bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic reduction of novel 3,4–dichloro‐5‐nitrofurans in Salmonella typhimurium
Authors: Hatcher James F. , Yamamoto Katsumi , Ichikawa Masataka , Bryan George T. , Swaminathan Santhanam
Published: February 2007

To gain insight on biochemical mechanisms of mutagenesis and carcinogenesis by the experimental carcinogens, 5–nitrofurans, a new series of 3,4‐dichloro‐5‐nitrofurans, comprised of 3,4‐dichloro‐5‐nitro‐2‐acetylfuran (I), 3,4‐dichloro‐5‐nitro‐2‐bromoacetylfuran (II), methyl 3,4‐dichloro‐5‐nitro‐2‐furoate (III), were synthesized and tested for their activation to mutagenic forms in the standard plate assay using Salmonella typhimurium TA98, TA100, and TA100NR, a derivative of TA100 deficient in nitroreductase activity. The mutagenic responses in TA98 were 2‐ to 6‐fold lower compared to TA100. Furthermore, I and II were less active in TA100NR, while compound Ill was about four times more mutagenic in TA100NR compared to the parent strain TA100. Incubation of Ill with NADPH and bacterial lysates showed that the extent of reduction was greater in TA100 compared to TA100NR. High‐pressure liquid chromatography analysis of the ethyl acetate extract obtained from incubation of Ill with lysates of TA100 revealed the formation of four metabolites with retention times of about 4.0, 5.7, 10.0, and 14.3 minutes. The spectroscopic and chromatographic properties of the components with retention times of 10.0 and 14.3 minutes were identical to two derivatives obtained by chemical reduction of Ill, and thus represent nitroreduction products. These derivatives have been identified as cisand frans‐oxime isomers of methyl 3,4‐dichloro‐2‐furoate, based on spectroscopic analyses. These oximes were not mutagenic for TA100. Furthermore, Ill was more mutagenic under anaerobic conditions, suggesting that secondary superoxide or nitroanion free radicals generated from nitroreduction are not responsible for the mutagenicity of Ill. In addition, the higher mutagenic response in TA100NR, and the lack of mutagenic activities of the amino and the oxime analogs of Ill suggest that the mutagenic activation of Ill might be due to the nitroso intermediate or involve mechanisms other than nitroreduction. © 1995 Wiley‐Liss, Inc.
Mutagenicity testing of nine herbicides and pesticides currently used in agriculture
Authors: Kale Purushottam G. , Petty Bobby T. , Walker Sophia , Ford Jeffery B. , Dehkordi Nahid , Tarasia Srikumar , Tasie Bertram O. , Kale Ranjini , Sohni Youvraj R.
Published: February 2007

Nine herbicides and pesticides were tested for their mutagenicity using the Drosophila sex‐linked recessive lethal mutation assay. These are Ambush, Treflan, Blazer, Roundup, 2,4‐D Amine, Crossbow, Galecron, Pramitol, and Pondmaster. All of these are in wide use at present. Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. Larval treatment may still be valuable and can complement adult treatment in environmental mutagen testing. © 1995 Wiley‐Liss, Inc.
Increased frequency of mutations at A:T base pairs in the bone marrow of B6C3F1 lacl transgenic mice exposed to 1, 3‐butadiene
Authors: Recio Leslie , Meyer Kathy G.
Published: February 2007

We have examined the spectra of mutations in a collection of 74 lacl mutants isolated from the bone marrow of B6C3F1 lacl transgenic mice exposed to 1, 250 ppm 1, 3‐butadiene (BD). Of the 49 independent mutations analyzed in the present study, 30 of 49 (61%) were point mutations at G:C base pairs, and 10 of 49 (20%) were point mutations at A:T base pairs. The remaining mutations consisted of small deletions and insertions and a single tandem change. An analysis of variance (ANOVA) on the frequency of specific mutations observed in each animal in this mutagenicity experiment [present study; also Sisk SC et al. (1994): Carcinogenesis 15:471–477] indicated that the frequency of point mutations at A:T base pairs is significantlantly greater (P < 0.05) in BD‐exposed mice than in the air controls. In addition, there was a decrease (P < 0.05; Fisher's exact test) in the frequency of G:C→A:T transitions at 5′‐CpG‐3′ sites in BD‐exposed mice (27%) relative to air controls (51%). These data indicate that subchronic exposures to BD induces an increased frequency of in vivo mutation at A:T base pairs in the bone marrow of B6C3F1 lacl transgenic mice. © 1995 Wiley‐Liss, Inc.
In vivo DNA adduct formation by bisphenol A
Authors: Atkinson Alfonza , Roy Deodutta
Published: February 2007

