bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of CXCR4 predicts adverse overall and event‐free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype
Authors: Konoplev Sergej , Rassidakis Georgios Z. , Estey Elihu , Kantarjian Hagop , Liakou Chrysoula I. , Huang Xuelin , Xiao Lianchun , Andreeff Michael , Konopleva Marina , Medeiros L. Jeffrey
Published: February 2007

BACKGROUND.

CXC chemokine receptor 4 (CXCR4) expression in acute myeloid leukemia (AML) is reported to correlate with FLT3 gene mutation and poorer prognosis. The prognostic significance of CXCR4 expression in patients with AML that have a normal karyotype and no evidence of FLT3 gene mutations was examined.

METHODS.

The prognostic significance of CXCR4 expression in 122 AML patients with normal karyotype and no evidence of FLT3 gene mutation treated at our institution between 1997 and 2003 was analyzed. All patients received intensive chemotherapy according to institutional protocols; 84% received cytarabine‐containing regimens. Bone marrow biopsy or clot specimens obtained before treatment were immunostained for CXCR4.

RESULTS.

There were 70 men and 52 women with a median age of 62 years (range, 22–82 years). Median follow‐up was 18 months (range, <1–97 months). Seventy‐six patients achieved complete remission (CR); 39 had recurrence. Sixty‐six patients died, including 9 with no evidence of disease. CXCR4 was positive in 70 and negative in 52 patients, with CR rates of 58% and 71%, respectively (P = .09). Multivariate analysis demonstrated that CXCR4 expression, presence of multilineage dysplasia, and high creatinine level predicted poorer overall (OS) and event‐free (EFS) survival.

CONCLUSIONS.

The results suggest that CXCR4 expression is associated with poor prognosis in AML patients with an unmutated FLT3 gene. Cancer 2007. © 2007 American Cancer Society.
Therapeutic radiation for lymphoma
Authors: Teta M. Jane , Lau Edmund , Sceurman Bonnielin K. , Wagner Meghan E.
Published: February 2007

BACKGROUND

Ionizing radiation has been used since the 1950s to treat a variety of cancers. Cancer patients who are treated with radiotherapy have shown increased risks for a variety of second malignancies, including mesothelioma, in several recent reports. The only existing study of Hodgkin lymphoma (HL) and subsequent mesothelioma had a short observation period.

METHODS

The authors used Surveillance, Epidemiology, and End Results data over a 30‐year period to identify patients with HL and non‐Hodgkin lymphoma (NHL) who also were diagnosed with mesothelioma. Standardized incidence ratios (SIR) and absolute excess risks were calculated by sex and treatment modality for both types of lymphoma.

RESULTS

Twenty‐six patients were identified who had mesothelioma as second primaries based on 21,881 diagnoses of HL and 101,001 diagnoses of NHL. There was a statistically significant increase in mesothelioma (4 diagnoses; SIR, 6.59; 95% confidence interval [95% CI], 1.79–16.87) among men with HL who received radiation, but no women survivors were identified who had a diagnosis of mesothelioma. For NHL survivors, there was a nonsignificant excess of mesothelioma among men (SIR, 1.91; 95% CI, 0.77–3.93) and women (SIR, 3.75; 95% CI, 0.77–10.95) who had received radiation treatment. There were no increases among patients who were unirradiated.

CONCLUSIONS

Mesothelioma rates for patients who had received radiotherapy were increased for survivors of HL and NHL. No increases were observed among the unirradiated. These findings and the existing body of supporting studies confirmed that radiotherapy is a cause of mesothelioma. Cancer 2007. © 2007 American Cancer Society.
Periodic group edge crack problem of half‐plane in antiplane elasticity
Authors: Chen Y. Z. , Wang Z. X. , Li F. L.
Published: February 2007

Using complex variable function, an elementary solution of a single‐edge crack problem for half‐plane is proposed. The elementary solution is obtained by distributing the dislocation density along the prospective place of crack, and it is composed of the principal part and the complementary part. Based on the elementary solution and the principle of superposition, a system of Cauchy singular integral equations for periodic group edge crack problems of half‐plane in antiplane elasticity can be formulated. In the solution of the singular integral equation, the influences of many neighbouring groups on the central group are evaluated exactly. In addition, the influences on the central group by the many remote groups are considered approximately. By using a semi‐open quadrature rule, the singular integral equations are solved and the stress intensity factors at the crack tips are evaluated. Several numerical examples are given. Copyright © 2007 John Wiley & Sons, Ltd.
Fine‐needle aspiration cytology of a membranous basal cell adenoma arising in an intraparotid lymph node
Authors: López José I. , Ballestin Claudio
Published: February 2007

The so‐called membranous basal cell adenoma is a rare subtype of monomorphic adenomas that usually presents in the parotid gland. The cytologic, histologic, and immunohistochemical findings of an example of this entity, arising in an intraparotid lymph node of a 75‐yr‐old woman, are reported. Only 7 cases of this tumor have been published in such a peculiar location. As far as we know, fine‐needle aspiration cytology has never been performed.
High T‐helper‐1 cytokines but low T‐helper‐3 cytokines, inflammatory cytokines and chemokines in children with high risk of developing type 1 diabetes
Authors: Stechova Katerina , Bohmova Kristyna , Vrabelova Zuzana , Sepa Annelie , Stadlerova Gabriela , Zacharovova Klara , Faresjö Maria
Published: February 2007

Background

Type 1 diabetes (T1D) is suggested to be of T‐helper (Th)1‐like origin. However, recent reports indicate a diminished interferon (IFN)‐γ secretion at the onset of the disease. We hypothesize that there is a discrepancy in subsets of Th‐cells between children with a high risk of developing T1D, children newly diagnosed with T1D and healthy children.

