bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNNB1 mutations and β‐catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1†
Authors: Devereux Theodora R. , Stern Mariana C. , Flake Gordon P. , Yu Mimi C. , Zhang Zhen‐Quan , London Stephanie J. , Taylor Jack A. 
Published: August 2002

Abstractβ‐Catenin plays a key role in the Wnt signaling pathway, and mutations of CTNNB1, the gene that encodes β‐catenin, have been identified in about one‐fourth of human hepatocellular carcinomas from regions of low aflatoxin B1 exposure. In this study 62 hepatocellular carcinomas (HCCs) from people highly exposed to aflatoxin B1 in Guangxi, People's Republic of China, were laser‐capture microdissected and examined for CTNNB1 mutations. In addition, 41 of the HCCs were evaluated for the presence of the β‐catenin protein by immunohistochemical methods. Twenty of the HCCs showed positive results for β‐catenin, with strong membrane staining, while adjacent non‐neoplastic liver tissue lacked or showed only weak membrane staining. One HCC, in which a CTNNB1 mutation was not detected, showed nuclear staining for the β‐catenin protein. Mutations of CTNNB1 were identified in five HCCs. These consisted of four point mutations in the glycogen serine kinase‐3β phosphorylation region of codons 32–45 and one deletion of codons 32–38. These mutations were similar to those previously reported for human HCC, although at a lower frequency. A signature mutation profile associated with aflatoxin B1 exposure could not be identified. The immunohistochemical findings indicate a role for accumulation of β‐catenin and possibly increased Wnt signaling in aflatoxin B1–associated HCC. The low frequency of CTNNB1 mutations, however, suggests that mutation of another Wnt signaling component, such as the Wnt scaffolding protein axin or the adenomatous polyposis coli protein, both of which modulate β‐catenin stability, also may be involved in aflatoxin‐associated HCC. Published 2001 Wiley‐Liss, Inc.
Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell line
Authors: Stettler Peter Markus , Sengstag Christian 
Published: August 2002

AbstractThe mycotoxin aflatoxin B1 (AFB1) is one of the most potent rodent and human liver carcinogens. Upon cytochrome P450–specific metabolism, it induces mutations as well as mitotic recombination events in in vitro systems. We have found that in the lower eukaryote yeast, the recombinagenic activity of AFB1 surpasses its mutagenic activity, and we speculated on possible consequences in terms of the mechanism of liver carcinogenesis. In this study we investigated whether the recombinagenic activity of AFB1 also would be identified in human cells. To address this question, we followed the fate of a heterozygous thymidine kinase (tk) allele in the human lymphoblastoid cell line TK6 upon exposure to AFB1. Individual mutants that had lost tk activity were subjected to loss of heterozygosity analysis of the tk locus and its flanking markers. Fluorescence in situ hybridization analysis on chromosome 17 also was performed. In parallel, a similar analysis was performed on TK6 cells exposed to the alkylating agent N‐nitrosomethylurea, a well‐known classic point mutagen. Our analysis showed a difference in the molecular mechanism leading to inactivation of the tk allele upon exposure to these two mutagens. In AFB1‐exposed cells the fraction of recombination‐derived mutants predominated, whereas in N‐nitrosomethylurea–exposed cells the fraction of point mutants was higher. Thus, the recombinagenic activity of AFB1 previously identified in a lower eukaryote also was found in the human cell line TK6. Our data support the hypothesis that mitotic recombination represents a central mechanism of action in AFB1‐induced liver carcinogenesis. © 2001 Wiley‐Liss, Inc.
Inhibition of osteoclast differentiation and bone resorption by cathepsin K antisense oligonucleotides
Authors: Ishikawa Takashi , Kamiyama Masako , Tani‐Ishii Nobuyuki , Suzuki Hiroaki , Ichikawa Yasushi , Hamaguchi Yohei , Momiyama Nobuyoshi , Shimada Hiroshi 
Published: August 2002