We have previously shown that bisphenol A (BPA) is oxidized to bisphenol‐o‐quinone in the presence of activation system and that the chemical reaction of DNA or deoxyguanosine 3′‐monophosphate (dGMP) with bisphenol‐o‐quinone produces adducts. In the present study, using the 32P‐postlabeling technique, we have investigated the in vivo DNA adduct formation by BPA by examining covalent modification in DNA. Administration of a single or multiple dose of 200 mg/kg of BPA to CD1 male rats produced two major and several minor adducts in liver DNA. The two major in vivo adducts matched the adduct profile of DNA or dGMP‐bis‐phenol‐o‐quinone. To determine how BPA may be converted to DNA‐binding metabolites, adducts were examined after incubation of DNA with BPA in the presence of a microsomal activation system. The in vitro incubation of BPA with DNA in the presence of a microsomal activation system revealed one major adduct and several minor adducts. The formation of adducts in DNA by BPA in the presence of a microsomal activation system was drastically decreased by known inhibitors of cytochrome P450. Adduct formation in DNA when cumene hydroperoxide or NADPH was used as a cofactor showed adducts with similar chromatographic mobilities as those from the reaction of dGMP‐bisphenol‐o‐quinone. These data demonstrate that BPA is capable of binding covalently to DNA. DNA binding can be inhibited by the inhibitors of cytochrome P450. One of the DNA‐binding metabolite(s) both in vitro and in vivo may be bisphenol‐o‐quinone. Covalent modifications in DNA by in vivo exposure of BPA may be a factor in the induction of hepatotoxicity. © 1995 Wiley‐Liss, Inc.
Reconsideration of the genetic risk assessment for ethylene oxide exposures
Authors: Preston R. Julian , Fennell Timothy R. , Leber A. Philip , Sielken Robert L. , Swenberg James A.
Published: February 2007

The US Environmental Protection Agency (EPA) developed a genetic risk assessment model for exposures to ethylene oxide utilizing data on the induction of reciprocal translocations in male germ cells [Rhomberg et al. 1990]. This particular approach served as a reasonable initial attempt, albeit somewhat limited with regard to endpoint and only partially attentive to the mechanisms of induction of genetic alterations and the behavior of chromosomes during meiosis. The present paper discusses the scientific basis for a reassessment of the EPA model, providing data and hypotheses related to effective dose to the target cells and shape of the dose‐response relationship at low doses, and dose rates. While the present genetic risk assessment approach is discussed in terms of ethylene oxide, it would be applicable to most mutagenic chemicals. The outcome of the discussion is that the genetic risk for exposed males from reciprocal translocation induction will be negligible at low doses since the dose‐response curve is likely to be a function of the square of the dose. In addition, the proportion of genetically unbalanced live born offspring in humans arising from reciprocal translocation carriers is less than 10% of the frequency formed through meiotic segregation and fertilization for such carriers. Simply from a consideration of mechanism—namely, the very high probability of DNA repair prior to the next S‐phase for a resting oocyte—it would be predicted that there would be a very low to negligible frequency of translocations in female germ cells from ethylene oxide exposure. It is further stressed that additional components of a genetic risk model require a consideration of all germ cell stages in the male, and the inclusion of calculations for point and deletion mutations. Some indications of likely response are presented with these points in mind. © 1995 Wiley‐Liss, Inc.
Aflatoxin b1, 2‐aminoanthracene, and 7,12‐dimethylbenz[a]anthracene‐induced frameshift mutations in human APRT
Authors: Zhu Yuan , Bye Steven , Stambrook Peter J. , Tischfield Jay A.
Published: February 2007

Aflatoxin BI, 2‐aminoanthracene, and 7,12‐dimethylbenz[a]anthracene have been implicated in the etiology of human cancers. In this study, we demonstrate that these three chemicals can be activated by rat liver homogenate S9 coupled with NADPH coenzymes to produce a dose‐dependent increase in the frequency of APRT reversion in the APRT‐deficient human cell line HTD114. HTD114 contains single nucleotide insertions at different positions in each APRT allele and the spontaneous reversion frequency is < 10−8. However, the highest reversion frequency induced by these chemicals is 1.2–2.0 × 10−5, at least a 103‐fold increase over the frequency of spontaneous reversion. Reversion of either mutant allele was observed to be a consequence of a frame‐restoring loss of a single nucleotide, which indicates that these three chemicals can function as frameshift mutagens in human cells. © 1995 Wiley‐Liss, Inc.
Evaluation of the micronucleus test in vitro using chinese hamster cells: Results of four chemicals weakly positive in the in vivo micronucleus test
Authors: Miller Beate M. , Pujadas Eva , Gocke Elmar
Published: February 2007

A rapid and simple procedure for the micronucleus test (MNT) in vitro using Chinese hamster ovary (CHO) cells was established in our laboratory. The assay is intended to quickly screen chromosomal aberrations in vitro within the framework of industrial genotoxicity studies. To test the sensitivity of the assay in the experiments described here, four substances, classified as noncarcinogens but reported as weak inducers of micronuclei (MN) in bone‐marrow cells of mice, were evaluated in the MNT in vitro. Of the four compounds, ascorbic acid, phenol, and 2,6‐diaminotoluene proved to be genotoxic in the MNT in vitro. Titanium dioxide, which could not be dissolved in the culture medium, did not induce MN. The MNT in vitro proved to be quick and relatively simple and to yield highly reproducible results when testing the four chemicals. © 1995 Wiley‐Liss, Inc.
Indications for a threshold of chemically‐induced aneuploidy in vitro in human lymphocytes
Authors: Elhajouji Azeddine , Van Hummelen Paul , Kirsch‐Volders Micheline
Published: February 2007

