bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer
Authors: Crul M. , de Klerk G. J. , Swart M. , van’t Veer L. J. , de Jong D. , Boerrigter L. , Palmer P. A. , Bol C. J. , Tan H. , de Gast G. C. , Beijnen J. H. , Schellens J. H.M. 
Published: October 2002

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with R115777 using an interpatient dose escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days 1, 28, and 56. RESULTS: Twenty-eight patients were entered onto the study and the median duration of treatment was 55 days. The dose-limiting toxicities were myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4 leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300 mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea, vomiting, and fatigue. The recommended dose for phase II/III testing in this scheme is 300 mg bid. The pharmacokinetic studies indicated dose proportionality. Little accumulation occurred and steady-state levels were reached within 2 to 3 days. Analyses of historic tumor material showed that five of 15 of patients had a K-ras mutation in codon 12. Three patients with pancreatic, colon, and cervix carcinomas had stable disease and one patient with a colon carcinoma had a minor response accompanied by a more than 50% decrease in carcinoembryonic antigen tumor marker. A fifth patient, with platinum-refractory non–small-cell lung cancer, showed a partial response that lasted for 5 months. CONCLUSION: Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.
Trisomy 18 in a 20‐year‐old woman
Authors: Kelly Michael , Robinson Bradley W. , Moore John W. 
Published: October 2002

AbstractA 20‐year‐old female with trisomy 18 is described. Survival past infancy is rare in this disorder. Little is known concerning the factors that contribute to prolonged survival with this syndrome. This case provides an opportunity to review the management of older children and young adults with trisomy 18. © 2002 Wiley‐Liss, Inc.
Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy‐Walker malformation
Authors: McCormack W. Michael , Shen Joseph J. , Curry Stacey M. , Berend Sue Ann , Kashork Catherine , Pinar Halit , Potocki Lorraine , Bejjani Bassem A. 
Published: October 2002

AbstractTwo patients with partial deletions of the long arm of chromosome 13, del(13)(13q21‐q34) and del(13)(13q22‐q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy‐Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage‐sensitive gene in 13q22‐q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22‐q33 may cause this anomaly. These findings suggest that microdeletions in 13q22‐q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high‐resolution cytogenetic analysis (550 band level or greater) of 13q22‐q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM. © 2002 Wiley‐Liss, Inc.
Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation
Authors: Turner Gillian , Partington Michael , Kerr Bronwyn , Mangelsdorf Marie , Gecz Jozef 
Published: October 2002

AbstractTwo families, originally diagnosed as having nonsyndromic X‐linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24‐bp duplication (428‐45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441–445]. This same duplication had also been found in three other families: one with X‐linked infantile spasms and hypsarrhythmia (X‐linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 bp in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C>T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene. © 2002 Wiley‐Liss, Inc.
Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene
Authors: Pawlik Timothy M. , Nakamura Hideo , Mullen John T. , Kasuya Hideki , Yoon Sam S. , Chandrasekhar Soundararajalu , Chiocca E. Antonio , Tanabe Kenneth K. 
Published: October 2002

AbstractBACKGROUNDHerpes simplex virus 1 (HSV‐1) infection of cancer cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent tumor cells. rRp450 is a novel replication‐conditional HSV‐1 mutant that expresses both the endogenous herpes viral thymidine kinase gene and the rat p450 CYP2B1 transgene; p450 bioactivates such cancer prodrugs as cyclophosphamide.METHODSViral cytotoxicity and replication assays were performed in colon carcinoma cells as well as primary human hepatocytes. For in vivo studies, diffuse liver metastases were generated by inoculating MC26 cells into the portal system of BALB/c mice. Mice were treated with control media, rRp450, or rRp450 plus cyclophosphamide.RESULTSCytopathic effects induced by rRp450 replication in colon carcinoma cells were equivalent to those induced by wild type HSV‐1 in vitro. Assays developed to separate cytotoxicity mediated by viral replication from cytotoxicity mediated by chemotherapy confirmed that HSV‐1 thymidine kinase bioactivates ganciclovir and CYP2B1 bioactivates cyclophosphamide in rRp450‐infected cells. rRp450 mediated cytotoxicity in the presence of cyclophosphamide was increased by 21% to 30% above that achieved by viral replication alone. Cyclophosphamide bioactivation produced bystander killing of colon carcinoma cells but not hepatocytes. In contrast to these effects of cyclophosphamide, rRp450 mediated cytotoxicity was reduced in the presence of ganciclovir. These findings are explained by further experiments showing that bioactivation of cyclophosphamide only minimally affected HSV‐1 replication in colon carcinoma cells, whereas bioactivation of ganciclovir markedly attenuated HSV‐1 replication. In vivo studies revealed a substantial decrease in hepatic tumor burden in all rRp450‐treated animals compared to controls. The addition of cyclophosphamide augmented rRp450's in vivo anti‐neoplastic effect.CONCLUSIONSThe rRp450 mutant HSV‐1 is highly oncolytic against colon carcinoma cells both in vitro and in vivo. rRp450 displays preferential replication in colon carcinoma cells compared to normal hepatocytes. Activation of cyclophosphamide by the p450 transgene augmented the anti‐neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by HSV‐1 replication combined with cyclophosphamide prodrug activation warrants further investigation as a potential therapy for colon carcinoma liver metastases. Cancer 2002;95:1171–81. © 2002 American Cancer Society.DOI 10.1002/cncr.10776
Technical Note: Reduction of rational integrals related to linear and convex quadrilateral finite elements
Authors: Rathod H.T. , Islam Md. Shafiqul 
Published: October 2002