AbstractWe confirmed the expression of cathepsin K, the most abundant and specific cysteine protease found in osteoclasts, at the mRNA level in most of our cases of breast cancer, and even at the protein level in bone metastatic lesions. Therefore, we investigated the functions of cathepsin K in osteoclasts with special attention to bone metastasis from breast cancer. Mouse osteoclast‐like cells (OCLs) were established by coculture of mouse bone marrow cells and osteoblastic cells. Rodent cathepsin K antisense (AS) or random control (CL) oligonucleotides were added on day 0, 3, or 6 of culture. Tartrate‐resistant acid phosphatase staining confirmed the formation of OCLs after 9 d of incubation. AS treatment significantly reduced both the number of TRAP‐positive cells and the percentage of multinuclear cells. For the pit‐forming assay, after 9 d of incubation, mature OCLs were collected and incubated on ivory slices with AS or CL for 48 h. The antisense oligonucleotides also inhibited the bone‐resorbing activity of OCLs. CL treatment did not affect either the number of TRAP‐positive cells or pit formation. Cathepsin K may play important roles in bone resorption as well as in differentiation of osteoclasts. These findings indicate that the inhibition of this enzyme may prevent the development of bone metastasis from breast cancer. © 2001 Wiley‐Liss, Inc.
Material handling device selection in cellular manufacturing
Authors: Braglia Marcello , Gabbrielli Roberto , Miconi Dante 
Published: August 2002

AbstractThis paper presents a new multi‐criteria decision model for the material handling device (MHD) selection problem in cellular manufacturing systems. Given a set of manufacturing cells based on several automatic work‐centres, the technique makes it possible to select a particular MHD for each cell in an integrated way, with different constraints being taken into consideration. The approach is based on two different multi‐attribute analyses executed with analytic hierarchy process (AHP) methodology, and a final integer linear programming including important limitations faced by the designer when making MHD investment decisions. An example using real data is provided to illustrate this methodology. Copyright © 2002 John Wiley & Sons, Ltd.
In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain
Authors: Ling ZaoDung , Gayle Dave A. , Ma Shang Yong , Lipton Jack W. , Tong Chong Wai , Hong Jau‐Shyong , Carvey Paul M. 
Published: August 2002

AbstractWe investigated whether in utero exposure to the Gram(−) bacteriotoxin lipopolysaccharide (LPS) induces dopamine (DA) neuron loss in rats. The proinflammatory cytokine tumor necrosis factor α (TNF‐α) kills DA neurons and is elevated in the brains of patients with Parkinson's disease (PD). LPS is a potent inducer of TNF‐α, and both are increased in the chorioamniotic environment of women who have bacterial vaginosis (BV) during pregnancy, suggesting that BV might interfere with the normal development of fetal DA neurons. Gravid female rats were injected intraperitoneally with either LPS or normal saline at embryonic day 10.5 and their pups were killed at postnatal day 21. The brains of the pups were assessed for DA and TNF‐α levels and DA cell counts in the mesencephalon using tyrosine hydroxylase immunoreactive (THir) cells as a DA neuron marker. Prenatal LPS exposure significantly reduced striatal DA (29%) and increased DA activity (72%) as well as TNF‐α (101%). Stereological cell counts in the mesencephalon were also significantly reduced (27%) by prenatal LPS exposure. Prenatal exposure to LPS, as might occur in humans with BV, produces a significant loss of THir cells in rats that is still present 33 days following a single injection of LPS. Since this cell loss is well past the normal phase of DA neuron apoptosis that occurs in early postnatal life, rats so exposed may have a permanent loss of DA neurons, suggesting that prenatal infections may represent risk factors for PD. © 2001 Movement Disorder Society.
Emergence of complex, involuntary movements after gamma knife radiosurgery for essential tremor
Authors: Siderowf Andrew , Gollump Stephen M. , Stern Matthew B. , Baltuch Gordon H. , Riina Howard A. 
Published: August 2002

AbstractGamma knife radiosurgery is generally considered a safer alternative to traditional pallidotomy or thalamotomy. We report the case of a 59‐year‐old patient with essential tremor who developed a complex, disabling movement disorder following gamma knife thalamotomy. This case illustrates the need for long‐term follow‐up to fully evaluate the potential for complications following radiosurgery. © 2001 Movement Disorder Society.
Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinson's disease
Authors: Allert N. , Volkmann J. , Dotse S. , Hefter H. , Sturm V. , Freund H.‐J. 
Published: August 2002

AbstractBilateral high‐frequency stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) both alleviate akinesia, rigidity, and tremor in idiopathic Parkinson's disease. To test the specific effect of these procedures on gait, we used quantitative gait analysis in addition to relevant subscores of the Unified Parkinson's Disease Rating Scale in a group of 10 patients with advanced Parkinson's disease treated by GPi stimulation and eight patients treated by STN stimulation. Patients were assessed before and 3 months after surgery. Thirty age‐matched healthy subjects served as controls. The non‐random selection allowed a descriptive but no direct statistical comparison of the respective procedure. Gait analysis showed significant stimulation‐induced improvements of spatiotemporal gait and step parameters in both patient groups. Moreover, the effects on step length and cadence suggested a differential effect of both basal ganglia targets. Hence, the increase in gait velocity in the STN group was almost exclusively due to a significant increase in step length, while in the GPi group statistically non‐significant increases in both step length and cadence contributed. © 2001 Movement Disorder Society.
Postural asymmetries following unilateral subthalomotomy for advanced Parkinson's disease
Authors: Su Philip C. , Tseng Ham‐Min , Liou Horng‐Huei 
Published: August 2002

