bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P
Authors: Kneifel Stefan , Cordier Dominik , Good Stephan , Ionescu Mihai C.S. , Ghaffari Anthony , Hofer Silvia , Kretzschmar Martin , Tolnay Markus , Apostolidis Christos , Waser Beatrice , Arnold Marlene , Mueller-Brand Jan , Maecke Helmut R. , Reubi Jean Claude , Merlo Adrian 
Published: June 2006

Abstract
Purpose: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid 125I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins.
Experimental Design: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg1 of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC50 of 0.88 ± 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, 90Y was mostly used. To reduce the “cross-fire effect” in critically located tumors, 177Lut and 213Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3.
Results: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation.
Conclusions: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.
Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibody L8A4
Authors: Yang Weilian , Barth Rolf F. , Wu Gong , Kawabata Shinji , Sferra Thomas J. , Bandyopadhyaya Achintya K. , Tjarks Werner , Ferketich Amy K. , Moeschberger Melvin L. , Binns Peter J. , Riley Kent J. , Coderre Jeffrey A. , Ciesielski Michael J. , Fenstermaker Robert A. , Wikstrand Carol J. 
Published: June 2006

Abstract
Purpose: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98npEGFRvIII.
Experimental Design: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98npEGFRvIII glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [125I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later.
Results: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (&lt;0.5 μg/g) at the corresponding times. Based on these favorable biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology Research Reactor-II. Rats received BD-L8A4 (∼40 μg 10B/∼750 μg protein) by CED either alone or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out 24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those animals that received both agents. Rats that received BD-L8A4 by CED in combination with i.v. BPA had a mean ± SE survival time of 85.5 ± 15.5 days with 20% long-term survivors (&gt;6 months) and those that received BD-L8A4 alone had a mean ± SE survival time of 70.4 ± 11.1 days with 10% long-term survivors compared with 40.1 ± 2.2 days for i.v. BPA and 30.3 ± 1.6 and 26.3 ± 1.1 days for irradiated and untreated controls, respectively.
Conclusions: These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.
Expression of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptors 1 and 2 in Melanoma
Authors: McCarthy Mary M. , DiVito Kyle A. , Sznol Mario , Kovacs Daniela , Halaban Ruth , Berger Aaron J. , Flaherty Keith T. , Camp Robert L. , Lazova Rossitza , Rimm David L. , Kluger Harriet M. 
Published: June 2006

AbstractPurpose: The proapoptotic receptors tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 are targets of drugs in clinical development, and receptor expression levels may be important determinants of sensitivity to receptor agonists. We assessed TRAIL-R1 and TRAIL-R2 expression patterns in a large cohort of melanomas and benign nevi.Experimental Design: We analyzed tissue microarrays containing 546 melanomas and 540 nevi using our automated quantitative method to measure protein levels in situ (AQUA). The system uses S100 to define pixels as melanoma (tumor mask) within the array spot and measures intensity of TRAIL-receptor expression using Cy5-conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables.Results: TRAIL-R1 and TRAIL-R2 expression was higher in melanomas than in nevi (P &lt; 0.0001), and higher in primary than in metastatic specimens (P = 0.0031 and P &lt; 0.0001, respectively). TRAIL-R1 and TRAIL-R2 expression exceeding the 95th percentile for nevi was found in 19% and 74% of melanoma specimens, respectively. Although on univariate analysis, high TRAIL-R2 expression correlated with increased survival (P = 0.0439), it was not associated with survival within the primary or metastatic subcohorts. TRAIL-R1 expression was not associated with survival.Conclusions: TRAIL-R1 and TRAIL-R2 expression is higher in malignant melanocytes than in their benign counterparts, suggesting that these receptors might be effective therapeutic targets in melanoma. Expression is higher in early-stage disease than in metastatic specimens, and expression exceeding that found in nevi is found in a substantially larger fraction of melanomas for TRAIL-R2 compared with TRAIL-R1. Assessment of baseline tumor TRAIL receptor expression may be important in analysis of clinical trials involving TRAIL receptor agonists.
Functional Screen for Genes Responsible for Tamoxifen Resistance in Human Breast Cancer Cells
Authors: Meijer Danielle , van Agthoven Ton , Bosma Peter T. , Nooter Kees , Dorssers Lambert C.J. 
Published: June 2006