Methods

Peripheral blood mononuclear cells (PBMC) were collected from children at high risk for T1D (islet cells antibodies [ICA] ≥ 20 IJDF‐U), those newly diagnosed and healthy children carrying the HLA‐risk gene DQB1*0302 or DQB1*0201 and DQA1*0501. Th1‐ (IFN‐γ, tumour necrosis factor [TNF]‐β, interleukin [IL]‐2), Th2‐ (IL‐4,‐5,‐13), Th3‐ (transforming growth factor [TGF‐β], IL‐10) and inflammatory associated cytokines (TNF‐α, IL‐1α,‐6) and chemokines (monocyte chemoattractant protein [MCP]‐1,‐2,‐3, Monokine unregulated by IFN‐γ [MIG], Regulated on Activation, Normal T‐cell Expressed and Secreted [RANTES], IL‐7,‐8,‐15) were detected in cell‐culture supernatants of PBMC, stimulated with glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA), by protein micro array and enzyme linked immunospot (ELISPOT) technique.

Results

The Th1 cytokines IFN‐γ and TNF‐β, secreted both spontaneously and by GAD65‐ and mitogen stimulation, were seen to a higher extent in high‐risk children than in children newly diagnosed with T1D. In contrast, TNF‐α and IL‐6, classified as inflammatory cytokines, the chemokines RANTES, MCP‐1 and IL‐7 as well as the Th3 cytokines TGF‐β and IL‐10 were elevated in T1D children compared to high‐risk children.

Conclusion

High Th‐1 cytokines were observed in children with high risk of developing TID, whereas in children newly diagnosed with T1D Th3 cytokines, inflammatory cytokines and chemokines were increased. Thus, an inverse relation between Th1‐like cells and markers of inflammation was shown between children with high risk and those newly diagnosed with T1D. Copyright © 2007 John Wiley & Sons, Ltd.
Comparison of the anti‐diabetic effects of GIP‐ and GLP‐1‐receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N‐AcGIP and exendin(1–39)amide
Authors: Irwin Nigel , McClean Paula L. , Cassidy Roslyn S. , O'Harte Finbarr P. M. , Green Brian D. , Gault Victor A. , Harriott Patrick , Flatt Peter R.
Published: February 2007

Background

The two major incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are being actively explored as anti‐diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP‐1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short‐lived, but stable agonists such as N‐acetylated GIP (N‐AcGIP) and exendin(1‐39)amide have been advocated as stable and specific GIP and GLP‐1 analogues.

Methods

The present study examined the sub‐chronic (14 days) anti‐diabetic actions of single daily doses of N‐AcGIP and exendin(1‐39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14‐day period.

Results

Initial experiments confirmed the potent anti‐hyperglycaemic and insulinotropic properties of N‐AcGIP and exendin(1‐39)amide. Sub‐chronic administration of N‐AcGIP alone or in combination with exendin(1‐39)amide significantly decreased non‐fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N‐AcGIP and exendin(1‐39)amide also significantly decreased glycated haemoglobin. Exendin(1‐39)amide alone had no significant effect on any of the metabolic parameters monitored. In addition, no significant effects were observed on body weight and food intake in any of the treatment groups.

Conclusions

The results illustrate significant anti‐diabetic potential of N‐AcGIP alone and in combination with exendin(1‐39)amide. Copyright © 2007 John Wiley & Sons, Ltd.
Mixed primary culture and clonal analysis provide evidence that NG2 proteoglycan‐expressing cells after spinal cord injury are glial progenitors
Authors: Yoo Soonmoon , Wrathall Jean R.
Published: February 2007

NG2+ cells in the adult rat spinal cord proliferate after spinal cord injury (SCI) and are postulated to differentiate into mature glia to replace some of those lost to injury. To further study these putative endogenous precursors, tissue at 3 days after SCI or from uninjured adults was dissociated, myelin partially removed and replicate cultures grown in serum‐containing or serum‐free medium with or without growth factors for up to 7 days in vitro (DIV). Cell yield after SCI was 5–6 times higher than from the normal adult. Most cells were OX42+ microglia/macrophages but there were also more than twice the normal number of NG2+ cells. Most of these coexpressed A2B5 or nestin, as would be expected for glial progenitors. Few cells initially expressed mature astrocyte (GFAP) or oligodendrocyte (CC1) markers, but more did at 7 DIV, suggesting differentiation of glial precursors in vitro. To test the hypothesis that NG2+ cells after SCI express progenitor‐like properties, we prepared free‐floating sphere and single cell cultures from purified suspension of NG2+ cells from injured spinal cord. We found that sphere cultures could be passaged in free‐floating subcultures, and upon attachment the spheres clonally derived from an acutely purified single cell differentiated into oligodendrocytes and rarely astrocytes. Taken together, these data support the hypothesis that SCI stimulates proliferation of NG2+ cells that are glial progenitor cells. Better understanding the intrinsic properties of the NG2+ cells stimulated by SCI may permit future therapeutic manipulations to improve recovery after SCI. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
5‐HT2 receptors in Drosophila are expressed in the brain and modulate aspects of circadian behaviors
Authors: Nichols Charles D.
Published: February 2007

