bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simple way of quantifying immunostained cell nuclei on the whole histologic section
Authors: Elie Nicolas , Plancoulaine Benoît , Signolle Jehan‐Pierre , Herlin Paulette 
Published: October 2003

AbstractBackgroundQuantification of nuclei, immunostained for proliferation or differentiation markers, is widely recommended for prognostication and treatment of numerous solid tumors. However, many problems concerning reproducibility of the results obtained still remain, partially due to the lack of standardization of the method used and to the difficulty of taking into account tumor tissue heterogeneity. Technical solutions exist but they are expensive and time consuming, and their complexity limits their diffusion in routine pathology departments.MethodsIn the present study, we use a simple, fast and inexpensive system of acquisition, a 4,000 dots‐per‐inch slide scanner, to get a single true color numerical image of the whole histologic section. The analysis is done thanks to fully automatic image processing, allowing computation of the stain proportion on the whole histologic section, as well as in “hot spots.”ResultsAfter having precisely fixed settings of the slide scanner, one can easily detect counterstained and immunostained structures, by image analysis. This simple and stable processing can be done under 6 min.ConclusionsThe association of immunohistochemistry, stable acquisition device and computer‐assisted image analysis provides an objective, reproducible, and easy to standardize quantification of the nuclear markers, in relation to the total tumor tissue architecture. Cytometry Part A 56A:37–45, 2003. © 2003 Wiley‐Liss, Inc.
Flow cytometry and GFP: A novel assay for measuring the import and turnover of nuclear‐encoded mitochondrial proteins in live PC12 cells
Authors: Sirk Daniel P. , Zhu Ziping , Wadia Jehangir S. , Mills Linda R. 
Published: October 2003

AbstractBackgroundMitochondrial protein import is typically measured by adding radiolabeled precursor proteins to isolated mitochondria. We have developed a novel, high‐throughput method for measuring protein import in live differentiated PC12 cells using a tetracycline (Tet) regulated, nuclear encoded, mitochondrially‐targeted GFP fusion protein and flow cytometry.MethodsWe generated a PC12 cell line stably transfected with an inducible GFP fusion protein (GFPmt) targeted to mitochondria. GFPmt PC12 cells were treated with NGF for one week to induce neuronal differentiation in the presence of Tet to silence GFP expression. On day seven GFPmt expression was induced by removal of Tet and these “GFP‐on” cells were exposed to sublethal levels of CCCP (2 μM) for 24 h. At 24 h, the cells were harvested in Ca++‐free PBS and the GFPmt signal in live intact cells was measured using flow cytometry. Since GFPmt is not fluorescent prior to being imported into mitochondria, the GFPmt signal reflected only GFPmt imported to mitochondria. PI was used to gate out contributions from dead cells. Turnover of GFPmt in mitochondria was also assessed; in this case, Tet was added to arrest GFPmt expression in GFP‐on cells, and the subsequent decline of the fluorescent signal, in the absence of any new GFP synthesis, was measured by flow cytometry.ResultsExposure to 2 μM CCCP for 24 h caused a 61% ± 0.4 decline in GFPmt fluorescence compared to controls. This decline corresponded to a 30% ± 7 decrease in GFPmt protein levels measured by Western blot of mitochondrial fractions, and a 72% ± 5 decline in the import of newly synthesized GFPmt to mitochondria over a 1 h period 24‐h after addition of 2 μM CCCP measured by autoradiography. CCCP partially depolarized mitochondria but was not lethal for up to five days.ConclusionsThis novel GFP‐based flow cytometry assay is a rapid and sensitive technique for quantifying protein import to mitochondria in live neuronal cells. Cytometry Part A 56A:15–22, 2003. © 2003 Wiley‐Liss, Inc.
The place of inpatient care in the treatment of anorexia nervosa: Questions to be answered
Authors: Vandereycken Walter 
Published: October 2003