AbstractWe reduce a rational function of bivariate nth degree polynomial numerator with a linear denominator to a simple bivariate polynomial of degree (n − 1) and a rational function of a single variate nth degree polynomial numerator with the same bivariate linear denominator. This has very greatly contributed to the evaluation of (n + 1)(n + 2)/2 rational integrals in bivariates to mere (n + 1) rational integral of a single variate and an integration of simple polynomial in bivariates. Thus the effort of integration is reduced several times and leads to simple analytical expressions in terms of the nodal coordinates. In order to illustrate the numerical process two examples are considered. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 18: 759–770, 2002; Published online in Wiley InterScience (www.interscience.wiley.com); DOI 10.1002/num.10026.
A lot sizing and sequencing algorithm for dynamic demands upon a single facility
Authors: Aras Ömer A. , Swanson Lloyd A. 
Published: October 2002

AbstractA heuristic algorithm is developed and applied to determine lot sizes and production sequence on a single facility. The various product demands are treated as deterministic and time varying (dynamic) over a finite planning horizon, such as that generated from a material requirements planning (MRP) system.In contrast to other approaches available, the algorithm considers the sequencing decision in each period by realistically assuming inventory holding cost occurrence in the period of production, and in addition, it is capable of considering set‐up times where such set‐up times consume available productive capacity. The ability to handle numerous products, and the capability of being able to specify maintenance time and holidays is an integral aspect of the algorithm.The results of an application of the algorithm in a medium size bearing company have shown very significant reduction in the controllable inventory holding cost while eliminating late deliveries. In an effort to cope with potential realistic schedule alterations, different solutions were developed for managerial evaluation providing greater flexibility but at a higher cost.
A dynamic priority rule for scheduling against due‐dates
Authors: Baker Kenneth R. , Bertrand J.W.M. 
Published: October 2002

AbstractWe simulate the performance of a simple production system in which due‐dates are set internally. We investigate priority rules aimed at minimizing tardiness, emphasizing a “modified duedate rule” which functions effectively in conjunction with internally‐set deadlines and which adapts to both tight and loose conditions in the due‐dates. This rule is simple and logical, and shows considerable promise for application in complex production systems.
EOQ application in a pharmaceutical environment: A case study
Authors: Ouellet Roch , Roy Jacques , Cardinal Claude , Rosconi Yves 
Published: October 2002

AbstractThis paper describes a successful application of classical inventory theory at a drug manufacturing plant located in Montreal that has resulted in annual savings in the order of $110,800 and assisted management in its decision to invest in larger production equipment. The basic assumptions underlying EOQ models are reviewed and dealt with. For instance, an algorithm was devised to handle the peaks in the demand of many A class items. Following the implementation of this algorithm, buffer stocks were reduced signifi cantly while maintaining the same high levels of service.
Short interval forecasting of emergency phone call (911) work loads
Authors: Mabert Vincent A. 
Published: October 2002