Dysregulation of 5‐HT2 receptor function has been strongly implicated in many neuropsychiatric disorders, including schizophrenia. At present, the molecular mechanisms linking 5‐HT2 receptor activation to behaviors is not well understood. In efforts to elucidate these processes, the fruit fly, Drosophila melanogaster, is proposed to serve as a powerful genetically tractable model organism to study 5‐HT2 receptor function. Data are presented here on the expression of the fly ortholog of the mammalian 5‐HT2 receptor, 5‐HT2Dro, in the larval and adult brain of the fly, and on the involvement of these circuits in certain circadian behaviors. In the adult brain, 5‐HT2Dro is expressed in the protocerebrum and ellipsoid body, areas believed to participate in higher order behaviors including learning, locomotion, and sensory perception. In the third instar larva, 5‐HT2Dro receptor expression is detected in a specific pattern that markedly changes from early to late third instar. To probe the function of this receptor we have examined the effects of the 5‐HT2 receptor‐specific agonist DOI in wild type and 5‐HT2Dro hypomorphic flies on circadian behaviors. DOI was found to increase early day activity, eliminate anticipatory behavior, and reduce viability. The effects of DOI were significantly diminished in a 5‐HT2Dro hypomorphic strain. Identifying the 5‐HT2Dro receptor circuitry and behaviors they mediate are significant steps towards developing this model system to study conserved molecular mechanisms underlying behaviors mediated by 5‐HT2 receptors in mammalian systems. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Recruitment of FoxP2‐expressing neurons to area X varies during song development
Authors: Rochefort Christelle , He Xiaolu , Scotto‐Lomassese Sophie , Scharff Constance
Published: February 2007

In adult songbirds, neural progenitors proliferate along the lateral ventricles. After migration, many of the subsequently formed neuroblasts integrate into the song nuclei HVC and Area X that participate in auditory‐guided vocal motor learning and singing. Recruitment of postembryonically generated neurons into HVC, rodent hippocampus, and olfactory bulb has been linked to learning and memory. The cellular identity and the role of postembryonically generated neurons in Area X are unknown. Here we describe that the majority of new neurons in postembryonic Area X of male zebra finches expressed DARPP32 but not choline acetyltransferase or parvalbumin. This suggests that they are spiny neurons. Retrogradely labeled neurons projecting to thalamic nucleus DLM were not renewed. The spiny neurons in Area X were recently shown to express FoxP2, a transcription factor critical for normal speech and language development in humans. Since increased FoxP2 mRNA expression was previously observed during periods of vocal plasticity we investigated whether this increase might be associated with neuronal recruitment. Consistent with their spiny phenotype, new neurons in Area X did express FoxP2 and recruitment increased transiently during the juvenile song learning period. Moreover we found that FoxP2 was expressed in the ventricular zone of adult songbirds but was absent from the germinal zones in adult mouse brains, the hippocampus, and the subventricular zone. Together these results raise the possibility that neuronal recruitment and FoxP2 expression in Area X are associated with vocal learning. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Hormonal and environmental control of song control region growth and new neuron addition in adult male house finches, Carpodacus mexicanus
Authors: Strand Christine R. , Deviche Pierre
Published: February 2007

In songbirds, testosterone (T) mediates seasonal changes in the sizes and neuroanatomical characteristics of brain regions that control singing (song control regions; SCRs). One model explaining the mechanisms of the growth of one SCR, the HVC, postulates that in the spring increasing photoperiod and circulating T concentrations enhance new neuron survival, thus increasing total neuron number. However, most research investigating the effects of T on new neuron survival has been done in autumn. The present study investigated the effects of photoperiod and T treatment on SCR growth and new neuron survival in the HVC in photosensitive adult male House Finches, Carpodacus mexicanus, under simulated spring‐like conditions. Birds were castrated, given T‐filled or empty Silastic capsules and maintained on short days (SD; 8L:16D) or long days (LD; 16L:8D). To mark new cells, birds received bromodeoxyuridine injections 11 days after experimental manipulations began and were sacrificed 28 days later. Testosterone treatment increased the sizes of two SCRs, the HVC and Robust nucleus of the arcopallium (RA). Exposure to LD did not affect HVC volume, but did increase RA volume. Testosterone treatment increased the total number of HVC neurons, but did not affect the number of new HVC neurons. Thus, T initiates SCR growth and increases neuron survival, but effects of T on new neuron incorporation may be limited in photosensitive birds under spring‐like conditions. These results provide new insight into the effects of photoperiod and T treatment on vernal SCR growth and new neuron incorporation and support current models explaining this growth. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Impacts of distributed Raman amplification transmission technologies on terrestrial large‐capacity WDM systems
Authors: Masuda Hiroji , Tomizawa Masahito , Miyamoto Yutaka , Hagimoto Kazuo
Published: February 2007