AbstractBackgroundThe chance that an anorexia nervosa patient will be hospitalized depends more on circumstantial rather than on scientifically based factors. Although there is a lot of information on the treatment of anorexia nervosa patients in a residential setting, answers to questions relating to the “when,” “where,” and “how” of treatment are subjective. There is no clinical consensus and the paucity of controlled research is hampering the development of an evidence‐based practice.ResultsIncreasing economic restraints through managed care policies limit the length of inpatient treatment, which leads to early discharge at a lower body weight, which leads to a higher likelihood of readmissions, which leads to increasing costs.DiscussionWe will highlight important issues in the ongoing debate between economic demands and clinical challenges. Our goal is to stimulate critical reflections and systematic research. © 2003 by Wiley Periodicals, Inc. Int J Eat Disord 34: 409–422, 2003.
Generation mechanism on fiber fuse phenomenon in single‐mode optical fibers
Authors: Shuto Yoshito , Yanagi Shuichi , Asakawa Shuichiro , Nagase Ryo 
Published: October 2003

AbstractUnsteady‐state thermal conduction process in the single‐mode (SM) optical fiber was theoretically studied with the explicit finite‐difference method. In the numerical calculation it was assumed that the electrical conductivity of the core layer increased rapidly above 1050 °C. The core‐center temperature changed suddenly and reached over ten thousand Kelvin when the optical power of 1 W was input to the core layer heated above 1000 °C. This rapid heating phenomenon also occurred when the optical power was reflected at the edge wall of the thermally produced cavity in the core layer. The occurrence of this phenomenon was restricted by the decrease in either the input optical power or the normalized frequency of the SM optical fiber. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(11): 11–20, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10150
Development of high‐frequency SiC‐MESFETs
Authors: Arai Manabu , Honda Hirotake , Ono Shuichi , Sawazaki Hiroshi , Ogata Makoto 
Published: October 2003

AbstractWith rapid growth of mobile communications represented by portable telephones, further increases in the output of high‐frequency power transistors for the base stations are required. Also, in the fields of satellite communications and radar, realization of high‐power transistors replacing electron tubes such as TWTs and magnetrons is desirable for size reduction, weight reduction, and extension of transmitter life. As a transistor meeting such needs, the metal semiconductor field effect transistor (MESFET) based on silicon carbide (SiC) has been attracting attention. SiC is superior in material characteristics such as the electric breakdown field and thermal conductivity and is expected theoretically to provide high power density as a high‐frequency transistor. To date, higher output power density than MESFETs based on Si and GaAs of the same size has been achieved, including an output power density of 4.2 W/mm at 1 GHz. In this paper, the high‐frequency characteristics of the tested SiC high‐frequency MESFET are presented and trends in research on improvement of the high‐frequency characteristics are described. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(11): 1–10, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10160
Automatic shot size discrimination for a video editing support system
Authors: Kumano Masahito , Ariki Yasuo , Uehara Kuniaki , Shimojo Shinji , Sunto Kenji , Tsukada Kiyoshi 
Published: October 2003

AbstractSince the advent of the digital era the lack of video coding has been a problem. In order to resolve this problem, the editing work, which takes the most time during the production of video content, must be made more efficient. In general, broadcast video is set up using video grammar, a set of standard principles used for broadcasting any video content. Therefore, in order to make editing work more efficient, a video editing support system which reflects this video grammar must be developed. In order to create this kind of video editing support system, indexing information must be set up beforehand for the raw video shot by the camera operator so as to take advantage of the video grammar. Within the video grammar the particularly important rules have to do with connecting shots. In this paper the authors propose a method to automatically index shot size, along with proposing a video editing support system based on video grammar. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 86(11): 61–71, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10201
An active noise control system using frequency domain simultaneous perturbation method with a variable perturbation magnitude
Authors: Mori Takashi , Kajikawa Yoshinobu , Nomura Yasuo 
Published: October 2003

AbstractAn active noise control (ANC) system is proposed that uses a new frequency domain simultaneous perturbation (FDSP) method automatically controlling the magnitude of perturbation. The proposed method automatically controls the magnitude of perturbation so that the convergence speed can be improved substantially over the conventional case where the magnitude of perturbation is fixed. Specifically, when the error signal is large, the magnitude of the perturbation is made large, while the latter is reduced when the error signal is small. As a result, the present system resolves the problem of instability caused by the block process and also the step size can be set to a larger value. The present control is effective when the magnitude of perturbation needs to be set small. In particular, if the magnitude of perturbation is 0.08, the convergence speed is improved by more than 50 times. Also, the present control is effective for suppression of the noise generated due to addition of perturbation. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 87(2): 43–53, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.10112
Improvement of accuracy and stability in numerically solving hyperbolic equations by IDO (interpolated differential operator) scheme with Runge‐Kutta time integration
Authors: Yoshida Hiroshi , Aoki Takayuki , Utsumi Takayuki 
Published: October 2003