The possible existence of a threshold for compounds inducing chromosomal loss was investigated for four known aneugens (colchicine, COL; carben‐dazim, MBC; mebendazole, MEB; nocodazole, NOC) and two clastogens (methyl methanesulfo‐nate, MMS; mitomycin C, MMC) using the micronu‐cleus (MN) test in human lymphocytes. The presence of a whole chromosome in the MN was studied by fluorescent in situ hybridization (FISH) using a synthetic pancentromeric oligonucleotide probe. FISH was applied on two different MN preparations: cytokinesis‐blocked MN (MNCB) assay, and MN sorted by flow cytometry. At subtoxic concentrations analyzed by MNCB and FISH, COL, MEB, MBC, and NOC induced a concentration‐dependent increase in centromere‐positive MN (MNCen+), MMC seemed to induce an increase in both types of MN (MNCen‐ and MNCen+), while MMS induced only MNCen‐. On the sorted micronuclei (in a wide range of low to subtoxic concentrations), the concentration‐effect profile for MNCen+, with the four aneugens tested, showed a statistically nonsignificant increase over a range of concentrations, followed by a second range of high concentrations with a statistically significant increase. To analyze the existence of a threshold, a piecewise linear regression was applied to the data. The first concentration that showed a statistically significant increase in MNCen+ was chosen as a breakpoint (0.037 μM for COL, 2.62 μM for MBC, 0.27 μM for MEB, and 0.066 μM for NOC). The statistical correlation between observed and predicted values showed a high correlation (r = 0.99), indicating a clear threshold for aneuploidy induction. However, for MMS the concentration‐effect profile for MNCen+ showed a continuous concentration‐dependent decrease with no threshold. With the two cytotoxicity assays used (Bio‐Rad and MTT), no significant reduction was detected either in the protein content or in mitochondrial succinate dehydrogenase activity with all chemicals tested for MN induction. Therefore, our data suggest that the observed thresholds were not due to indirect toxic effects but to real aneugenic effects. © 1995 Wiley‐Liss, Inc.
An investigation of the DNA‐damaging ability of benzene and its metabolites in human lymphocytes, using the comet assay
Authors: Anderson D. , Yu T.‐W. , Schmezer P.
Published: February 2007

Benzene and five of its known metabolites—muconic acid, hydroquinone, catechol, p‐benzoquinone, and benzentriol—were examined for DNA damage in human lymphocytes using the alkaline Comet assay, and conditions were optimised to determine responses. Metabolic activation (S‐9 mix) was included in the assay for varying times to try to enhance effects. In addition, the effects of catalase were investigated as it is known to be present in S‐9 mix reducing oxidative damage, and some benzene metabolites are known to react through oxygen radical mechanisms. Effects were also examined in cycling cells to determine whether they were more sensitive to damage then noncycling cells. Comets were measured either by eye or by image analysis. Data have been presented according to length of treatments.

When Comets were measured by eye after treatment with hydrogen peroxide (H2O2), the positive control, and each compound for 0.5 hr, only H lymphocytes.

When comets were measured by image analysis, a 0.5‐hr treatment with H2O2 and benzenetriol and catechol confirmed results analysed by eye, with S‐9 mix greatly reducing responses. When treatments were increased to 1 hr in the presence and absence of S‐9 mix, benzene at a 5‐fold increased dose produced a significant positive response but not at the lower dose. When treatment times were increased to 2 and 4 hr, doses were also increased, and muconic acid, hydroquinone, catechol, and benzoquinone in the presence of S‐9 mix showed positive time and dose‐related responses, and at the highest dose of benzoquinone the morphology of the nucleus was affected. Effects tended to become more pronounced at high doses and after longer exposures, although this was not always consistent from experiment to experiment.

In conclusion, benzene and all metabolites investigated gave positive responses. Where altered responses were observed, they were significantly different from the corresponding controls. © 1995 Wiley‐Liss, Inc.
Solution of depth‐averaged tidal currents in Persian Gulf on unstructured overlapping finite volumes
Authors: Sabbagh‐Yazdi Saeed‐Reza , Zounemat‐Kermani Mohammad , Kermani Ali
Published: February 2007

Hydrodynamic simulation of tidal currents in Persian Gulf due to tidal fluctuations in Hurmoz strait and inflow for Arvand River is presented in this paper and tidal constituents of M2 and K1 are attained. The mathematical model utilized consists of depth‐averaged equations of continuity and motion in two‐dimensional horizontal plane which considers hydrostatic pressure distribution. The effect of evaporation is considered in the continuity equation and the effects of bed slope and friction, as well as the Coriolis effects are considers in two equations of motion. The cell vertex finite volume method is applied for converting the governing equations into discrete forms for unstructured overlapping control volumes. Using unstructured triangular meshes provides great flexibility for modelling of complex geometries in the real world flow domain. The accuracy of the developed flow solver is assessed using two test cases. Firstly, the results of the hydrodynamic model for fluctuating flow on the variable bed slope are compared with available analytical solution. Secondly, in order to simulate circulating flow patterns the numerical results are compared with the reported data in the literature for deep flow in a canal with sudden expansion. Finally, the performance of the computer model to simulate tidal flow in a geometrically complex domain is examined by simulation of tidal currents in the Persian Gulf and computing tidal constituents. Copyright © 2007 John Wiley & Sons, Ltd.
An optimizing reduced order FDS for the tropical Pacific Ocean reduced gravity model
Authors: Luo Zhendong , Chen Jing , Zhu Jiang , Wang Ruiwen , Navon I. M.
Published: February 2007