The impact of distributed Raman amplification (DRA) technologies on long‐distance large‐capacity transmission systems is discussed from the viewpoint of improving the signal‐to‐noise ratio (SNR). First, we show the characteristics of this technology, which has brought significant improvement to the SNR, and its trends, the basic configuration for our proposed DRA system (a DRA/EDFA hybrid configuration), and safety aspects for high‐power pumped light. In addition, we show the merits of the DRA system, including the amount of improvement in the optical SNR, transmission fiber (DSF and SMF) dependence, and superiority of DSF over SMF (about 2 to 3 dB). Furthermore, in a long‐distance large‐capacity wavelength division multiplexing transmission field trial using DRA in the L band on DSF, we confirm good transmission characteristics. In other words, the impact of DRA technologies lies in the significant improvement of the SNR in terrestrial long‐distance large‐capacity optically amplified transmission systems with field‐installed fibers, and in the improvement of performance in systems utilizing these technologies. © 2007 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 90(6): 20–28, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20340
Design and implementation of a fully distributed ultrasonic positioning system
Authors: Minami Masateru , Morikawa Hiroyuki , Aoyama Tomonori
Published: February 2007

In the ubiquitous computing environment, the physical locations of persons and goods are extremely important information. In this paper, the design of a fully distributed localization system based on ultrasound, mainly for the indoor environment, is described. This system performs localization with as few positioning references as possible by an iterative technique. When such a localization method is used, deterioration of localization accuracy due to no‐line‐of‐sight signals and to accumulated errors is a problem. In this paper, the resolution of these problems is discussed and system evaluation by implementation experiments is carried out. With 24 devices, localization with an accuracy of about 20 cm is demonstrated. © 2007 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 90(6): 17– 26, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.20249
A design of ΔΣ A‐D converter
Authors: Hayahara Etsuro , Aoki Ken'Ichi , Hirano Satoshi
Published: February 2007

The ΔΣ modulation A‐D converter is widely used in practice as a high‐resolution A‐D converter suitable for LSI implementation. However, in general, if the order of the loop filter in the ΔΣ modulation A‐D converter exceeds three, stability of the circuit is no longer guaranteed. In this paper, the relationship of the loop filter coefficients in the A‐D converter is studied. Based on the results, a design method is proposed for a higher‐order ΔΣ modulation A‐D converter such that stability is assured while maximizing the signal‐to‐noise (SN) ratio. Further, the results of a PSPICE simulation and experimental results obtained using individual components confirm that the present design method is sufficiently practical. © 2007 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 90(6): 10– 16, 2007; Published online in Wiley InterScience (www.interscience. wiley.com). DOI 10.1002/ecjc.20269
CE‐ and HPLC‐TOF‐MS for the characterization of phenolic compounds in olive oil
Authors: Carrasco‐Pancorbo Alegría , Neusüß Christian , Pelzing Matthias , Segura‐Carretero Antonio , Fernández‐Gutiérrez Alberto
Published: February 2007

We present an easy and rapid method for the analysis of phenolic compounds in extra‐virgin olive oil by CZE coupled with ESI‐TOF‐MS. Optimum electrophoretic separation was obtained using a basic carbonate electrolyte. We thus achieved the determination of several important families (phenyl alcohols, phenyl acids, lignans, flavonoids, and secoiridoids) of the polar fraction of the olive oil. Furthermore, other “unknown” compounds were also identified. In addition to the CZE method, HPLC analyses were made, separating compounds belonging to the main families present in this polyphenolic fraction, as well as other new compounds. We compared the results obtained with both techniques and found it was possible to determine more than 45 compounds with both methods. The sensitivity, together with mass accuracy and true isotopic pattern of the TOF‐MS, allowed the identification of a broad series of known and so far not described phenolic compounds present in extra‐virgin olive oil.
Control of EOF in CE by different ways of application of radial electric field
Authors: Sázelová Petra , Kašička Václav , Koval Dušan , Prusík Zdeněk , Fanali Salvatore , Aturki Zeineb
Published: February 2007

Various ways of application of radial electric field for the control of electrokinetic potential and EOF in a home‐made device for CE are presented. The device comprises three high‐voltage power supplies, which are used to form a radial electric field across the fused‐silica capillary wall. One power supply provides the internal electric field – a driving force for electrophoretic migration of charged analytes and for the EOF. Two power supplies are connected to the ends of the outer low‐conductivity polymeric coating, which is formed by the dispersion of insoluble conductive copolymer of aniline and p‐phenylendiamine in polystyrene matrix (dissolved in N‐methylpyrrolidone) attached to the original outer polyimide coating of the capillary. They are able to constitute the external longitudinal electric field with variable values of electric potential at both ends of the outer coating. The potential gradient between the external and internal electric field is perpendicular to the capillary wall and forms a radial electric field across the capillary wall, which affects the electrokinetic potential at the solid–liquid interface and EOF inside the capillary. The developed device and methodology has been applied for the analysis of both chiral and achiral molecules such as terbutaline enantiomers and oligopeptides (diglycine and triglycine). The effect of magnitude, orientation, and different ways of application of the radial electric field on the flow rate of the EOF and on the speed, efficiency, and resolution of CZE separations of the above analytes in the internally noncoated fused‐silica capillaries have been evaluated.
Modulation of induced reversion frequency by nucleotide pool imbalance as a tool for mutant characterization
Authors: Randazzo Rosalba , di Leonardo A. , Bonatti Stefania , Abbondandolo A.
Published: February 2007