AbstractThere has been an increasing emphasis over the last 5 to 10 years to improve productivity in the Service Sector of the U.S. economy. Much of the improvement obtained by these managers has come about through better scheduling of the work force in these organizations. Effective scheduling of this personnel requires good estimates of demand, which may exhibit substantial variations between days for certain times of the year. The Indianapolis Police Department (IPD) Communications area is one such organization that exhibits varying workloads and is interested in improving staff scheduling of dispatch operators.This article explores the use of six different forecasting techniques for predicting daily emergency call workloads for the IPD's communications area. Historical call volume data are used to estimate the model parameters. A hold‐out sample of five months compares forecasts and actual daily call levels. The forecast system utilizes a rolling horizon approach, where daily forecasts are made for the coming month from the end of the prior month. The forecast origin is then advanced to the end of the month, where the current month's actual call data are added to the historical database, new parameters are estimated, and then the next month's daily estimates are generated. Error measures of residual standard deviation, mean absolute percent error, and bias are used to measure performance. Statistical analyses are conducted to evaluate if significant differences in performance are present among the six models.The research presented in this article indicates that there are clearly significant differences in performance for the six models analyzed. These models were tailored to the specific structure and this work suggests that the short interval forecasting problems faced by many service organizations has several structural differences compared to the typical manufacturing firm in a made‐to‐stock environment. The results also suggests two other points. First, simple modeling approaches can perform well in complex environments that are present in many service organizations. Second, special tailoring of the forecasting model is necessary for many service firms. Historical data patterns for these organizations tend to be more complex than just trend and seasonal elements, which are normally tracked in smoothing models. These are important conclusions for both managers of operating systems and staff analysts supporting these operating systems. The design of an appropriate forecasting system to support effective staff planning must consider the nature, scope, and complexity of these environments.
The Role of T‐Lymphocytes in Hypercholesterolemia‐Induced Leukocyte‐Endothelial Interactions
Authors: STOKES KAREN Y. , CLANTON E. CHRIS , BOWLES KIMBERLY S. , FUSELER JOHN W. , CHERVENAK DEBORAH , CHERVENAK ROBERT , JENNINGS STEPHEN R. , GRANGER D. NEIL 
Published: October 2002

ABSTRACTObjective: Hypercholesterolemia promotes the adhesion of leukocytes to vascular endothelium in large and microscopic blood vessels. Lymphocytes that can modulate endothelial cell adhesion molecule expression have been implicated in the altered structure and function of large arterial vessels associated with chronic hypercholesterolemia. This study assesses the contribution of CD4+ and CD8+ T‐cells to acute inflammatory responses observed in the microcirculation of hypercholesterolemic mice.Methods: Intravital microscopy was used to quantify baseline leukocyte‐endothelial cell interactions in cremasteric postcapillary venules of wild‐type (WT) and severe combined immunodeficient (SCID) mice placed on a normal (ND) or high‐cholesterol (HC) diet for 2 weeks. A group of SCID‐HC mice received splenocytes from WT‐HC mice (WT→SCID). Separate WT‐HC groups were depleted of neutrophils or CD4+ and/or CD8+ T‐cells.Results: WT‐HC mice, compared with WT‐ND, exhibited exaggerated leukocyte adherence and emigration. These leukocytes were predominantly granulocytes. These responses were absent in neutropenic WT‐HC mice. SCID‐HC mice also showed significantly less leukocyte adherence and emigration than WT‐HC mice. Elevated leukocyte adherence and emigration were restored in WT→SCID mice, despite a continued absence of circulating blood lymphocytes. Selective depletion of either CD4+ or CD8+ cell populations attenuated HC‐induced leukocyte adhesion but not emigration. However, simultaneous depletion of both CD4+ and CD8+ cells attenuated both leukocyte adhesion and emigration to ND levels.Discussion: These findings indicate that both CD4+ and CD8+ T‐cells contribute to granulocyte adhesion and emigration elicited in postcapillary venules by hypercholesterolemia.
Transcription Factor CBF4 Is a Regulator of Drought Adaptation in Arabidopsis
Authors: Haake Volker , Cook Daniel , Riechmann JoséLuis , Pineda Omaira , Thomashow Michael F. , Zhang James Z. 
Published: October 2002

Abstract
In plants, low temperature and dehydration activate a set of genes containing C-repeat/dehydration-responsive elements in their promoter. It has been shown previously that the Arabidopsis CBF/DREB1 transcription activators are critical regulators of gene expression in the signal transduction of cold acclimation. Here, we report the isolation of an apparent homolog of the CBF/DREB1 proteins (CBF4) that plays the equivalent role during drought adaptation. In contrast to the three already identified CBF/DREB1 homologs, which are induced under cold stress, CBF4 gene expression is up-regulated by drought stress, but not by low temperature. Overexpression of CBF4 in transgenic Arabidopsis plants results in the activation of C-repeat/dehydration-responsive element containing downstream genes that are involved in cold acclimation and drought adaptation. As a result, the transgenic plants are more tolerant to freezing and drought stress. Because of the physiological similarity between freezing and drought stress, and the sequence and structural similarity of the CBF/DREB1 and the CBF4 proteins, we propose that the plant's response to cold and drought evolved from a common CBF-like transcription factor, first through gene duplication and then through promoter evolution.
ACTCAT, a Novel cis-Acting Element for Proline- and Hypoosmolarity-Responsive Expression of theProDHGene Encoding Proline Dehydrogenase in Arabidopsis
Authors: Satoh Rie , Nakashima Kazuo , Seki Motoaki , Shinozaki Kazuo , Yamaguchi-Shinozaki Kazuko 
Published: October 2002