Proper orthogonal decomposition (POD) and singular value decomposition (SVD) methods are used to study a finite difference discretization scheme (FDS) for the tropical Pacific Ocean reduced gravity model. Ensembles of data are compiled from transient solutions computed from the discrete equation system derived by FDS for the tropical Pacific Ocean reduced gravity model. The optimal orthogonal bases are used to reconstruct the elements of the ensemble with POD and SVD. Combining the above approach with a Galerkin projection procedure yields a new optimizing FDS model of lower dimensions and high accuracy for the tropical Pacific Ocean reduced gravity model. An error estimate of the new reduced order optimizing FDS model is then derived. Numerical examples are presented illustrating that the error between the POD approximate solution and the full FDS solution is consistent with previously obtained theoretical results, thus validating the feasibility and efficiency of POD method. Copyright © 2007 John Wiley & Sons, Ltd.
A posterioriestimators for vertex centred finite volume discretization of a convection–diffusion‐reaction equation arising in flow in porous media
Authors: Amaziane B. , Bergam A. , El Ossmani M. , Mghazli Z.
Published: February 2007

We present an adaptive numerical technique for solving convection–diffusion‐reaction problems, modelling the transport of contaminant in porous media. We develop and analyse residual error estimators using finite volume approximations. The error estimators with respect to both time and space yield global upper and local lower bounds on the error measured in the energy norm. Computational results of various model simulations of fluid flow and transport of contaminant in heterogeneous aquifers are presented and discussed. Copyright © 2007 John Wiley & Sons, Ltd.
Molecular genetic analysis of tumors in von recklinghausen neurofibromatosis: Loss of heterozygosity for chromosome 17
Authors: Skuse Gary R. , Kosciolek Barbara A. , Rowley Peter T.
Published: February 2007

The most common inherited syndrome in man predisposing to neoplasia is neurofibromatosis‐1 (von Recklinghausen disease) (NF1). We investigated the hypothesis that affected individuals carry a single inactive allele at the NF1 locus in the germline and that a tumor arises from a cell in a susceptible tissue in which the remaining normal allele has been lost or inactivated. DNA from tumor and nontumor tissue from 27 NF1 patients was analyzed with three markers closely linked to the NF1 locus and two additional markers from chromosome 17. No loss of heterozygosity was observed in neurofibromas, plexiform or not. For other tumor types analyzed, seven of 14 showed a loss. A loss of heterozygosity was observed in six of 11 of the malignant peripheral nerve tumors analyzed. Of the seven malignancies demonstrating a loss, five involved a neurofibrosarcoma. These findings suggest that the pathogenesis of neurofibrosarcoma in NF1 involves a deficiency of the NF1 gene product. In any given patient, loss of heterozygosity was detected at some marker loci but not others. Thus the mutations demonstrated in these tumors comprise a set of overlapping mutations, which may facilitate more precise localization of the NF1 gene.
Leukemic differentiation of a mediastinal germ cell tumor
Authors: Chaganti R. S. K. , Ladanyi Marc , Samaniego Felipe , Offit Kenneth , Reuter Victor E. , Jhanwar Suresh C. , Bosl George J.
Published: February 2007

The biological basis for acute leukemia associated with mediastinal germ cell tumors has remained unexplained due to lack of critical data that would illuminate the genetic relationship between the two tumors in a given patient. Here we present results of serial cytogenetic investigations on the pretreatment and posttreatment mediastinal yolk sac tumor and immature teratoma biopsies and two separate leukemic bone marrow aspirates from a patient who developed acute nonlymphocytic leukemia 11 months after the initial diagnosis of the germ cell tumor. Presence of an i(12p) in all tumor clones and trisomy 21 in one clone in the posttreatment mediastinal tumor and all leukemic clones establishes the common origin of all tumor clones and shows that in this case the leukemia was derived from the malignant germ cell clone.
Suggestive evidence that genes controlling invasion and metastasis of T‐cell lymphomas are located on mouse chromosome 3
Authors: Verschaeve Luc , Verschueren Hendrik , Vandendriessche Thierry , van Hecke Dominique , Verhaegen Steven , de Baetselier Patrick
Published: February 2007

Cell lines differing in their malignant potential have been derived from the murine BW5147 T‐cell lymphosarcoma. To evalute the involvement of chromosomal aberrations in tumor progression within this model, we have analyzed the karyotypes and the in vitro invasiveness of 13 related nonmetastatic and metastatic variants. Giemsa banding revealed the presence of several marker chromosomes, one of which was of particular importance. Depending on the cell line, four variants of this marker I were found: Marker Ia corresponds to two translocated chromosomes 3, marker Ib is a deleted Ia marker, marker Ic is a Ib translocated to a small unidentified chromosome fragment, and marker Id is a further deleted Ib marker. The Ia and Id markers were characteristic for the noninvasive, nonmetastatic lines, whereas the Ib and Ic markers predominated in the invasive, metastatic variants. The results suggest that metastasis‐enhancing genes are located between the D and F1 band of mouse chromosome 3 and that metastasis‐suppressing genes are located between the F1 and H band of the same chromosome.
Amplification of cellular oncogenes: A predictor of clinical outcome in human cancer
Authors: Schwab Manfred , Amler Lukas C.
Published: February 2007

Increased dosage of cellular oncogenes resulting from amplification of DNA is a frequent genetic abnormality of tumor cells and the study of oncogene amplification has been paradigmatic for the usefulness of molecular genetic research in clinical oncology. Certain types of human tumors carry an amplified cellular oncogene at frequencies of up to 50–60%. Human neuroblastoma has been prototypic for the importance of oncogene amplification in tumorigenesis, and evidence is emerging that amplification may be an early event involved in a more malignant form of this cancer. It is unclear at which stage amplification plays a role in other cancers. Amplification of cellular oncogenes is a good predictor of clinical outcome in some human malignancies.
Molecular mapping of deletion sites in the short arm of chromosome 3 in human lung cancer
Authors: Brauch Hiltrud , Tory Kalman , Kotler Frederick , Gazdar Adi F. , Pettengill Olive S. , Johnson Bruce , Graziano Stephen , Winton Tim , Buys Charles H. C. M. , Sorenson George D. , Poiesz Bernard J. , Minna John D. , Zbar Berton
Published: February 2007

