead to rapid progress the last few years in our knowledge about glial cells, where an unexpected presence and diversity of receptors and ion channels have emerged. Basic mechanisms related to membrane potential and K+ transport and the presence of voltage gated ion channels (Na+, inwardly rectifying K+, Ca(2+)-activated K+, Ca2+, and Cl- channels) have been identified. Receptor function and intracellular signaling for glutamate, acetylcholine, histamine, serotonin, cathecolamines, and a large number of neuropeptides (bradykinin, cholecystokinin, endothelin, opioids, and tachykinins) have been characterized. Such studies are facilitated in cell lines which offer a more homogenous material than primary cultures. Although the expression of ion channels and receptors vary considerably between different cell lines and comparative studies are rare, a few differences (compared to astrocytes in primary culture) have been identified which may turn out to be characteristic for glioma cells. Future identification of specific markers for receptors on glial and glioma cells related to cell type and growth properties may have great potential in clinical diagnosis and therapy.

Amino Acids↗
PubMedDate not supplied

DNA ploidy in oral cavity carcinomas, with special reference to prognosis.

Single-cell DNA cytofluorometry was performed on paraffin-embedded tissue of 140 patients with squamous cell carcinomas of the oral cavity. Half of the tumors (71 of 140) were DNA nondiploid. Well-differentiated carcinomas were more often DNA diploid than moderately well-differentiated ones (P less than 0.001; chi-square). The aneuploid tumors responded better to preoperative radiotherapy than did the DNA diploid (P less than 0.001) and polyploid tumors (P less than 0.05; chi-square). Using the multivariate Cox's regression analysis multiploid type tumor, age of the patients and presence of lymph node metastases were the only significant factors influencing survival. DNA diploid tumors in stages I and II had a better prognosis than DNA nondiploid (P less than 0.01; Kaplan-Meier). The reverse was true for stages III and IV, where DNA nondiploid tumors had a better prognosis (P less than 0.05; Kaplan-Meier). Tumor stages (P less than 0.001; Kaplan-Meier) and especially lymph node metastases (P less than 0.0005; Kaplan-Meier) were major prognostic factors. Tumor DNA ploidy may be a complement to clinical and morphologic parameters as a prognostic predictor in squamous cell carcinoma of the oral cavity.

Adult↗
PubMed1994

Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes.

Liver injury was induced by a single dose (60 mg/kg) of cocaine in male albino Swiss mice untreated or pretreated with phenobarbital (in drinking water 1 gm/L), for 5 days before cocaine administration. One parameter of liver injury, serum isocitrate dehydrogenase activity, showed sharp increases at 24 hr of cocaine treatment; we also noted decrease hepatic levels of ATP, GSH, cytochrome P-450 and NADPH/NADP+ ratio and increases in malondialdehyde concentration. Histopathological study of liver slices showed perivenous and periportal necrosis induced by cocaine in untreated mice and mice pretreated with phenobarbital, respectively. A regenerative postnecrotic response, which peaked at 48 hr, was demonstrated by the appearance of mitotic cells. Mitotic index analysis showed that proliferative cells appear to be unevenly distributed in the hepatic acinus and were mainly located in the vicinity of the damaged acinar region. Genomic DNA ploidy and the distribution of DNA in the phases of the cell cycle were studied in nuclei of isolated hepatocytes. At 12 hr of cocaine administration, both in untreated and phenobarbital-pretreated mice, the following changes were observed: a sharp decrease in tetraploid (4N) cells (40% to 17% and 25% to 6%, respectively) and octoploid (8N) cells (5% to 2% and 2% to 1%, respectively), together with the appearance of a hypodiploid population (13% and 31%, respectively). Hypodiploid population was characterized as apoptotic cells by detection of DNA fragmentation in agarose gel. These results suggest that a significant percentage of cell death induced by cocaine occurs by means of the apoptosis death program. Comparison of the initial values of DNA ploidy with those obtained at 7 days of cocaine administration showed remarkable increases in polyploid populations (4N and 8N) and a decrease in diploid cells (2N), indicating that the process of differentiation occurs when liver restores its functionality.

