bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of multi‐parameter flow cytometry using fluorescent probes to study substrate toxicity in the indene bioconversion
Authors: Amanullah A. , Hewitt C. J. , Nienow A. W. , Lee C. , Chartrain M. , Buckland B. C. , Drew S. W. , Woodley J. M. 
Published: October 2002

AbstractThe bioconversion of indene to cis‐(1S,2R) indandiol, a potential key intermediate in the synthesis of Merck's HIV protease inhibitor, CRIXIVAN™, can be achieved using a Rhodococcus strain. This study using Rhodococcus I24 reports on the application of multiparameter flow cytometry for the measurement of cell physiological properties based on cytoplasmic membrane (CM) integrity and membrane depolarization as indicators of toxic effects of the substrate, indene. Quantification of intact polarized CM, intact depolarized CM and permeabilized CM of a large population of bacterial cells has been conducted using specific intracellular and membrane‐binding fluorescent stains. Measurements of oxygen uptake rate (OUR) and optical density (OD) as indicators of metabolic activity and biomass growth, respectively, were also made. Indene concentrations of up to 0.25 g/L (0.037 g indene/g dry cell weight) did not significantly (<5% compared to control) affect cell light‐scattering properties, intact CM, membrane polarization, respiratory activity, or biomass growth. Between this value and 1.5 g/L (0.221 g indene/g dry cell weight), the changes in intact CM, respiratory activity and biomass growth were relatively insignificant (<5% compared to control), although dissipation of the membrane potential of a significant proportion of the cell population occurred at 0.50 g/L (0.074 g indene/g dry cell weight). At 2.5 g/L (0.368 g indene/g dry cell weight) there was a significant increase in the dead cell population, accompanied by changes in the extracellular cationic concentrations and substantial decrease in respiratory activity. The primary effect of indene toxicity was the disruption of the proton motive force across the cytoplasmic membrane which drives the formation of ATP. The disruption of the proton motive force may have been due to the measured changes in proton permeability across the membrane. In addition, indene may have directly inhibited the membrane‐bound enzymes related to respiratory activity. The overall consequence of this was reduced respiratory activity and biomass growth. The cell physiological properties measured via flow cytometry are important for understanding the effects of toxicity at the cellular level which neither measurements of biomass growth or indandiol formation rates can provide since both are cell averaged measurements. The technique described here can also be used as a generic tool for measuring cell membrane properties in response to toxicity of other indene‐resistant strains that may be possible to use as recombinant hosts to perform the biotransformation of indene. This study has demonstrated that flow cytometry is a powerful tool for the measurement of cell physiological properties to assess solvent toxicity on whole cell biocatalysts. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 239–249, 2002.
Stability and linearization: discrete‐time systems
Authors: Sandberg Irwin W. 
Published: October 2002

AbstractA theorem by Hadamard gives a two‐part condition under which a map from one Banach space to another is a homeomorphism. The theorem, while often very useful, is incomplete in the sense that it does not explicitly specify the family of maps for which the condition is met. Recently, under a typically weak additional assumption on the map, it was shown that Hadamard's condition is met if and only if the map is a homeomorphism with a Lipschitz continuous inverse. Here an application is given concerning the relation between the stability of a discrete‐time non‐linear system and the stability of related linear systems. Copyright © 2002 John Wiley & Sons, Ltd.
Targeting APP metabolism for the treatment of Alzheimer's disease
Authors: Sambamurti Kumar , Hardy John , Refolo Lorenzo M. , Lahiri Debomoy K. 
Published: October 2002