We used 10 restriction fragment length polymorphism (RFLP) probes spanning the length of the short arm of chromosome 3 (3p) to map deletion sites in human lung cancer. Two approaches were used. 1) When a patient's tumor and normal tissue were available, loci with allelic heterozygosity in the normal tissue were tested for loss of alleles at 3p. 2) When the corresponding normal tissue was not available, the frequency of heterozygosity at each locus in a panel of tumors was compared to the corresponding published frequencies in nontumor tissue of healthy individuals or patients with lung cancer. In 14 small cell lung carcinomas (SCLC) with normal DNA for comparison, allele loss was found at all heterozygous loci, with one exception at a locus near the 3p centromere (D3S4). In the total of 53 SCLCs, which included tumors without paired normal tissue, frequency of heterozygosity was significantly reduced in all 10 3p loci. Three loci, DNF15S2, RAF1, and D3S18, were homozygous in all tumors in the SCLC panel. These loci, which are in regions 3p21 and 3p25, may thus be involved in the origin or evolution of SCLC. We also investigated 24 non‐SCLC tumors. In this panel, frequency of heterozygosity was significantly reduced at seven of the 10 loci tested. Comparison of the results shows that the pattern of allele loss on 3p is different in SCLC and non‐SCLC, suggesting a difference in pathogenesis at the genetic level.
Identification of a transcriptional unit adjacent to the breakpoint in the 14;19 translocation of chronic lymphocytic leukemia
Authors: McKeithan Timothy W. , Ohno Hitoshi , Diaz Manuel O.
Published: February 2007

The t(14;19)(q32.3;q13.1) is a recurring translocation found in the neoplastic cells of some patients with chronic lymphocytic leukemia (CLL). We have previously cloned the translocation breakpoint junction present in the leukemic cells from one such patient. In the present study, we have cloned and sequenced the breakpoint junction from a second patient. The breakpoint on chromosome 14 occurs within a switch region upstream of the immunoglobulin heavy chain Cα1 sequence. We detected a 2.1–2.3 kb transcript on Northern blots using a probe from chromosome 19 adjacent to this breakpoint. S1 nuclease protection experiments showed that transcription of the gene proceeds in a direction away from the breakpoint junction. This gene (for which we propose the name BCL3) may contribute to the malignant development of B‐lymphocytes following the chromosome translocation. If so, it is the first protooncogene identified whose activation is principally associated with CLL.
Trisomy 5 and loss of the Y chromosome as the sole cytogenetic anomalies in a cavernous hemangioma/angiosarcoma
Authors: Mandahl Nils , Jin Yuesheng , Heim Sverre , Willén Helena , Wennerberg Johan , Biörklund Anders , Mitelman Felix
Published: February 2007

Cytogenetic analysis of a cavernous hemangioma with transition to angiosarcoma revealed the mosaic karyotype 47, XY,+5/46, X,‐Y,+5/45, X,‐Y/46, XY. No cytogenetically analyzed hemangiomas or angiosarcomas have been reported before.
Uterine leiomyoma cytogenetics
Authors: Nilbert Mef , Heim Sverre
Published: February 2007

Uterine leiomyoma—a benign smooth muscle tumor—has recently been found to contain tumor‐specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14‐15;q23‐24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one‐third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra‐myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors—leiomyosarcoma and rhabdomyosarcoma—are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13‐15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exist also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13‐15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor‐specific rearrangement.
The “missing” mouse plasmacytoma (MPC) associated translocation T(15;16) occurs repeatedly in new MPC induction systems
Authors: Wiener Francis , Silva Santiago , Sugiyama Hiroyuki , Babonits Magdalena , Klein George
Published: February 2007

A reciprocal translocation between chromosomes 15 and 16 has been detected in seven murine plasmacytomas induced by a combination of pristane and Abelson virus. Six of the tumors were induced in a new, unconventional experimental system based on transfer of uninfected or Abelson virus infected bone marrow and spleen cells, respectively, into pristane treated mice. All six tumors were of donor type. The seventh tumor appeared in a conventional pristane + Abelson virus treated mouse. This tumor was unusual in carrying both the 15;16 variant translocation and the typical 12;15 translocation, in the same tumor cells. In the new 15;16 variant, the breakpoint of chromosome 15 was at the interphase of the D2/3 sub‐bands, as in mouse plasmacytomas with the previously well‐known typical 12;15 and variant 6;15 translocations. The breakpoint on chromosome 16 was mapped to band 16B1, corresponding to the presumed cytogenetic site of the lg‐lambda gene. In three of the seven tumors with the 15;16 translocation, the derivative chromosome 15 had undergone a duplication, a feature that has not been previously encountered in the MPC‐associated 12;15 and 6;15 translocation carriers. The reciprocal derivative chromosome 16 was lost from one of the seven tumors. We postulate that the 15;16 translocation results in juxtaposition of the myc gene to lambda sequences, probably in a similar orientation as previously described for the variant 6;15 translocation.
No difference in expression of chromosomal fragile sites in patients with solid malignant tumours and normal controls
Authors: Kampmann Thomas , Schmidt Angela , Rüdiger Hugo W. , Tan Tjhoen Lien , Passarge Eberhard
Published: February 2007