Adenosine Triphosphate↗
PubMed1997

Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: matched case-control study, pathological analysis, and pathogenetic hypothesis.

Large cell change (LCC), characterized by cellular enlargement, nuclear pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain uncertain. Therefore, we assessed the prognostic value of LCC as a marker of subsequent hepatocellular carcinoma (HCC) through a case-control study that compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant recipients with HCC to specimens from a control group of recipients without HCC, matched for sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in 16 (43%) of the study and 7 (19%) of the control group biopsy specimens. By matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a morphological transition or a histogenetic association between the two lesions. LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a greater degree of apoptosis than normal hepatocytes (labeling indices of 1.9 and 0.23; P = .03) To reconcile these findings, we propose that LCC derives from derangements in the hepatocyte's normal process of polyploidization. Such derangements, possibly caused by chronic inflammation-induced DNA damage, could yield a population of enlarged liver cells with nuclear atypia and pleomorphism, frequent binuclearity, and minimal proliferation. According to this hypothesis, LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC but would not represent a direct malignant precursor.

Adult↗
PubMed1998

Control of mouse hepatocyte proliferation and ploidy by p53 and p53ser246 mutation in vivo.

The effect of expression of the p53 gene, in the presence or absence of the p53ser246 mutation (p53*), on ploidization (image cytometry), proliferation (expression of proliferating cell nuclear antigen and radioactive thymidine histoautoradiography), and apoptosis (in situ detection of DNA fragments) is determined in hepatocytes of p53-null and p53*-transgenic mice. The mouse p53ser246 mutation is equivalent to the p53ser249 mutation found in human hepatomas associated with hepatitis B virus infection and aflatoxin exposure. The hepatocytes of heterozygous or homozygous p53-knockout mice (p53+/-; p53-/-), as well as knockout mice expressing one allele of p53ser246 (p53+/-, p53*; p53-/-, p53*), do not undergo normal polyploidization with aging and show an increase in the number of cycling (G1-, S-, and M-phase) cells. In addition, p53ser246-transgenic mice (p53+/+, p53*; p53+/-, p53*; and p53-/-, p53*) have a greatly increased number of hepatocytes in the G1 phase. No differences in rates of apoptotic hepatocytes are found among any of the mouse groups studied, so the increased proliferation results in a hyperplasia manifested by a increased number of small periportal cells. We conclude that loss of p53 removes blocks in the cell cycle, leading to increased proliferation, whereas expression of the p53ser246 mutation stimulates G0 to G1 and/or M to G1 transition of hepatocytes. Increased proliferation of hepatocytes, combined with no concomitant increase in apoptosis, may in part explain the enhanced development of hepatocellular carcinomas in p53-knockout and p53*-transgenic mice exposed to aflatoxin.

Amino Acid Sequence↗
PubMed1983

Establishment and characterization of a human non-secretory plasmacytoid cell line and its hybridization with human B cells.

A human non-secretory plasmacytoid cell line has been established for 6 years in more than 170 passages. Over 300 passages have been made from several early and late passages. The cell line is karyotypically normal, easily grown and has the characteristic features of a non-secretory plasmablast. Its characteristics suggest its use for hybridization by new methods as well as a study of its secretory defect. HPRT-negative phenotypic mutants can be derived from this line and a single polyploid clone has also been isolated. Hybridization with the HPRT+ and HPRT- lines X human B cells is described.

Aged↗
PubMed1988

DNA content and genetic evolution of human colorectal adenocarcinoma. A study by flow cytometry and cytogenetic analysis.