AbstractSenile plaques consisting largely of extracellular deposits of a 38–42 residue peptide, amyloid β protein (Aβ) and intraneuronal deposits of the microtubule‐associated protein, tau, as neurofibrillary tangles (NFT) are defining features of Alzheimer's disease (AD). Aβ is produced after cleavage of a larger Aβ protein precursor (APP) by β‐secretase to the secreted sAPPβ and cell‐associated CTFβ followed by cleavage of CTFβ by γ‐secretase to secreted Aβ and the cognate cytoplasmic fragment, CTFγ. Most Aβ is 40 residues long, but a small fraction is 42–43 residues in length. A currently favored hypothesis is that Aβ42 forms toxic aggregates that induce NFT formation and ultimately the neuronal dysfunction characteristic of AD. Based on this hypothesis, the popular targets for drug development are the enzymes that generate or degrade Aβ42, block Aβ aggregation or toxicity and other factors that regulate these pathways in the brain. This article examines the evidence supporting the amyloid hypothesis and alternative hypotheses based on APP metabolism. In addition, the current drug targets for modifying APP metabolism to reduce Aβ42 are discussed. We further discuss evidence that suggests that other APP fragments such as CTFγ are altered by tested familial AD mutations and their role in AD pathogenesis needs to be carefully examined. We conclude that it is important to develop drugs based on alternative APP fragments (i.e., CTFγ) as well as the other identified pathways (i.e., oxidative stress) to provide alternatives if antiamyloid drugs fail to treat AD. Drug Dev. Res. 56:211–227, 2002. © 2002 Wiley‐Liss, Inc.
Genetic determination of biological age in the mennonites of the midwestern United States
Authors: Duggirala Ravindranath , Uttley Meredith , Williams Ken , Arya Rector , Blangero John , Crawford Michael H. 
Published: October 2002

AbstractNumerous studies have shown that longevity is moderately heritable in human populations. Longevity, however, contains limited information on functional status, since individuals may exhibit differential survival patterns. In this study, we employed a stepwise multiple regression approach to estimate biological aging in a Mennonite population, using chronological age as a dependent variable and various predictors of chronological age including subphenotypes related to diabetes, coronary heart disease, hypertension, renal function, and markers of functional ability. The residual (the difference between chronological and predicted ages) is considered a marker of biological age. In fact, two different data sets were used to obtain residuals due to the availability of data. In each analysis, chronological age was regressed on predictor variables in a stepwise manner, retaining the variables significant at the 5% level. The first analysis (N=729) included 6 significant predictors (R2=44.3%): glucose, blood urea nitrogen (BUN), cholesterol, albumin, systolic blood pressure (SBP), and ln potassium, and the second analysis (N=232) included 9 significant predictors (R2=71.5%): BUN, albumin, SBP, low‐density lipoprotein cholesterol, forced expiratory volume in 1 sec (FEV1), grip strength, trunk flexibility, reaction time, and FEV1×sex. Using a variance components approach, we found that the data set‐specific residuals were significantly heritable (h2±SE): first analysis=0.265±0.106, and second analysis=0.469±0.180. The residuals from the second data set appear to be more informative for biological aging, perhaps due to the inclusion of functional ability‐related phenotypes in addition to the blood chemistry variables. In summary, we have shown that markers of biological aging in Mennonites are under substantial additive genetic influences. Genet. Epidemiol. 23:97–109, 2002. © 2002 Wiley‐Liss, Inc.
On a general class of conditional tests for family‐based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations
Authors: Lange Christoph , Laird Nan M. 
Published: October 2002

AbstractFamily‐based association tests (FBATs) provide simple and powerful tests to detect association between a genetic marker and a disease‐susceptibility locus, manifest in subjects by a phenotype or disease trait. Here we propose a new class of conditional tests for family‐based association studies that includes most of the established tests and their generalizations. The class of tests is very general; it can be applied to longitudinal and multivariate traits or phenotypes, multiple genetic markers, and many other situations not yet discussed in the literature. For any test in this class, we derive the asymptotic distribution under the null hypothesis, the conditional power under any alternative hypothesis, and the optimal offset for single degree of freedom tests. The proposed methodology is illustrated with a genetic study of asthma. Genet. Epidemiol. 23:165–180, 2002. © 2002 Wiley‐Liss, Inc.
The pattern of expression of Mn and Cu‐Zn superoxide dismutase varies among squamous cell cancers of the lung, larynx, and oral cavity
Authors: Piyathilake Chandrika J. , Bell Walter C. , Oelschlager Denise K. , Heimburger Douglas C. , Grizzle William E. 
Published: October 2002