Abstract
Antiestrogens, such as tamoxifen, are widely used for endocrine treatment of estrogen receptor–positive breast cancer. However, as breast cancer progresses, development of tamoxifen resistance is inevitable. The mechanisms underlying this resistance are not well understood. To identify genes involved in tamoxifen resistance, we have developed a rapid screening method. To alter the tamoxifen-sensitive phenotype of human ZR-75-1 breast cancer cells into a tamoxifen-resistant phenotype, the cells were infected with retroviral cDNA libraries derived from human placenta, human brain, and mouse embryo. Subsequently, the cells were selected for proliferation in the presence of 4-hydroxy-tamoxifen (OH-TAM) and integrated cDNAs were identified by sequence similarity searches. From 155 OH-TAM-resistant cell colonies, a total of 25 candidate genes were isolated. Seven of these genes were identified in multiple cell colonies and thus cause antiestrogen resistance. The epidermal growth factor receptor, platelet-derived growth factor receptor-α, platelet-derived growth factor receptor-β, colony-stimulating factor 1 receptor, neuregulin1, and fibroblast growth factor 17 that we have identified have been described as key regulators in the mitogen-activated protein kinase pathway. Therefore, this pathway could be a valuable target in the treatment of patients with breast cancer resistant to endocrine treatment. In addition, the putative gene LOC400500, predicted by in silico analysis, was identified. We showed that ectopic expression of this gene, designated as breast cancer antiestrogen resistance 4 (BCAR4), caused OH-TAM resistance and anchorage-independent cell growth in ZR-75-1 cells and that the intact open reading frame was required for its function. We conclude that retroviral transfer of cDNA libraries into human breast cancer cells is an efficient method for identifying genes involved in tamoxifen resistance. (Mol Cancer Res 2006;4(6):379–86)
Lateral Reynolds Stress and Eddy Viscosity in a Coastal Strait
Authors: Colbo Keir 
Published: June 2006

Abstract
The lateral Reynolds stress uυ, representing the transfer of along-strait momentum toward the sides of Juan de Fuca Strait, is measured with an array of ADCPs. The contributions to the stress from a number of frequency bands are analyzed to highlight the roles of different processes. Motion in a frequency band that includes internal waves and Doppler-shifted subinertial eddies gives a Reynolds stress that, when scaled by the observed shear, is consistent with an eddy viscosity of O(10 m2 s−1). This viscosity acts on the tides and the estuarine flow. The tides can also impart a viscous stress upon the low-frequency estuarine flow. These tidal currents, although strong, are largely nondivergent within the area of the array and thus appear to be less important for the cross-strait transfer of momentum. The long-term mean estuarine circulation can be acted upon by meanders of the estuarine flow, defined as features with periods of 3–5 days. These meanders are found to also have a horizontal eddy viscosity of O(10 m2 s−1). The measured Reynolds stress divergences are consistent with both the strongly curved profile of the estuarine mean flow and also the more slablike tidal current profile. This paper represents the first direct calculation of eddy viscosity on the medium-sized scale of the array, O(1 km).
Possible Sources Driving the Potential Vorticity Structure and Long-Wave Instability of Coastal Upwelling and Downwelling Currents
Authors: Morel Yves G. , Darr David S. , Talandier Claude 
Published: June 2006

AbstractIt is well known that upwelling and downwelling currents are unstable to perturbations. Less is, however, known about the physical mechanism responsible for the observed and modeled instabilities. It is shown that the origin of the long-wave barotropic/baroclinic instability observed on upwelling currents has to be sought among diabatic or thermobaric mechanisms. In particular, the role of mixing associated with Kelvin–Helmholtz instability and of wind forcing is investigated. Low Richardson numbers occur when the pycnocline outcrops at the sea surface. The criterion for instability (Ri ≤ 1/4) can be reached in a narrow region close to the upwelling front, permitting Kelvin–Helmholtz instability and mixing. This can precondition the current for long-wave instability by transforming the current's potential vorticity. A constant wind can likewise modify the potential vorticity. The resulting potential vorticity anomaly is always negative for both upwelling and downwelling currents, and this anomaly interacts with the outcropped front, destabilizing it. Examples are provided via numerical calculations using an idealized front. A wind stress is an effective means of inducing the negative PV necessary for instability; with wind, Kelvin–Helmholz instability, when present, merely modifies the instability characteristics. In addition, upwelling fronts are always less stable than comparable downwelling fronts.
A Coupled Coastal Polynya–Atmospheric Boundary Layer Model
Authors: Walkington I. A. , Willmott A. J. 
Published: June 2006