AbstractProline (Pro) is one of the most widely distributed osmolytes in water-stressed plants. We previously isolated from Arabidopsis a gene encoding Pro dehydrogenase (ProDH), a mitochondrial enzyme involved in the first step of the conversion of Pro to glutamic acid. The ProDH gene in Arabidopsis is up-regulated by rehydration after dehydration but is down-regulated by dehydration.ProDH is also induced by l-Pro and hypoosmolarity. The induction of ProDH expression under rehydration seems to be caused by both accumulated Pro and hypoosmolarity. We analyzed a DNA region that is located 5′ to the transcription start site (a promoter region) of ProDH to identify cis-acting elements involved in l-Pro-induced and hypoosmolarity-induced expression in transgenic tobacco (Nicotiana tabacum) and Arabidopsis plants. We found that a 9-bp sequence, ACTCATCCT, in the ProDH promoter is necessary for the efficient expression of ProDH in response to l-Pro and hypoosmolarity. Moreover, ACTCAT is a core cis-acting element, which we have called Pro- or hypoosmolarity-responsive element (PRE), that is necessary forl-Pro-responsive and hypoosmolarity-responsive expression of ProDH. Microarray and RNA gel-blot analyses showed that 21 l-Pro-inducible genes have the PRE sequences in their promoter regions. These results indicate that the PRE sequence play an important role in the l-Pro-responsive gene expression.
Nature and mechanism of ilmenite alteration: a Mössbauer and X-ray diffraction study of oxidized ilmenite from the Beja-Acebuches Ophiolite Complex (SE Portugal)
Authors: Waerenborgh J. C. , Figueiras J. , Mateus A. , Gonçalves M. 
Published: October 2002

AbstractIlmenites from the least-altered rocks of the Beja-Acebuches Ophiolite Complex (SE Portugal), with low Ti values and excess Fe, despite rare optical evidence of hematite exsolution, were studied by 57Fe Mössbauer spectroscopy and X-ray diffraction. According to single-crystal XRD the sequence of alternate layers characteristic of the ideal ilmenite structure is preserved, the excess Fe being accommodated in the Ti layers. No superparamagnetic oxides were detected by 57Fe Mössbauer spectroscopy. The typical spectra of bulk αFe2O3 and of Fe3+-containing ilmenite, in the paramagnetic state above 49 K and magnetically ordered at 6 K, are observed. The average degree of oxidation of the ilmenites, estimated from the chemical analysis assuming ideally stoichiometric full cation site occupancies, is also confirmed by 57Fe Mössbauer data. Since our crystal chemistry study gave no evidence of crypto-exsolution textures within the ilmenite with the observed compositions, fast cooling from magmatic temperatures and decomposition of ilmenite in supergene conditions is suggested.
P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells
Authors: Guimond Martin , Balassy Antonia , Barrette Mélanie , Brochu Sylvie , Perreault Claude , Roy Denis Claude 
Published: October 2002

AbstractT lymphocytes have been found to harbor P-glycoprotein (Pgp) and to demonstrate modulation of its ion channel transporter function according to the state of activation of T lymphocytes. We hypothesized that cytotoxic chemicals that are extruded by Pgp could be used to specifically eliminate immunoreactive T-cell populations. In this study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer structurally similar to rhodamine, a dye transported by Pgp, and which becomes highly cytotoxic on activation with visible light to selectively deplete alloreactive T lymphocytes. Stimulation of T cells with mitogens or allogeneic major histocompatibility complex–mismatched cells resulted in the preferential retention of the TH9402 rhodamine-derivative in activated T cells, both CD4+ and CD8+. Photodynamic cell therapy of TH9402-exposed T cells led to the selective elimination of immunoreactive T-cell populations. In addition, this treatment preserved resting T cells and their capacity to respond to third-party cells. Inhibition of Pgp enhanced cellular trapping of the dye in nonactivated T cells and resulted in their depletion after exposure to light. Targeting of Pgp-deficient cells may therefore represent an appealing strategy for the prevention and treatment of graft-versus-host disease and other alloimmune or autoimmune disorders.