Addition of thymidine (TdR) or deoxycytine (CdR) to the culture medium during posttreatment incubation affected the frequency of mutagen‐induced reversion in three hypoxanthine‐guanine phosphoribosyl transferase‐deficient mutants of V79 Chinese hamster cells. With two of the mutants (E20 and 13), reversions induced by N‐ethylnitrosourea, ethyl methanesulfonate, and methyl methanesulfonate were enhanced by TdR and were either decreased (E20) or not affected (13) by CdR. With the third mutant (E21), alkylating agent‐induced reversions were enhanced by CdR and decreased by TdR. Finally, 6‐amino‐2‐hydroxypurine induced reversions were enhanced by TdR in mutant I3 and were decreased by TdR or deoxyadenosine (AdR) and enhanced by CdR in mutant E21. An attempt was made to reconcile these results with simple mutation mechanisms, based on either G:C to A:T or A:T to G:C transitions. It is suggested that the present approach may add useful information to studies of specific revertibility of mammalian cell mutants with known mutagens.
Variation in the human lymphocyte sister chromatid exchange frequency as a function of time: Results of daily and twice‐weekly sampling
Authors: Tucker James D. , Christensen Mari L. , Strout Cheryl L. , McGee Keith A. , Carrano Anthony V.
Published: February 2007

The variation in lymphocyte sister chromatid exchange (SCE) frequency was investigated in healthy nonsmokers who were not taking any medication. Two separate studies were undertaken. In the first, blood was drawn from four women twice a week for 8 weeks. These donors recorded the onset and termination of menstruation and times of illness. In the second study, blood was obtained from two women and two men for 5 consecutive days on two separate occasions initiated 14 days apart. One donor participated in both studies. Analysis of the mean SCE frequencies in each study indicated that significant temporal variation occurred in each donor, and that more variation occurred in the longer study. Some of the variation was found to be associated with the menstrual cycle. Peaks in the SCE frequency were observed at times that corresponded approximately to ovulation and to the beginning and end of menstruation. In the daily study, most of the variation appeared to be random, but occasional day‐to‐day changes occurred that were greater than those expected by chance. To determine how well a single SCE sample estimated the pooled mean for each donor in each study, we calculated the number of samples that encompassed that donor's pooled mean within 1 or more standard errors. For both studies, about 75% of the samples encompassed the pooled mean within 2 standard errors. An analysis of high‐frequency cells (HFCs) was also undertaken. The results for each study indicate that the proportion of HFCs, compared with the use of Fisher's Exact test, is significantly more constant than the means, which were compared by using the t‐test. These results coupled with our previous work suggest that HFC analysis may be the method of choice when analyzing data from human population studies.
Binding of ethylene oxide in spermiogenic germ cell stages of the mouse after low‐level inhalation exposure
Authors: Sega G. A. , Owens J. G.
Published: February 2007

Mice received inhalation exposures of 3H‐labeled ethylene oxide (EtO) gas at levels from 0.65 to 3.2 parts per million‐hours (ppm‐hr), which are below the exposure limits currently allowed for humans. Subsequently, spermatozoa were recovered from the reproductive tracts of the animals over a two‐week period and assayed for the amount of bound EtO. A strong increase in the level of EtO binding occurred in late spermatid stages; these stages are also genetically sensitive to the action of EtO. The maximum binding of EtO in late spermatids amounted to 6 × 103 alkylations/sperm head/ppm‐hr of exposure. Alkylation of the DNA within the sperm accounted for a very small fraction of the total sperm head alkylation, averaging about 20 DNA alkylations per sperm per ppm‐hr of exposure over the two‐week period. However, alkylation of protamine, a protein unique to sperm cells, was found to be correlated with total sperm head alkylation and accounted for nearly all of the EtO binding. Protamine alkylation appears to be a significant cause of EtO‐induced genetic damage in spermiogenic cells of the mammal.
Differential sensitivity of mouse oocytes to colchicine‐induced aneuploidy
Authors: Mailhes John B. , Yuan Zhi Ping
Published: February 2007

Unpublished results from our laboratory showed that colchicine increased the incidence of hyperploid mouse metaphase II (MII) oocytes when injected at the same time as human chorionic gonadotrophin (HCG). The objective of the present study was to determine whether the time of administering colchicine influenced the incidence of aneuploidy in MII oocytes. CD‐1 mice were given pregnant mare's serum (PMS) and, 48 hr later, HCG. An intraperitoneal injection of 0.2 mg/kg colchicine was given at +4, +2, 0, −2, or −4 hr relative to HCG. Oocytes were collected 17 hr post‐HCG and processed, and chromosomes were subsequently C‐banded. The percentage of hyperploid oocytes was 0.77, 2.56, 5.71, 7.79, 3.54, and 2.70 for control, +4, +2, 0, −2, or −4 hr pre/post‐HCG, respectively. Chi‐square analyses of these data demonstrated that colchicine significantly increases the proportion of aneuploid oocytes, and that the relative sensitivity of colchicine‐induced aneuploidy depends upon the time that this drug is administered relative to HCG.
Induction and transmission of chemically induced chromosome aberrations in female germ cells
Authors: Albanese R.
Published: February 2007

Female mice were dosed with a number of chemical clastogens. The dosed females were then mated 28.5, 6.5, and 0.5 days after dosing, corresponding to various developmental stages of oogenesis (ie, early pre‐antral to late antral stages). One‐cell embryos derived from these matings were then isolated and analysed for structural and/or numerical chromosome aberrations. Chromosome damage, either structural or numerical, was induced only in oocytes at the late antral stages of oogenesis (i.e. when females were dosed 0.5 days prior to mating). There were few chromosome aberrations in embryos obtained from females dosed 6.5 or 28.5 days prior to mating. The results show that the analysis of one‐cell embryos derived from the germ cells of dosed females is a potentially useful test system for the identification of chemically induced structural and numerical chromosome aberrations. However, the technically demanding methods involved in the preparation of these one‐cell embryos prevent their use for routine screening purposes.
Low oxygen tension, as found in tissues in vivo, alters the mutagenic activity of aristolochic acid I and II in primary fibroblast‐like rat cells in vitro
Authors: Maier Peter , Schawalder Hanspeter , Weibel Beatrice
Published: February 2007