AbstractBackgroundDespite the importance of reactive oxygen species (ROS) in the development of smoking‐related cancers, little is known about the pattern of expression of ROS scavengers in these cancers.MethodsIn this present study, we examined the expression of manganese superoxide dismutase (Mn‐SOD) and copper/zinc superoxide dismutase (Cu‐Zn‐SOD), which are essential enzymes that eliminate ROS, in squamous cell cancers (SCCs) of the lung (n = 12), larynx (n = 13), and oral cavity (n = 20).ResultsSCCs of larynx and oral cavity showed significantly enhanced immuhistochemical expression of Mn‐SOD compared with the matched uninvolved epithelium. The higher expression of Mn‐SOD was shown to be late and early events in the process of SCC development in the larynx and the oral cavity, respectively. The expression of Mn‐SOD in SCCs of the lung was significantly lower compared with luminal cells of the uninvolved epithelium but not compared with basal cells or an average expression of SOD in basal and luminal cells. The expression of both Mn‐SOD and cytoplasmic or nuclear Cu‐Zn‐SOD in bronchial epithelium adjacent to invasive cancer was significantly lower compared with its expression in the uninvolved bronchial epithelium away from cancer. This resulted in a significant difference in SOD expression between cancer and uninvolved bronchial epithelium away from cancer but not between cancer and uninvolved epithelium adjacent to cancer.ConclusionsThere are significant differences in the expression of Mn‐SOD and Cu‐Zn‐SOD among SCCs of the lung, larynx, and oral cavity. The results also suggest that variations in distance between cancer and uninvolved tissues evaluated could contribute to conflicting results of SOD expression. © 2002 Wiley Periodicals, Inc. Head Neck 24: 859–867, 2002
Human papillomavirus and p53 mutational status as prognostic factors in head and neck carcinoma
Authors: Sisk Elizabeth A. , Soltys Scott G. , Zhu Shaobo , Fisher Susan G. , Carey Thomas E. , Bradford Carol R. 
Published: October 2002

AbstractBackgroundMutations of the p53 tumor‐suppressor gene are common in squamous cell carcinoma of the head and neck (SCCHN) and may portend a worse prognosis. Human papillomavirus (HPV) represents another potential prognostic factor for SCCHN. The oncogenic potential of HPV may be due to the ability of its E6 oncoprotein to promote degradation of wild‐type p53 protein. We wish to determine whether there is a lower incidence of p53 mutations in HPV‐positive versus HPV‐negative tumors, and if HPV and/or p53 status has an impact on survival.MethodsThirty‐two SCCHN specimens were analyzed for mutations of the p53 gene using single‐strand conformational polymorphism (SSCP) analysis followed by DNA sequencing. The HPV status of all specimens was evaluated by use of polymerase chain reaction with HPV consensus primers and Southern blot hybridization. Pertinent clinical information was obtained from chart review.ResultsNonsilent p53 mutations were present in 2 of 15 (13%) of HPV‐positive tumors compared with 6 of 17 (35%) of HPV‐negative tumors (p = .229; Fisher's exact test, odds ratio .28). A survival advantage was found between HPV‐positive compared with HPV‐negative specimens (p = .0264) and between p53 wild type compared with p53 mutant specimens (p = .01) by univariate log rank analysis. When stratified according to both HPV and p53 status, a statistically significant survival difference was observed largely because of a 100% survival for the HPV‐positive/p53 wild‐type group (p = .003).ConclusionsThis preliminary study supports the notion that the presence of HPV confers a survival advantage among HNSCC patients, particularly when p53 is wild type. © 2002 Wiley Periodicals, Inc. Head Neck 24: 841–849, 2002
Developing competency models to promote integrated human resource practices
Authors: Rodriguez Donna , Patel Rita , Bright Andrea , Gregory Donna , Gowing Marilyn K. 
Published: October 2002