AbstractIn order to solve hyperbolic partial differential equations by means of the Interpolated Differential Operator (IDO) scheme, time integration of the dependent variable has been carried out by Taylor expansion, and time differentiation has been performed by replacing it with a spatial differentiation. However, in such a method, the time accuracy is limited by the order of the interpolation function and in addition the spatial accuracy is not sufficient in multidimensional problems due to the complexity of the calculations. In terms of numerical stability, the stable region indicated by the CFL (Courant‐Friedrich‐Levy) number is narrow. Hence, in order to improve the space‐time accuracy and to secure numerical stability, time integration by the Runge‐Kutta method is applied. Further, a method for increasing the order of the Runge‐Kutta method without increasing the computational cost is proposed, taking advantage of the characteristics of the IDO scheme with the physical quantity and its spatial derivative as the dependent variables. The two‐dimensional advection equation and the one‐dimensional wave equation are solved and the results are quantitatively compared with those obtained by the conventional Taylor expansion. Also, in order to demonstrate the adaptability of this approach to practical problems, we consider Williamson's test case 5 for the shallow‐water equation in spherical geometry. It is found that the Runge‐Kutta method for multiple dimensions yields accuracy and stability higher than those of the Taylor expansion, demonstrating the effectiveness of the approach. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 87(2): 33–42, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.10127
Hereditary renal carcinogenesis fitting Knudson's two‐hit model: Genotype, environment, and phenotype
Authors: Hino Okio 
Published: October 2003

AbstractCancer is a heritable disorder of somatic cells. Environment and heredity both operate in the origin of human cancer. The Eker (Tsc2 gene mutant) rat model of hereditary renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. To the best of our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary renal carcinoma in the rat in Japan, and the rat was named the “Nihon” rat, and its predisposing (Nihon) gene could be a novel renal tumor suppressor gene. We present these unique models, comparing these two predisposing genes (both are located on rat chromosome 10), for the study of problems in carcinogenesis, for instance, species‐specific difference in tumorigenesis, cell stage and tissue/cell‐type specific tumorigenesis, multistep carcinogenesis, modifier gene(s) in renal carcinogenesis, cancer prevention, and the development of the therapeutic treatments that can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s). © 2003 Wiley‐Liss, Inc.
NF2: The wizardry of merlin
Authors: Xiao Guang‐Hui , Chernoff Jonathan , Testa Joseph R. 
Published: October 2003

AbstractNeurofibromatosis type II (NF2) is an autosomal dominant cancer syndrome characterized by the formation of tumors of the nervous system, particularly schwannomas and meningiomas. TheNF2gene is also implicated in the development of sporadic schwannomas and meningiomas, as well as tumor types seemingly unrelated to the NF2 disorder, such as malignant mesotheliomas. Inactivation ofNF2occurs by a “two‐hit” mechanism, as proposed by Al Knudson, and theNF2gene behaves as a classical tumor suppressor gene. TheNF2gene product, merlin, exhibits homology with the ezrin–radixin–moesin family of membrane–cytoskeleton‐linking proteins. During the past several years, there has been intensive investigation aimed at elucidating the mechanisms underlying merlin's functions. In this review, we summarize the involvement ofNF2inactivation in tumorigenesis. We also discuss observations implicating merlin in cell motility and cell proliferation, with a focus on recent findings linking merlin to Rac signaling. © 2003 Wiley‐Liss, Inc.
Genetic hits and mutation rate in colorectal tumorigenesis: Versatility of Knudson's theory and implications for cancer prevention
Authors: Bellacosa Alfonso 
Published: October 2003