AbstractTwo cases of postural asymmetries following unilateral stereotaxic subthalamotomy were observed with head and body tilting to the side contralateral to the STN lesion, which corrected itself completely or partially with levodopa treatment. After subsequent contralateral STN surgery, the postural asymmetry disappeared in both patients. Possible mechanism is discussed. © 2002 Movement Disorder Society.
Nonsteroidal aromatase inhibitors: Recent advances
Authors: Recanatini Maurizio , Cavalli Andrea , Valenti Piero 
Published: August 2002

AbstractAromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure–activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase‐inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 3, 282–304, 2002; Published online in wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10010
Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonist
Authors: Nicholson Nancy S. , Abood Norman A. , Panzer‐Knodle Susan G. , Frederick Leo G. , Page Jimmy D. , Salyers Anita K. , Suleymanov Osman D. , Szalony James A. , Taite Beatrice B. , Anders Robert J. 
Published: August 2002

AbstractA key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t1/2 of 18 hr. The high bioavailability, long half‐life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large‐scale trials. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 211–226, 2001
Vancomycin, teicoplanin, and ramoplanin: Synthetic and mechanistic studies†
Authors: Boger Dale L. 
Published: August 2002

AbstractVancomycin, teicoplanin, and ramoplanin are potent glycopeptide antibiotics that act by inhibiting bacterial cell wall biosynthesis. The former are used clinically as the antibiotics of last resort for the treatment of methicillin‐resistant Staphylococcus aureus and the latter is a promising new antibiotic that is not susceptible to the emerging bacterial resistance to vancomycin and teicoplanin. A summary of our recent total synthesis of the vancomycin aglycon, our first and second generation total syntheses of the teicoplanin aglycon, and our progress on the total synthesis of the ramoplanins is presented. This work lays the foundation for ongoing structure–function studies on the antibiotics that may clarify or define their site and mechanism of action leading to the development of improved or reengineered antibiotics. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 356–381, 2001
Pharmacokinetics and its role in small molecule drug discovery research
Authors: Jang Graham R. , Harris Robert Z. , Lau David T. 
Published: August 2002

AbstractPharmacokinetics (PK), which describes the disposition of a drug in the body, should be a primary consideration in the selection of a drug candidate, ultimately contributing to its eventual clinical success or failure. Accordingly, a sound understanding of PK concepts and an appreciation of the judicious use of PK and related (e.g., metabolism, transporter) data in drug discovery can be beneficial to those involved in the process. This review defines important PK parameters (e.g., clearance, volume of distribution, half‐life), describes methods of PK data analysis (noncompartmental vs. compartmental) and provides an overview of additional concepts such as allometric scaling, PK/pharmacodynamic modeling, and nonlinear PK. Furthermore, the role and strategic use of PK screens in drug discovery are discussed. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 382–396, 2001
Optimization of metabolic stability as a goal of modern drug design
Authors: Thompson Thomas N. 
Published: August 2002

AbstractMetabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high‐throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called “early ADME” studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as “metabolic stability” studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half‐life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 412–449, 2001
Muscle preservation using an implantable electrical system after nerve injury and repair
Authors: Nicolaidis Stephen C. , Williams H. Bruce 
Published: August 2002

AbstractThe value of continuous electrical stimulation of denervated muscles after nerve injury and repair has been clearly shown in a series of laboratory experiments in three animal models. This experimental background, which showed improved muscle preservation and better functional results, evolved into a clinical study that included 15 patients with peripheral nerve injuries in the upper extremities, 3 patients with brachial plexus injuries, and three patients with facial nerve paralysis. Improved functional results were obtained using this implantable system, which were similar to those achieved with the animal experiments. All patients had muscle stimulation for extended periods ranging from 127 to 346 days. Analysis of the results showed satisfactory nerve regeneration on clinical examination and with electromyographic studies. Functional muscle analysis varied somewhat from patient to patient, but every patient had a satisfactory to excellent recovery. The results from this study have clearly shown the benefits of continuous muscle stimulation using an implantable electrical system after nerve injury and repair expansion of the project to a larger patient cohort is indicated. © 2001 Wiley‐Liss, Inc. MICROSURGERY 21:241–247 2001
Perturbation of microstrip ring structure by grain moisture and its angle dependence
Authors: Abegaonkar Mahesh P. , Karekar R. N. , Aiyer R. C. 
Published: August 2002