We have conducted in parallel DNA flow cytometry (FCM) and cytogenetic (CG) analysis of a series of surgical specimens from 35 human colorectal adenocarcinomas. An excellent quantitative correlation was observed (r = 0.99) between modal peak values of FCM histograms and chromosome counts. This observation confirms that aneuploidy, as defined by FCM, accurately reflects the deviation from diploidy of the genomic DNA. FCM-derived DNA patterns have been analyzed in the context of the clonal chromosomal evolution determined by CG analysis. In the metaphases of a given tumor, even if karyotypes of different ploidy exist, the presence of identical marker chromosomes suggests a common origin for the multiple populations observed by FCM. Thus, heterogeneity in DNA content within a tumor, including the polyploidization step, would be indicative of genetic evolution.

Adenocarcinoma↗
PubMed1989

Preservation of chromosome and DNA characteristics of human colorectal adenocarcinomas after passage in nude mice.

Twenty-seven human colorectal adenocarcinomas were implanted s.c. into nude mice. A comparative study of chromosomes and DNA between fresh tumor (FT) and xenografted tumor cells (XT) could be performed in 9 cases. Losses or deletions were consistently found in FTs as well as in XTs, particularly on chromosomes 17 and/or 18. This was correlated with loss of heterozygosity for these chromosomes. Comparison between corresponding FT and XT karyotypes showed great similarities. However, the tendency toward polyploidization, which exists in FTs, appeared to be more pronounced in XTs. Passage in nude mice makes it possible to repeat cytogenetic analyses in order to obtained interpretable metaphases. Xenografting not only increases the number of tumorigenic cells, but also eliminates human normal stromal or blood cells and gives unambiguous data on allelic loss.

Adenocarcinoma↗
PubMed1990

Prognostic significance of DNA-ploidy in a series of 690 primary breast cancer patients.

Flow cytometric DNA-ploidy measurements were performed on paraffin-embedded and fresh tumor specimens from 690 patients with Stage I-III breast cancer. The conventional classification of DNA-ploidy (diploid versus aneuploid) was compared with a division of tumor ploidy into 5 classes based on DNA index (DI) range. The DI-classification showed a better correlation with tumor size and TNM stage than the conventional classification. Aneuploidy was associated with an impaired survival and distant relapse-free survival (p = 0.02) but the DI-classification improved the discrimination between different prognostic groups of patients. In general, this indicated a more aggressive phenotype for tumors evolved via polyploidization. Hyper-tetraploidy (DI greater than 2.10) indicated a very poor prognosis in pre-menopausal patients. No prognostic effect of aneuploidy and DI-class was found in node-negative and TI patients. Cox multivariate regression analysis showed that aneuploidy was an additional prognostic factor to nodal status (I less than or equal to N less than or equal to 3, N greater than 3 vs. N = 0) and tumor size (T2-4 vs. TI) for overall and distant relapse-free survival. Subdivision according to DI-class did not improve the prognostic power of DNA-ploidy due to stronger correlations with established prognostic factors.

Aged↗
PubMed1992

GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.

GATA-1, a transcription factor of the 'zinc-finger' family, is required for the development of mature erythroid cells and is also highly expressed in the megakaryocytic and mast cell lineages. The helix-loop-helix gene SCL (or TAL) is expressed in the same three hematopoietic lineages as GATA-1. To explore the role of GATA-1 and SCL in hematopoietic differentiation, we introduced a new expression vector bearing each gene into the early myeloid cell line 416B, which could originally differentiate in vivo along the megakaryocytic and granulocytic lineages. Enforced expression of SCL at high levels did not provoke differentiation, but GATA-1 induced the appearance of megakaryocytes as assessed by morphology, the presence of acetylcholinesterase and a polyploid DNA content. Although GATA-1 is thought to stimulate its own transcription in erythrocytes, expression of the endogenous gene was not increased in the megakaryocytic lines; hence GATA-1 may not be autoregulatory in this lineage. Megakaryocytic differentiation was accompanied by a marked decrease in the myeloid surface marker Mac-1. The absence of mast cell or erythroid differentiation suggests that GATA-1 may not be sufficient to provoke maturation along these lineages or that these pathways are impeded in 416B cells. These results demonstrate that a member of the GATA gene family can act as an important regulator of megakaryocytic differentiation.

Acetylcholinesterase↗