AbstractToday, competencies are used in many facets of human resource management, ranging from individual selection,
development, and performance management to organizational strategic planning. By incorporating competencies into
job analysis methodologies, the Office of Personnel Management (OPM) has developed robust competency
models that can form the foundation for each of these initiatives. OPM has placed these models into automated
systems to ensure access for employees, human resources professionals, and managers. Shared access to the data
creates a shared frame of reference and a common language of competencies that have provided the basis for
competency applications in public sector agencies. © 2002 Wiley Periodicals, Inc.
Selecting the best and brightest: Leveraging human capital
Authors: O'Leary Brian S. , Lindholm Mary Lou , Whitford Richard A. , Freeman Stephen E. 
Published: October 2002

AbstractThis article provides a brief discussion of the changing nature of work and describes how automation and the Internet are changing the way the U.S. government recruits and hires employees. The authors discuss the validity of various assessment methods used to select and promote employees and the return on investment that can result from using valid assessment techniques. The authors review several illustrative assessment programs used in the federal government. Finally, the authors explore the next generation of assessments. © 2002 Wiley Periodicals, Inc.
Presentation of native TROP‐2 tumor antigens to human cytotoxic T lymphocytes by engineered antigen‐presenting cells
Authors: Mangino Giorgio , Grazia Capri Maria , Barnaba Vincenzo , Alberti Saverio 
Published: October 2002

AbstractProfessional antigen‐presenting cells (APC), e.g. dendritic cells, express immuno‐proteasome components and process proteins for MHC presentation differently from non‐immune cells. Thus, they induce reactivities against sets of peptides that do not overlap with those generated by non‐professional APC, i.e., tumor cells, and stimulate cytotoxic T lymphocytes (CTL) that may not recognize them. The goal of this work was to establish a system for antigen presentation and in vitro stimulation of human CTL using “tumor‐cell‐like” engineered APC. Murine fibroblasts were transfected with human HLA Class I alleles, together with the B7.1, ICAM‐1 and germ‐line TROP2 genes. The last encodes a cell surface glycoprotein widely expressed by human cancers. Unseparated peripheral blood mononuclear cells from HLA Class I‐matched individuals were stimulated in vitro by the engineered APC. These efficiently induced the activation and proliferation of antigen‐specific HLA‐restricted CTL lines and clones. The Trop‐2‐specific CTL demonstrated high specific cytotoxicity against the appropriate transfected target cells. They also efficiently lysed MCF‐7 human tumor cells expressing endogenous HLA‐A2.1, Trop‐2 together with ICAM‐1. These results demonstrate that Trop‐2 is a target molecule recognized by human CTL. Moreover, they demonstrate that non‐immune engineered APC efficiently process and present native tumor‐specific proteins in the context of human MHC Class I, and stimulate the growth and cytotoxicity of specific anti‐tumor CTL. © 2002 Wiley‐Liss, Inc.
Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats
Authors: Kohno Hiroyuki , Tanaka Takuji , Kawabata Kunihiro , Hirose Yoshinobu , Sugie Shigeyuki , Tsuda Hiroyuki , Mori Hideki 
Published: October 2002

AbstractThe modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM‐induced colon carcinogenesis was investigated in male F344 rats. In the short‐term study, the effects of silymarin on the development of AOM‐induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM‐induced colon carcinogenesis were evaluated using a long‐term animal experiment. In the short‐term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose‐dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long‐term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM‐induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. β‐Glucuronidase activity, PGE2 level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer. © 2002 Wiley‐Liss, Inc.
Epstein‐Barr virus antagonizes the antiproliferative activity of transforming growth factor‐β but does not abolish its signaling
Authors: Horndasch Manuela , Raschke Eva E. , Bommer Guido , Schuhmacher Marino , Dumont Elisabeth , Kuklik‐Roos Conny , Eick Dirk , Kempkes Bettina 
Published: October 2002