AbstractA microstrip ring resonator (MRR) is perturbed by overlaying mug grains (Phaseolus Radiatus Linn.), having different moisture contents (7–42%), at eight different angles. Out of the two orthogonal degenerate modes (even and odd) of MRR, only the even mode is sensitive to the strength of perturbation (grain moisture). The overlay angle and moisture‐dependent perturbation factor is reported. The results are compared with the reported perturbation results of Yogi et al. [16]. © 2002 Wiley Periodicals, Inc. Microwave Opt Technol Lett 33: 128–132, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.10252
Cytogenetics in pediatric low‐grade astrocytomas
Authors: Orr Lesley C. , Fleitz Julie , McGavran Loris , Wyatt‐Ashmead Josephine , Handler Michael , Foreman Nicholas K. 
Published: August 2002

AbstractBackgroundCytogenetic analysis in certain tumors is a vital part of classification and assignment of prognosis. Few studies have examined the value of cytogenetic analysis in pediatric brain tumors. This is especially true of low‐grade astrocytomas (LGA) of childhood. This study examines the correlation between cytogenetic abnormalities and survival in children with low‐grade astrocytomas. The literature on adults with LGA suggest better survival for those whose tumors have normal cytogenetics compared to those with abnormal. We hypothesized this would also be true of children with low‐grade astrocytomas.ProcedureA retrospective study was performed of children presenting between 1980 and 1998 to The Children's Hospital, Denver, who had LGA and on whose tumors informative cytogenetics had obtained.ResultsOne hundred and forty‐nine children were diagnosed with histologically proven LGA. Twenty‐nine had successful cytogenetic analysis. One or more chromosomal abnormalities were observed in eight tumors while normal karyotypes were observed in 21 tumors. Actuarial progression‐free survival at 5 years was 87.5% for the eight children with abnormal cytogenetics and 43% for those with normal (P = 0.56). Overall survival at 5 years was 83% for those with abnormal cytogenetics and 78% for those with normal (P = 0.8). The differences in progression‐free survival and overall survival between these two groups were not significant. Those children with WHO Grade I tumors had significantly superior progression‐free and overall survival than those with Grade II tumors.ConclusionsIt appears unlikely that, for children with LGA, those with normal cytogenetics have a better prognosis than those with abnormal. Histologic grade is a better predictor of outcome than cytogenetics. Med Pediatr Oncol 2002;38:173–177. © 2002 Wiley‐Liss, Inc.
Receptor mediated yolk protein uptake in the crab Scylla serrata: crustacean vitellogenin receptor recognizes related mammalian serum lipoproteins
Authors: Warrier Sudha , Subramoniam T. 
Published: August 2002

AbstractThe receptor‐mediated uptake of major yolk protein precursor, vitellogenin (Vg) is crucial for oocyte growth in egg laying animals. In the present study plasma membrane receptor for Vg was isolated from the oocyte of the red mud crab, Scylla serrata. Vitellogenin receptor (VgR) protein was visualized by ligand blotting using labeled crab Vg (125I‐Vg) as well as labeled low density lipoprotein (125I ‐LDL) and very low density lipoprotein (125I‐VLDL) isolated from rat. The endocytosis of Vg was visualized in the crab oocyte by ultrastructural immunolocalization of Vg. The Vg receptor was purified by gel filtration high performance liquid chromatography (HPLC) and its molecular weight was estimated to be 230 kDa. In direct binding studies, the receptor exhibited high affinity (dissociation constant Kd 0.8 × 10−6 M) for crab Vg. Vitellogenin receptor was observed to have an increased affinity to crab Vg in the presence of Ca2+ and the binding was inhibited by suramin, suggesting similarities between crab VgR and low density lipoprotein receptor (LDLR) superfamily of receptor protein. Furthermore, the crab VgR showed significant binding ability to mammalian atherogenic lipoproteins such as LDL and VLDL. This suggests that there is a tight conservation of receptor binding sites between invertebrate (crab) Vg and vertebrate (rat) LDL and VLDL. Mol. Reprod. Dev. 61:536–548, 2002. © 2002 Wiley‐Liss, Inc.