The frequency and distribution of rare and common chromosomal fragile sites in metaphases derived from peripheral lymphocytes were compared in 26 patients with malignant solid tumours and 24 normal controls. In order to avoid bias in evaluation, the identity of each individual as patient or control was disclosed only after the study was completed. Rare heritable folic acid inducible fragile sites were found in five patients (2q13; 6p23; 8q22; 16p12) and two controls (8q22). Common fragile sites were present in 21 of 26 patients and in 19 of 24 controls. These differences are statistically not significant in the Fisher test. We conclude that the expression of fragile sites does not indicate a predisposition for solid tumours.
Demonstration of acquired hemizygosity and clonality in acute lymphoblastic leukemia with chromosome 7 abnormalities using hypervariable DNA probes
Authors: Yamada Toshiyuki , Shippey Caroline A. , Martineau Mary , Secker‐Walker Lorna M.
Published: February 2007

Clonal abnormalities of chromosome(s) 7 were investigated in two patients with acute lymphoblastic leukemia. The abnormal karyotypes were 46,XY,–7,del(6)(q13q21),+i(7q)/47,XY,del(6),+i(7q) in case 1, and 46,XX,–7,t(4;11)(q21;q23),+i(7q) in case 2. DNA from leukemic tissue was investigated with Southern blotting using hypervariable DNA probes λMS31 and pλg3 located on 7p and 7q, respectively. Restriction fragment length polymorphisms (RFLPs) were detected on the short arm in case 1 and on both arms in case 2, and a marked difference in intensity between the two alleles was observed. In case 1 the acquired hemizygosity of 7p, suggested by the cytogenetic findings, was confirmed by Southern blotting. Thus, one chromosome 7 formed the i(7q) and the other No. 7 was duplicated. In case 2 the results of the Southern blotting indicated that the size of the clone with i(7q) was considerably greater than suggested by cytogenetic analysis of the few available metaphase cells.
RAS gene mutations in childhood acute myeloid leukemia: A pediatric oncology group study
Authors: Vogelstein Bert , Civin Curt I. , Preisinger Antonette C. , Krischer Jeffrey P. , Steuber Philip , Ravindranath Y. , Weinstein Howard , Ellferich Peter , Bos Johannes
Published: February 2007

Mutations at codon 12, 13, and 61 of the HRAS, KRAS, and NRAS genes were evaluated in 99 cases of pediatric acute myeloid leukemia (AML) using oligonucleotide hybridization to polymerase chain reacted derived products. Twenty‐four mutations were identified in the NRAS gene, 13 in the KRAS gene, and none in the HRAS gene. The mutations occurred in a broad spectrum of cases, and there was no specific association of RAS gene mutations with patient subsets defined on the basis of clinical or hematologic features. These data demonstrate that RAS gene mutations are at least as common in childhood AML as in adult AML and suggest that RAS gene mutations play a role in myeloid neoplasia in both age groups.
The 11q13 amplicon of a mammary carcinoma cell line
Authors: Lafage Marina , Nguyen Catherine , Szepetowski Pierre , Pébusque Marie‐Josèphe , Simonetti Jacqueline , Courtois Geneviéve , Gaudray Patrick , Delapeyriere Odile , Jordan Bertrand , Birnbaum Daniel
Published: February 2007

Fifteen to 20% of breast carcinomas show amplification of genes located at 11q13. The HST/FGFK and INT2 fibroblast growth factor (FGF)‐related genes and the BCL1 locus are usually present in the amplification units. We have investigated the structure and chromosomal location of the 11q13 amplicon of the MDA‐MB‐134 mammary carcinoma cell line by using in situ chromosomal and pulsed field gel hybridizations. The results indicate that a limited number of amplification units are involved in the constitution of an extended chromosomal region located on 11q. These units do not show any important rearrangement over rather large distances around the HST/INT2 and BCL1 loci.
Genomic alterations in human breast carcinomas
Authors: Larsson Catharina , Byström Camilla , Skoog Lambert , Rotstein Sam , Nordenskjöld Magnus
Published: February 2007

All human chromosomes were screened in 52 human breast carcinomas for the occurrence of allele losses, in order to identify genomic alterations involved in initiation and progression of the disease. Loss of chromosome 22 alleles was detected in 6 out of 8 lobular carcinomas, while chromosome 17 losses were most frequent in ductal carcinomas. Furthermore, patients who developed advanced disease after many years of mild clinical course showed significantly higher frequencies of allele losses in their primary tumors, compared to patients with a persistently mild disease course. Finally, in one case, molecular examination suggested a translocation t(10;17) with coamplification of the ERBB2 oncogene and chromosome 10 sequences present in the two tumors from this patient, consistent with one of the tumors being a metastasis originating from a subclone of cells in the other tumor.
Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinomas of the head and neck
Authors: Jin Yuesheng , Higashi Koichiro , Mandahl Nils , Heim Sverre , Wennerberg Johan , Biörklund Anders , Dictor Michael , Mitelman Felix
Published: February 2007