AbstractThe multistep model of carcinogenesis is now widely accepted for colorectal cancer and other common epithelial tumors of the adult. The challenges ahead are to define the number of genetic hits necessary for conversion of a normal cell into a cancer cell and to determine whether the observed increase in the mutation rate (mutator phenotype) is required. The beauty of Knudson's two‐hit theory is its ability to explain diverse experimental situations and guide specific predictions, including some directly relevant to cancer prevention. © 2003 Wiley‐Liss, Inc.
Targeting tumor cells by enhancing radiation sensitivity
Authors: McKenna W. Gillies , Muschel Ruth J. 
Published: October 2003

AbstractThe work of Al Knudson created the paradigm in which we see cancer as a result of the accumulation of multiple mutations. Our goal has been to exploit these mutations to develop strategies to enhance therapy for cancer by targeting the malignant cell while sparing the normal tissue. In studying the RAS oncogene, we observed that its expression when activated resulted in enhanced radioresistance. Conversely, inhibition of RAS made cells with activated RAS more radiosensitive. Hence, we postulated that it would be possible to sensitize tumors with RAS mutations to radiation without affecting the sensitivity of the normal tissue in patients with such tumors. This proved to be the case in animal models and has led to current clinical trials. These studies raised the question of identifying the downstream effectors of RAS that are responsible for altering the radiosensitivity of cells. We have found that phosphoinositide‐3‐kinase (PI3 kinase) is a critical component of this pathway. Blocking PI3 kinase enhanced the radiation response in vitro or in vivo of cells actively signaling through that pathway, but did not affect cells not actively signaling through PI3 kinase at the time of irradiation. Identification of tumors with active signaling in this pathway by immunohistochemical staining for phosphorylated AKT, the downstream target of PI3 kinase correlated with those patients for which radiation failed to achieve local control. Thus, characterization of the active signaling pathways in a given tumor might enable the selection of patients likely to respond to radiation. Pathways upstream from RAS may also be useful targets to consider for enhancing radiation therapy. Epidermal growth factor receptor (EGFR), which is upstream of PI3 kinase, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3 kinase pathway. Identifying a common signal for EGFR, RAS, and PTEN that results in radiation resistance may uncover targets for developing molecular‐based radiosensitization protocols for tumors resistant to radiation and thus lead to improvement of local control. © 2003 Wiley‐Liss, Inc.
Detection of point mutations of the Axin1 gene in colorectal cancers
Authors: Jin Li‐Hua , Shao Qiu‐Jie , Luo Wen , Ye Zhi‐Yun , Li Qing , Lin Sheng‐Cai 
Published: October 2003

AbstractAxin is a recently identified tumor suppressor that plays an important role in liver and colon cancers. To gain further insights into the structure and function of Axin in controlling cell growth, we analyzed 54 colorectal cancer tissues for mutations in AXIN1 gene. We employed PCR amplification with 23 sets of primers against introns that encompassed the whole coding region of AXIN1 followed by single‐strand conformation polymorphism (SSCP) analysis. After subcloning and sequencing analysis of the reamplified DNA from the aberrant bands, we found, in addition to 3 silent mutations, 6 misssense point mutations in different functionally important regions. The missense mutation rate is hence 11%, suggesting that Axin deficiency may contribute to the onset of colorectal tumorigenesis. © 2003 Wiley‐Liss, Inc.
Nonsteroidal anti‐inflammatory drugs inhibit growth of human neuroendocrine tumor cells via G1 cell‐cycle arrest
Authors: Detjen Katharina M. , Welzel Martina , Wiedenmann Bertram , Rosewicz Stefan 
Published: October 2003