AbstractTGF‐β induces apoptosis and inhibits the proliferation of EBV‐negative B‐lymphoma cell lines. In contrast, EBV‐immortalized B cells are resistant to both the proapoptotic and the antiproliferative activities of TGF‐β. We have generated a lymphoblastoid cell line, in which we can switch on and off the EBV‐specific transcriptional program driven by EBNA2. When these cells express the EBNA2‐driven phenotype, they are resistant to TGF‐β‐mediated growth arrest. We used this cell line to readdress the question of how EBV can overcome the antiproliferative TGF‐β activity. We show here that EBV‐driven cells remain TGF‐β‐responsive since TGF‐β target genes are readily induced. Thus, EBV can overcome TGF‐β‐mediated growth arrest without interfering with the core machinery of the TGF‐β signaling pathway, which links ligand binding to the induction of TGF‐β target genes. © 2002 Wiley‐Liss, Inc.
Interval cancers following breast cancer screening in Singaporean women
Authors: Gao Fei , Chia Kee‐Seng , Ng Fook‐Cheong , Ng Erg‐Hen , Machin David 
Published: October 2002

AbstractOur study reports on the interval cancers arising in the subsequent 3 years in women screened as part of the Singapore Breast Cancer Screening Programme that commenced in 1994. Women, the majority of Chinese ethnicity, were either invited or not invited by random allocation to be screened. All women, other than those identified with breast cancer at screening, whether invited or not, were followed for 3 years, and information on all breast cancers arising in this period was obtained through the national registry. In particular, the cancers arising from those women who were deemed free of the disease at screening were noted. The mammographs taken at screening of those women who developed such an interval cancer were rereviewed by 3 radiologists. In the 28,099 women who were screened and deemed free of disease, 59 interval cancers were reported with annual rates of 2.1, 10.6 and 10.8 per 10,000 women‐years in the succeeding 3‐year periods. In 39,425 women who were invited but declined screening, the rates were 17.0, 15.5 and 11.7, while the corresponding rates from 97,294 women not invited were 12.8, 13.3 and 13.0. Whereas the annual incidence at 1 year in women who have been screened is much lower than those in the 2 groups who were not screened, it is of a similar magnitude by 2 years. This suggests that locally an optimal screening interval may be close to 1 year. The rereview of the mammograms of those 59 women with interval cancers suggested that the maximum possible number of these that might have been detected at screening was 10 (17%). © 2002 Wiley‐Liss, Inc.
Isotype switch‐mediated CH deletions are a recurrent feature of Myc/CH translocations in peritoneal plasmacytomas in mice
Authors: Kovalchuk Alexander L. , Janz Siegfried 
Published: October 2002

AbstractOncogene activating chromosomal translocations that interrupt IGH switch (S) regions at 14q32 are thought to be caused by misguided IGH isotype switching in postgerminal center B‐cell lymphomas and plasma cell myelomas in humans. Aberrant switching also seems to be involved in altering the fine structure of the translocation in some of these tumors, but the significance of these changes is not known. Here we report on 3 cases of IL‐6 transgenic mouse plasmacytomas (PCT) that harbor T(12;15) translocations that had been modified by frustrated switch attempts that result in CH deletions. When considered together with 6 similar cases of PCT described previously, our observations suggest that secondary deletions in CH are a regular feature in the molecular evolution of T(12;15) translocations and, thereby, in the progression of PCT. We propose that the T(12;15)+ mouse PCT offers a uniquely valuable model system for elucidating the dual role of abnormal isotype switching in causation and ‘remodeling’ of chromosomal translocations. © 2002 Wiley‐Liss, Inc.