We report the finding of clonal structural chromosome abnormalities in short‐term cultures from 15 squamous cell carcinomas of the head and neck region. When the distribution of chromosomal breakpoints in these 15 tumors and in the 16 head and neck carcinomas previously described are assessed, a marked clustering is seen at bands 1p22 and 11q13, which are rearranged in eight and nine tumors, respectively. No other band was involved in aberrations in more than five tumors. Cytogenetic evidence of gene amplification was seen in four tumors, three times in the form of homogeneously staining regions (twice located in 11q13), and in one tumor as double minutes. Among the candidate genes for such amplification are BCL1, INT2, and HST1, all of which map to 11q13, and NRAS, which maps to 1p22. All these oncogenes have previously been shown to be amplified in subsets of head and neck carcinomas. We conclude that bands 1p22 and 11q13 are nonrandomly involved in chromosomal rearrangements in head and neck carcinomas and suggest that activation of oncogenes located in these bands may proceed via cytogenetic mechanisms.
Molecular characterization of the t(10;14) translocation breakpoints in T‐cell acute lymphoblastic leukemia: Further evidence for illegitimate physiological recombination
Authors: Lu Ming , Dubé Ian , Raimondi Susana , Carroll Andrew , Zhao Ying , Minden Mark , Sutherland Peter
Published: February 2007

The t(10;14)(q24;q11) translocation is a non‐random chromosome change seen in the leukemic cells of 5–10% of patients with T‐cell acute lymphoblastic leukemia (T‐ALL). Recent studies support the hypothesis that the translocation occurs in the course of aberrant physiological recombination and results in the juxtaposition of a T‐cell receptor (TCR) gene in 14q11 with a putative oncogene, TCL3, in 10q24. We cloned and sequenced the translocation breakpoints on both derivative 10q+ and 14q– chromosomes from a patient with t(10;14)(q24;q11) T‐ALL. Two distinct diversity segments of TCRD, Dδ2 and Dδ3, were identified at the two translocation breakpoints on chromosome 14. The 9.5 kb DNA that separates these two subunits in the germline was deleted, possibly in the course of a D‐D joining event. The two chromosome 10 breakpoints were 10 nucleotides apart and occurred in the immediate vicinity of a pseudo‐heptamer signal motif. N‐region addition is also evident at the breakpoint on the derivative chromosome 10. Our observations strongly suggest that the IG/TCR recombinase normally involved in V‐(D)‐J joining was involved in the process of the t(10;14)(q24;q11) translocation.
Break in the BCL1 locus is closely associated with intermediate lymphocytic lymphoma subtype
Authors: Rimokh Ruth , Berger Françoise , Cornillet Pascale , Wahbi Kamal , Rouault Jean‐Pierre , Ffrench Martine , Bryon Paul‐André , Gadoux Myfène , Gentilhomme Odile , Germain Daniel , Magaud Jean‐Pierre
Published: February 2007

The t(11;14)(q13;q32) is a recurring translocation associated with some chronic B‐cell lymphocytic malignancies; the putative protooncogene BCL1, located at the chromosome band 11q13, can be involved during the translocation process. In order to determine if BCL1 rearrangement is associated with a particular subtype of lymphoma, we analysed 131 B‐cell non‐Hodgkin's lymphoma samples by Southern blot analysis, using a BCL1 probe. The BCL1 locus was rearranged in 9 out of 25 (36%) cases of intermediate lymphocytic cell lymphomas (ILL), in 1 out of 8 cases of diffuse small cleaved cell lymphoma, in 1 out of 12 cases of diffuse mixed cell lymphoma, and in 1 out of 21 cases of diffuse large cell lymphoma. In contrast, BCL1 was never found rearranged in any of the 46 follicular lymphomas analysed. The BCL2 gene was in germ‐line configuration in all ILL. Sequential hybridization of Southern blots with JH, Cμ, and BCL1 probes identified comigrating fragments in only one case of ILL, which suggests that, in all the other cases, either the rearrangement of BCL1 did not result from a t(11;14) translocation or the break on chromosome 14 occurred outside the JH or Cμ regions. These results indicate that rearrangement of the BCL1 locus may be closely associated with ILL and could be considered as a genotypic marker of this lymphoma subtype.
Constitutional translocation t(1;17)(p36;q12–21) in a patient with neuroblastoma
Authors: Laureys Geneviève , Speleman Frank , Opdenakker Ghislain , Benoit Yves , Leroy Jules
Published: February 2007

A constitutional chromosome translocation t(1;17)(p36;q12–21) is reported in a boy with neuroblastoma. This is the first description of a cytogenetic abnormality possibly predisposing to the development of neuroblastoma.
Chromosomal breakpoints in cholangiocarcinoma cell lines
Authors: Storto Patrick D. , Saidman Susan L. , Demetris Anthony J. , Letessier Eric , Whiteside Theresa L. , Gollin Susanne M.
Published: February 2007