AbstractTherapeutic options to inhibit growth of human NETs of the GEP system are limited. Since NSAIDs might provide an antiproliferative treatment alternative with acceptable toxicity, we examined the effects of different NSAIDs on growth and survival in a representative set of human GEP NET cell lines. Growth and apoptosis were determined based on cell numbers, cell‐cycle analyses, kinase assays, DNA fragmentation and PARP cleavage. Expression of COX and cell cycle–regulatory molecules was examined by immunoblotting and reporter gene assays. Depending on the drug and cell line investigated, NSAID treatment resulted in profound growth inhibition of GEP NET cells. Growth‐inhibitory effects were achieved with either COX‐2 selective (NS398) or unselective (indomethacin, sulindac) compounds. Cell‐cycle analyses documented a G1 arrest in NSAID‐treated GEP NET populations. In addition, 100 μM sulindac or indomethacin induced apoptosis. All 3 COX inhibitors prevented CDK‐2 activation. In parallel to the NSAID‐mediated reduction of CDK‐2 activity, p21cip‐1 promoter activity and cellular p21cip‐1 levels increased and p21cip‐1 was sequestered into CDK‐2 complexes. Thus, the G1 arrest likely resulted from p21cip‐1‐dependent inhibition of CDK‐2 activity. At therapeutically relevant concentrations, sulindac significantly reduced GEP NET cell numbers, whereas IFN‐α and octreotide remained ineffective. The extent of growth inhibition in GEP NETs was comparable to the antiproliferative effects of sulindac in established NSAID‐sensitive cell models. NSAIDs acted as potent antiproliferative agents in GEP NET cells via G1 cell‐cycle arrest and might therefore offer a therapeutic alternative to current treatment modalities. © 2003 Wiley‐Liss, Inc.
Generation of a highly stable, internalizing anti‐CD22 single‐chain Fv fragment for targeting non‐Hodgkin's lymphoma
Authors: Arndt Michaela A.E. , Krauss Jürgen , Schwarzenbacher Robert , Vu Bang K. , Greene Shailen , Rybak Susanna M. 
Published: October 2003

AbstractThe generation of a single chain Fv (scFv) fragment derived from the anti‐CD22 monoclonal antibody LL2 resulted in a molecule with good antigen binding but very poor stability properties, thus hampering its clinical applicability. Here we report on the construction of an engineered LL2 scFv fragment by rational mutagenesis. The contribution of uncommon wild‐type sequence residues for providing stability to the conserved common core structure of immunoglobulins was examined. Aided by computer homology modeling, 3 destabilizing residues within the core of the wild‐type VH domain were identified. Owing to the conserved nature of the buried core structure, mutagenesis of these sites to respective consensus residues markedly stabilized the molecule but did not influence its antigen binding properties: the engineered scFv MJ‐7 exhibited exceptional biophysical stability with a half‐life not reached after 6 days of incubation in human serum at 37°C, while fully retaining the epitope specificity of the monoclonal antibody, and antigen binding affinity of the wild‐type scFv. Furthermore, both the monoclonal antibody LL2 and the engineered scFv fragment became fully internalized after only 30 min of incubation at 37°C with CD22+ tumor cells. These properties predict scFv MJ‐7 could become a novel powerful tool to selectively deliver cytotoxic agents to malignant CD22+ cells. © 2003 Wiley‐Liss, Inc.
Long‐term risk of second malignant neoplasms after neuroblastoma in childhood: Role of treatment
Authors: Rubino Carole , Adjadj Elisabeth , Guérin Sylvie , Guibout Catherine , Shamsaldin Akhtar , Dondon Marie‐Gabrielle , Valteau‐Couanet Dominique , Hartmann Olivier , Hawkins Mike , de Vathaire Florent 
Published: October 2003

AbstractThe aim of our study was to quantify the risk of second malignant neoplasms (SMNs) among long‐term survivors of neuroblastoma and to study the influence of treatment on this risk. We studied data from 544 5‐year survival patients diagnosed with neuroblastoma before age 16 years at 8 French and British treatment centres from 1948 to 1986. After an average follow‐up of 15 years (range, 5–38 years), 12 children developed a total of 13 SMNs, whereas 1.19 were expected from general population rates. Among these SMNs, there were 5 thyroid and 3 breast cancers. Increases of the risks of SMN were observed with time since neuroblastoma diagnosis and attained age. In a multivariate analysis, the relative risk of SMN associated with radiotherapy was 4.3 (95% CI 0.8–78), whereas no increased risk of SMN was associated with the administration of chemotherapy as a whole (RR = 0.4, 95% CI 0.1–1.9). Young children treated for a neuroblastoma have significantly increased risks of SMN over 3 decades of follow‐up. Radiotherapy treatment was found to be an important risk factor for developing SMNs, whereas no effect of chemotherapy was evidenced. Although our findings reflect the late effects of past therapeutic modalities, they underscore the importance of long‐term surveillance of young children treated for a neuroblastoma. For these patients, many more years of follow‐up are required to appreciate their overall risks of treatment‐related SMNs. © 2003 Wiley‐Liss, Inc.