Abstract
This paper formulates and presents opening solutions of a one-dimensional coastal polynya flux model in which frazil ice is characterized by its depth and concentration. In comparison with polynya flux models in which variable frazil ice concentration is absent, this model is found to predict a smaller heat flux to the atmosphere. Consequently the model in this paper exhibits a wider steady-state polynya and longer opening times when compared with models in which ice concentration is neglected. The aforementioned polynya flux model is then coupled to a lower-atmosphere boundary layer model, and it is demonstrated that the polynya opening time and the steady-state width are significantly altered in the coupled, as compared with the decoupled, system. In essence, the heating of the lower atmosphere above the evolving polynya in the coupled system reduces the sensible heat flux between the ocean and atmosphere, thereby reducing the frazil ice production rate and hence leading to longer polynya opening time and wider steady-state width. This phenomenon is particularly noticeable when the potential temperature of the atmosphere at the coast is only slightly below the freezing point. In addition, a cutoff atmospheric wind speed is shown to exist, above which a steady-state polynya can never be obtained. Solutions calculated by the two models, using parameters representative of the St. Lawrence Island polynya, show that the new models contain substantial predictive capability.
Two-Way Feedback Interaction between the Thermohaline and Wind-Driven Circulations
Authors: MacMynowski Douglas G. , Tziperman Eli 
Published: June 2006

AbstractThe thermohaline circulation (THC) affects the meridional atmospheric temperature gradient and therefore the atmospheric wind and the wind-driven ocean circulation. The wind-driven circulation (WDC), in turn, affects the THC by the advection of salinity anomalies into deep-water formation sites. This paper considers this two-way coupling between the WDC and THC using a simple box-type model and analysis tools from engineering feedback control. The two-way feedback can have a significant effect on the dynamics of the coupled system. For a reasonable choice of parameters, the feedback destabilizes the THC equilibrium for low freshwater forcing. For higher freshwater forcing, the feedback results in a new stable equilibrium instead of the large amplitude oscillation that develops without feedback. It is expected that the analysis approach used here may be broadly applicable to the study of feedback interconnections of other climate systems as well.
Evolution of the Deep Water in the Canadian Basin in the Arctic Ocean
Authors: Timmermans M-L. , Garrett Chris 
Published: June 2006

Abstract
An overflow of magnitude 0.25 Sv (Sv ≡ 106 m−3 s−1) has been predicted to enter the Makarov Basin (part of the Canadian Basin in the Arctic Ocean) from the Eurasian Basin via a deep gap in the dividing Lomonosov ridge. The authors argue that this overflow does not ventilate the deep Makarov Basin (below 2400 m) where the water is too warm and salty to be compatible with such a large cold fresh inflow. However, complete isolation of the homogeneous bottom layer of the Makarov Basin must be ruled out because changes there are too small to arise from more than a small fraction of the measured geothermal heat flux into the basin. A small cold fresh inflow of about 0.01 Sv from the Amundsen Basin seems to be required. This could occur if the gap in the dividing Lomonosov Ridge is shallower than previously thought. It could also occur if there is active mixing and dilution of the predicted overflow in the gap, leaving only a small fraction to descend into the deep Makarov Basin. Hydraulic theory and hydrographic observations are used to rule out any significant flow of dense water from the Makarov Basin into the deep Canada Basin, confirming previous hypotheses of isolation of the deep water in the Canada Basin.
Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells
Authors: Balakrishnan Kumudha , Nimmanapalli Ramadevi , Ravandi Farhad , Keating Michael J. , Gandhi Varsha 
Published: June 2006

Abstract
Purine nucleoside phosphorylase (PNP) deficiency in humans results in T lymphocytopenia. Forodesine, a potent inhibitor of PNP, was designed based on the transition-state structure stabilized by the enzyme. Previous studies established that forodesine in the presence of deoxyguanosine (dGuo) inhibits the proliferation of T lymphocytes. A phase 1 clinical trial of forodesine in T-cell malignancies demonstrated significant antileukemic activity with an increase in intracellular dGuo triphosphate (dGTP). High accumulation of dGTP in T cells may be dependent on the levels of deoxynucleoside kinases. Because B-cell chronic lymphocytic leukemia (B-CLL) cells have high activity of deoxycytidine kinase (dCK), we hypothesized that these lymphocytes would respond to forodesine. This postulate was tested in primary lymphocytes during in vitro investigations. Lymphocytes from 12 patients with CLL were incubated with forodesine and dGuo. These CLL cells showed a wide variation in the accumulation of intracellular dGTP without any effect on other deoxynucleotides. This was associated with DNA damage-induced p53 stabilization, phosphorylation of p53 at Ser15, and activation of p21. The dGTP accumulation was related to induction of apoptosis measured by caspase activation, changes in mitochondrial membrane potential, and PARP cleavage. Based on these data, a phase 2 clinical trial of forodesine has been initiated for CLL patients.
ESTimating plant phylogeny: lessons from partitioning
Authors: de la Torre Jose EB , Egan Mary G , Katari Manpreet S , Brenner Eric D , Stevenson Dennis W , Coruzzi Gloria M , DeSalle Rob 
Published: June 2006