The mutagenic activities of aristolochic acid I (AAI) and II (AAII), the two main components of aristolochic acid (AA), were tested for mutagenicity in vivo in a subcutaneous granulation tissue in rats and in vitro in the corresponding freshly isolated and cultured target cells. In vivo at equimolar dose, AAI induced 16 times more 6‐thioguanine resistant cells than AAII. Oxygen tension in vitro was adjusted to that found in vivo: in the subcutaneous connective tissue, the pO2 was determined to be 40 ± 9 mm Hg, which corresponds in vitro to an O2 concentration of 5% in the incubator atmosphere. In vitro, AAI was 19 times more mutagenic than AAII at this low oxygen tension but exhibited only 4 times greater activity than AAII under standard culture conditions. These results indicate that the genotoxic activity of AA in mammals is mainly caused by AAI and that the exposure of cells to AAI and AAII in vitro at low pO2 corresponds more closely to the metabolic situation in vivo. Therefore, the mutagenic potency of the two chemicals can only be estimated correctly at tissue oxygen tension. The influence of pO2 on the mutation frequencies seems to arise from a modulation of the activation/detoxification pathways.
Mutagenicity testing of ethylene oxide in Escherichia coli strains with different repair capacities
Authors: Kolman Ada , Näslund Maria
Published: February 2007

Mutagenicity of ethylene oxide in Escherichia coli B strains with different repair capacities was studied. Deficiencies in excision repair (uvrA, polA) led to a considerable increase in mutation frequency compared with that in the wild‐type strain and in strains deficient in error‐prone repair (recA, lexA).
Stability and inactivation of mutagenic drugs and their metabolites in the urine of patients administered antineoplastic therapy
Authors: Monteith D. K. , Connor T. H. , Benvenuto J. A. , Fairchild E. J. , Theiss J. C.
Published: February 2007

Urine samples from patients administered mutagenic antineoplastic drugs are mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urine samples in the present study were tested for mutagenicity in several strains of Salmonella typhimurium that were uvr negative (TA98, TA100) or positive (TA102, UTH8413, UTH8414), and were analyzed for the presence of drugs and their metabolites using high‐pressure liquid chromatography (HPLC). Urine samples from cancer patients were kept at room temperature and their mutagenicity as well as the chemical stability of the drugs was tested for a period of 14 days. It was observed that, in general, the urine remained mutagenic for the 14‐day period while the parent compound degraded within the first seven days. An exception was cisplatin, which was chemically stable as platinum, but the urine decreased in mutagenicity with time. This decrease was probably the result of ligand exchange with the platinum. Inactivation methods were developed to reduce the genotoxic hazard posed by the mutagenic compounds in the urine. Cisplatin was inactivated by complexing with sodium diethyldithiocarbamate (DDTC). Oxidation of urine containing mitomycin C and doxorubicin (sodium thiosulfate must be added to urine containing doxorubicin) with 5.25% sodium hypochlorite solution (bleach) results in mutagenic inactivation. Urine containing cyclophosphamide and its metabolites was oxidized with alkaline potassium permaganate and the active degradation products trapped with sodium thiosulfate. Both chemical and mutagenic assays are necessary to determine the reduction of risk. Methods of inactivation of mutagenic urine developed in this study are both effective and practical for the reduction of exposure to genotoxic hazards.
A modified mouse peripheral blood lymphocyte culture system for cytogenetic analysis
Authors: Erexson Gregory L. , Kligerman Andrew D.
Published: February 2007

A detailed methodology is presented for culturing mouse peripheral blood lymphocytes isolated on density gradients and stimulated to divide using either phytohem‐agglutinin, concanavalin A, or lipopolysaccharide. The techniques described yield more than sufficient numbers of mitotic cells for analyzing sister chromatid exchange, chromosome aberrations, and micronuclei following in vitro or in vivo exposure to chemicals or radiation.
Aneuploidy induction in Saccharomyces cerevisiae by two solvent compounds, 1‐methyl‐2‐pyrrolidinone and 2‐pyrrolidinone
Authors: Mayer Vernon W. , Goin Carol J. , Taylor‐Mayer Rhoda E.
Published: February 2007

A number of solvent compounds that were tested in Saccharomyces cerevisiae were potent inducers of aneuploidy, although they did not induce any other genetic effects. As an extention of these earlier findings, 1‐methyl‐2‐pyrrolidinone was tested and was found to induce aneuploidy. Several structurally related compounds were also tested; 2‐pyrrolidinone induced aneuploidy, but succinimide, pyrrolidine, 1‐methylpyrrolidine, 1‐methyl‐3‐pyrrolidinol, and 2‐pyrrolidineethanol did not. Maleimide and its N‐hydroxy, N‐methyl, and N‐ethyl derivatives were also negative for aneuploidy induction.
In vitro BALB/3T3 cell transformation assay of nonoxynol‐9 and 1,4‐dioxane
Authors: Sheu Chingju W. , Moreland Frances M. , Lee Jung Keun , Dunkel Virginia C.
Published: February 2007