Little is known about the genetics and biology of cholangiocarcinoma (intrahepatic bile duct carcinoma). Only three human bile duct carcinoma cell lines have been described in the literature. We present the first detailed cytogenetic analysis of two cell lines; a new cell line designated PCI:SG231, established in our laboratory, and RPMI‐7451, a previously established cell line. Both lines had highly aneuploid karyotypes with complex rearrangements including marker chromosomes. PCI:SG231, harvested after 50 days in culture, had a modal and median chromosome number of 65, and many cells contained double‐minute chromosomes. RPMI‐7451 had a modal and median chromosome number of 67. C‐banding confirmed the presence of dicentric chromosomes in PCI:SG231. Q‐banding confirmed the absence of the Y chromosome in PCI:SG231 and the presence of a der(1)t(Y;1)(q11;p11) chromosome in RPMI‐7451. Numerical abnormalities common to both lines included trisomies 2, 5, 11, and 20. Chromosomes 1, 5, 7, and 12 were most commonly involved in structural abnormalities in both lines. Consistent chromosomal breakpoints included 7q22 and 12p11–12 PCI:SG231 was tumorigenic in immunosuppressed nude mice and was histologically similar to the original tumor. Additional cholangiocarcinoma cell lines are being developed to continue the study of the genetics and cell biology of this disorder.
Irradiation microcell‐mediated chromosome transfer (XMMCT): The generation of specific chromosomal arm deletions
Authors: Dowdy Steven F. , Scanlon David J. , Fasching Clare L. , Casey Graham , Stanbridge Eric J.
Published: February 2007

The microcell‐mediated chromosome transfer technique has been used to introduce whole chromosomes into malignant cells and revert the tumorigenic phenotype. However, in most instances the limited availability of selectable chromosomes has hindered the ability to reduce the region containing the tumor suppressive information. The work presented here describes a new method to enrich for specific chromosomal arm deletions of selectable chromosomes and thereby more finely focus upon the genetic region of interest. The irradiation‐microcell mediated chromosome transfer (XMMCT) technique involves the irradiation of microcells containing single human chromosomes followed by fusion to a nonirradiated host and cytogenetic characterization. The XMMCT procedure was performed on a microcell hybrid containing a der(11) as the only human chromosome. The resultant irradiated microcell hybrids were found to have deletions that ranged from simple interstitial deletions to complex deletions/rearrangements involving only the human der(11) chromosome. The XMMCT procedure has broad applications in generating chromosomal reagents for mapping genetic loci and for use in functional analyses such as tumor suppression studies.
Breast cancer and other cancers in Norwegian families with ataxia‐telangiectasia
Authors: Børresen Anne‐Lise , Andersen Tone Ikdahl , Tretli Steinar , Heiberg Arvid , Møller Pål
Published: February 2007

Patients who are homozygous for ataxia‐telangiectasia (AT) have an exceptionally high incidence of cancer. Heterozygous individuals for the disease have been reported to be at an increased risk of cancer, particularly breast cancer in female carriers. We have analyzed eight Norwegian families with AT for cancer incidence in the parents, in the parents' sibs, grandparents, and grandparents' sibs. Two of the obligate heterozygote females have had premenopausal breast cancer. This incidence is significantly higher than expected for that group. No increase in the cancer incidence was observed in the parents' sibs, the grandparents, or the grandparents' sibs. Since the incidence of AT is low, data from many sources have to be combined to allow any conclusion.
Consistent cytogenetic aberrations in hepatoblastoma: A common pathway of genetic alterations in embryonal liver and skeletal muscle malignancies?
Authors: Fletcher Jonathan A. , Kozakewich Harry P. , Pavelka Karen , Grier Holcombe E. , Shamberger Robert C. , Korf Bruce , Morton Cynthia C.
Published: February 2007

Cytogenetic analyses of four consecutive hepatobiastomas revealed near‐diploid stemline karyotypes with relatively simple chromosome aberrations. Cytogenetic abnormalities shared by each tumor included trisomy for all of part of chromosome 2 and trisomy for chromosome 20. In two cases, partial trisomy for chromosome 2 resulted from direct duplication of long arm material with the shortest region of overlap being 2q23‐2q35. In one tumor, each metaphase also contained a variable number of double minute chromosomes found not to derive from NMYC amplification. Interestingly, trisomy for 2q and trisomy 20 are also characteristic events in pediatric embryonal rhabdomyosarcomas. Furthermore, others have reported loss of heterozygosity for the short arm of chromosome 11 in both hepatoblastoma and childhood embryonal rhabdomyosarcoma, and both these malignant diseases are associated with Beckwith‐Wiedemann syndrome. These cytogenetic and molecular findings suggest a parallel pathway of genetic steps in the initiation and/or progression of tumors of embryonal liver and skeletal muscle.
Direct pulsed field gel electrophoresis of Wilms' tumors shows that dna deletions in 11 p 13 are rare
Authors: Royer‐Pokora Brigitte , Ragg Susanne , Heckl‐Östreicher Brigitte , Held Manuela , Loos Ursula , Call Katherine , Glaser Tom , Housman David , Saunders Grady , Zabel Bernhard , Williams Bryan , Poustka Annemarie
Published: February 2007

In order to search for small tumor‐specific deletions in 11 p 13 we analysed DNA isolated from 30 fresh Wilms' tumor (WT) samples with pulsed field gel electrophoresis. For these studies we have isolated new probes from the ends of several Nod fragments. Using these and previously described probes from 11 p 13 we first completed and extended the existing map of the 11 p 13 region. The analysis of the tumor material showed that (1) tumor‐specific deletions were very rare: one homozygous deletion out of 30 tumors analysed, (2) hemizygous deletions were not observed in any of the tumors. The homozygous deletion in one patient spans 220 kb and is composed of a tumor‐specific translocation associated with a deletion on one chromosome and a deletion of about 220 kb on the other chromosome at the same site. The WT‐33 Wilms' tumor candidate gene maps to this deleted segment. A small constitutional deletion of 1,300 kb was identified in a patient with WT and genital tract malformations. These results suggest that in the majority of sporadic WT loss of gene function is due to subtle alterations in the gene, e.g., point mutations or very small deletions.