Abstract

Background
While Expressed Sequence Tags (ESTs) have proven a viable and efficient way to sample genomes, particularly those for which whole-genome sequencing is impractical, phylogenetic analysis using ESTs remains difficult. Sequencing errors and orthology determination are the major problems when using ESTs as a source of characters for systematics. Here we develop methods to incorporate EST sequence information in a simultaneous analysis framework to address controversial phylogenetic questions regarding the relationships among the major groups of seed plants. We use an automated, phylogenetically derived approach to orthology determination called OrthologID generate a phylogeny based on 43 process partitions, many of which are derived from ESTs, and examine several measures of support to assess the utility of EST data for phylogenies.

Results
A maximum parsimony (MP) analysis resulted in a single tree with relatively high support at all nodes in the tree despite rampant conflict among trees generated from the separate analysis of individual partitions. In a comparison of broader-scale groupings based on cellular compartment (ie: chloroplast, mitochondrial or nuclear) or function, only the nuclear partition tree (based largely on EST data) was found to be topologically identical to the tree based on the simultaneous analysis of all data. Despite topological conflict among the broader-scale groupings examined, only the tree based on morphological data showed statistically significant differences.

Conclusion
Based on the amount of character support contributed by EST data which make up a majority of the nuclear data set, and the lack of conflict of the nuclear data set with the simultaneous analysis tree, we conclude that the inclusion of EST data does provide a viable and efficient approach to address phylogenetic questions within a parsimony framework on a genomic scale, if problems of orthology determination and potential sequencing errors can be overcome. In addition, approaches that examine conflict and support in a simultaneous analysis framework allow for a more precise understanding of the evolutionary history of individual process partitions and may be a novel way to understand functional aspects of different kinds of cellular classes of gene products.
Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens
Authors: Zhang YueMei , Bhavnani Bhagu R 
Published: June 2006

Abstract

Background
Glutamate, a major excitatory amino acid neurotransmitter, causes apoptotic neuronal cell death at high concentrations. Our previous studies have shown that depending on the neuronal cell type, glutamate-induced apoptotic cell death was associated with regulation of genes such as Bcl-2, Bax, and/or caspase-3 and mitochondrial cytochrome c. To further delineate the intracellular mechanisms, we have investigated the role of calpain, an important calcium-dependent protease thought to be involved in apoptosis along with mitochondrial apoptosis inducing factor (AIF) and caspase-3 in primary cortical cells and a mouse hippocampal cell line HT22.

Results
Glutamate-induced apoptotic cell death in neuronal cells was associated with characteristic DNA fragmentation, morphological changes, activation of calpain and caspase-3 as well as the upregulation and/or translocation of AIF from mitochondria into cytosol and nuclei. Our results reveal that primary cortical cells and HT22 cells display different patterns of regulation of these genes/proteins. In primary cortical cells, glutamate induces activation of calpain, caspase-3 and translocation of AIF from mitochondria to cytosol and nuclei. In contrast, in HT22 cells, only the activation of calpain and upregulation and translocation of AIF occurred. In both cell types, these processes were inhibited/reversed by 17β-estradiol and Δ8,17β-estradiol with the latter being more potent.

Conclusion
Depending upon the neuronal cell type, at least two mechanisms are involved in glutamate-induced apoptosis: a caspase-3-dependent pathway and a caspase-independent pathway involving calpain and AIF. Since HT22 cells lack caspase-3, glutamate-induced apoptosis is mediated via the caspase-independent pathway in this cell line. Kinetics of this apoptotic pathway further indicate that calpain rather than caspase-3, plays a critical role in the glutamate-induced apoptosis. Our studies further indicate that glutamate- induced changes of these proteins can be inhibited by estrogens, with Δ8,17β-estradiol, a novel equine estrogen being more potent than 17β-estradiol. To our knowledge, this is the first demonstration that glutamate-induced apoptosis involves regulation of multiple apoptotic effectors that can be inhibited by estrogens. Whether these observations can help in the development of novel therapeutic approaches for the prevention of neurodegenerative diseases with estrogens and calpain inhibitors remains to be investigated.