The spermicidal surfactant nonoxynol‐9 (Igepal CO‐630, GAF Corp.) and a potential impurity, 1,4‐dioxane, were tested in the in vitro cell transformation assay using BALB/3T3 cells. Two treatment periods, 48 hr and 13 days, were used. Nonoxynol‐9, tested at levels up to 10 μg/ml, did not induce transformation, whereas dioxane was very active in the induction of type III foci in the cultured BALB/3T3 cells.
Photochemical formation of mutagenic compounds from alkenes and ozone or nitrogen dioxide
Authors: Victorin Katarina , Ståhlberg Margareta
Published: February 2007

In order to investigate the possible formation of mutagenic compounds from alkenes emitted in ambient air, laboratory experiments were performed with Salmonella typhimurium strain TA100 in a small‐scale flow‐through exposure system. The reaction time for mixtures of alkenes with ozone or nitrogen dioxide was 40 minutes, and the exposure time for bacteria was 6 hours. Ozone gave rise to a small mutagenic effect in combination with 1,3‐butadiene or vinyl chloride, with and without ultraviolet (UV) irradiation, but not in combination with ethene or propene. Nitrogen dioxide gave rise to a mutagenic effect in combination with propene, 1,3‐butadiene, or vinyl chloride, but only after UV irradiation. The mutagenic activity was highest with butadiene and seemed to be dose‐related to the concentration of nitrogen dioxide. Nitrogen dioxide with ethene did not produce a mutagenic effect. A mixture of ethene, propene, and butadiene, tested with ozone or nitrogen dioxide with UV irradiation, did not potentiate each other's mutagenic effect.
Metabolism of 2‐acetylaminofluorene in the chinese hamster ovary cell mutation assay
Authors: Heflich Robert H. , Casciano Daniel A. , Zhuo Zhou , Djurić Zora , Fullerton Nancy F. , Beland Frederick A.
Published: February 2007

Chinese hamster ovary (CHO) cells were exposed to 2‐acetylaminofluorene (2‐AAF) and 2‐aminofluorene (2‐AF), and several of their N‐oxidized metabolites in order to study the mechanisms by which arylamides and arylamines produce mutations in mammalian cells. The number of mutations induced at the hypoxanthine‐guanine phosphoribosyl transferase locus by each compound (mutants/106 CHO cells/nmol compound/ml) was estimated to be: N‐acetoxy‐2‐AAF, 310; N‐hydroxy‐2‐AF, 3; N‐hydroxy‐2‐AAF (with and without hepatic S9 activation), 0.7; 2‐AAF (with S9), 0.1; and 2‐AF (with S9), 0.09. With each compound, DNA adducts were also identified and quantified, and in all cases the major adduct was N‐(deoxyguanosin‐8‐yl)‐2‐AF. 2‐AAF and N‐hydroxy‐2‐AAF also formed minor amounts of N(deoxyguanosin‐8‐yl)‐2‐AAF and 3‐(deoxyguanosin‐N2‐yl)‐2‐AAF. The relationship between mutation induction and adduct formation for each of the derivatives was similar to that previously reported for N‐hydroxy‐2‐AF. Inclusion of the deacetylase inhibitor, paraoxon, reduced the mutagenicity of 2‐AAF, N‐hydroxy‐2‐AAF and N‐acetoxy‐2‐AAF, and the DNA adducts produced by N‐acetoxy‐2‐AAF to background levels. Acetyl coenzyme A increased the mutations and CHO cytosol‐mediated DNA binding of N‐hydroxy‐2‐AAF, but did not substantially increase these responses from N‐hydroxy‐2‐AF. N‐Hydroxy‐2‐AAF was not detectably metabolized by CHO cells. Taken together, these data indicate that CHO cells metabolized N‐acetoxy‐2‐AAF to a reactive derivative by N‐deacetylation to N‐acetoxy‐2‐AF, while N‐hydroxy‐2‐AF reacted direcitly with DNA. The major pathway of N‐hydroxy‐2‐AAF activation appeared to be an initial O‐acetylation to N‐acetoxy‐2‐AAF and this occurred to only a limited extent in the CHO cells. N‐Hydroxy‐2‐AAF also seemed to form an additional unknown ester intermediate that gave rise to acetylated DNA adducts. The limited O‐acetylase activity in CHO cells appeared to cntribute to the low sensitivity of these cells toward mutation induction by arylamines and arylamides.
Comparative mutagenicity of nine brands of coffee to salmonella typhimurium TA100, TA102, and TA104
Authors: Shane Barbara S. , Troxclair Alice M. , McMillin Debra J. , Henry Charles B.
Published: February 2007

Nine coffee preparations, four caffeinated instant brands, three caffeinated drip coffees, and two decaffeinated coffees, one of which was an instant brand, were evaluated for mutagenicity by the Ames assay using Salmonella typhimurium TA100, TA102, and TA104. All the coffees contained direct‐acting mutagens, which reverted the three strains. The inclusion of a rat microsomal enzyme preparation reduced the mutagenic response of the three strains in the presence of some of the coffee samples. Both glyoxal and methylglyoxal, 1,2‐dicarbonyls found in the coffees were mutagenic. The concentration of glyoxal, methylglyoxal, diacetyl, and guiacol were measured by gas chromatography/mass spectrometry. Caffeine, furfural, and 5‐methylfurfural concentrations were determined by high performance liquid chromatography. Although lower concentrations of methyglyoxal were found in the drip caffeinated coffees, the mutagenic potency of these preparations was higher than the instant coffees on a weight basis especially when TA104 was the indicator organism. Our findings agree with those of other workers who have shown that carbonyl compounds, which were present in all the brands tested, are partially responsible for the mutagenic response of coffee but that additional mutagens are also present.
Mutagenic potency of chlorofuranones and related compounds in salmonella
Authors: Ishiguro Yasuhisa , Santodonato Joseph , Neal Michael W.
Published: February 2007

One of the mutagenic byproducts associated with chlorinated humic waters and kraft pulp bleaching effluents was recently identified as 3‐chloro‐4‐(dichloromthyl)‐5‐hydroxy‐2(5H)‐furanone. This compound and several related chlorofuranones and precursors were synthesized and evaluated for direct‐acting mutagenicity in Salmonella typhimurium tester strain TA100. Mutagenicity was greatest for 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone, its 5‐methoxy derivative, and the precursor in their synthesis, 3‐(dichloromethyl)‐2,4,4‐trichloro‐2‐butenoic acid. Several of the compounds were tested in the presence of added rat liver homogenate S9 fraction, and in all cases mutagenicity was substantially reduced. An important structural feature which may govern the mutagenic response in these instances appears to be the cis arrangement of CHCl2 and Cl substituents on a carbon‐carbon double bond. These compounds may also be transformed in vitro to the same acyclic chlorine substituted alpha, beta‐unsaturated aldehyde derivative, which is proposed to be the agent responsible for the observed mutagenicity.
Chromosomal aberrations in the cotton rat, sigmodon hispidus, exposed to hazardous waste
Authors: Thompson Ruth A. , Schroder Gene D. , Connor Thomas H.
Published: February 2007

The study of chromosome damage in rodents living on hazardous‐waste sites may provide evidence of important biological consequences of chronic exposure to toxic chemical wastes. This study compared bone‐marrow cells of animals (Sigmodon hispidus) taken from two superfund waste‐disposal sites with those from an uncontaminated site and demonstrated that both populations exposed to hazardous wastes had significantly more structural and numerical aberrations than the control population.
Detection of carcinogenic glutamic acid pyrolysis products in worcestershire sauce by high‐performance liquid chromatography
Authors: Manabe Shigeo , Kanai Yoshikatsu , Yanagisawa Hiroyuki , Tohyama Kazuhiko , Ishikawa Shinsuke , Kitagawa Yasuhisa , Wada Osamu
Published: February 2007

Commercially available Worcestershire sauce was analyzed for mutagenic and carcinogenic glutamic acid pyrolysis products using high‐performance liquid chromatography. These carcinogenic heterocyclic amines were found to be present in all brands of Worcestershire sauce analyzed. The identity of the carcinogens was confirmed by spectrometric analyses and the SOS umu‐test. The concentrations of 2‐amino‐6‐methyldipyrido[l,2‐a:3′,2′‐d]imidazole (Glu‐P‐1) and 2‐amino‐dipyrido‐[1,2‐a:3′,2′‐d]imidazole (Glu‐P‐2) in the Worcestershire sauce were 695 ± 329 pmol/liter (mean ± SD, n = 5) and 1,839 ± 1,321 pmol/liter (n = 5), respectively.
Human mutagens: Evidence from paternal exposure?
Authors: Narod Steven A. , Douglas George R. , Nestmann Earle R. , Blakey David H.
Published: February 2007

The importance of inherited mutations as a cause of human disease has been established clearly through examples of well‐defined genetic anomalies, such as Down syndrome and retinoblastoma. Furthermore, it is suspected that environmental contaminants induce mutations resulting in increased risk for such defects in subsequent generations of persons exposed. The present lack of direct evidence for induced inherited genetic disorders in human beings hampers the development of risk estimation techniques for extrapolation from animal models. The most extensive prospective epidemiologic studies of inherited genetic effects have involved survivors of atomic bomb detonations and patients treated with cancer chemotherapy. In neither case has a significant elevation in inherited genetic effects or cancer been detected in the offspring of exposed individuals. Epidemiologic studies of subjects receiving chronic exposure may be confounded by the effect of maternal exposure during pregnancy. Consideration of only paternal exposure can minimize the confounding influence of teratogenicity, enhancing the resolving power of studies for inherited effects. Using this approach, retrospective (case‐control) studies of childhood cancer patients have provided limited but suggestive evidence for inheritance of induced effects. Endpoints, such as congenital malformations and spontaneous abortion following paternal exposure, can also be considered as indicators of heritable mutagenic effects. For example, there is limited evidence suggesting that paternal exposure to anaesthetic gases may cause miscarriage and congenital abnormalities as a result of induced male germ cell mutations. By comparing male‐exposure endpoints for which there are human data, as described above, with parallel or similar animal endpoints, such as dominant lethal, inherited cancer and “male teratogenic” effects, it is possible that suitable models for extrapolating to human risk can be developed. In order to establish a clearer relationship between induced mutation and genetic disease, the current surveillance systems should be expanded to include endpoints relevant to genetic study. The relaxation of regulations regarding access to census data could improve the chances of documenting such an association.
Utility of short‐term tests for genetic toxicity in the aftermath of the NTP's analysis of 73 chemicals
Authors: Brockman Herman E. , Demarini David M.
Published: February 2007

This manuscript has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.