bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2
Authors: Liu Weiguo , Baer Maria R. , Bowman Mary Jo , Pera Paula , Zheng Xiang , Morgan Janet , Pandey Ravindra A. , Oseroff Allan R. 
Published: April 2007

Abstract
Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDT efficacy.
Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second- and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1 tumor model.
Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3- to 6-fold in ABCG2+ cells, but not in ABCG2− cells, and enhanced PDT efficacy both in vitro and in vivo.
Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.
c-Kit/PDGFRA Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors
Authors: Miselli Francesca="C"&gt; , Casieri Paola , Negri Tiziana , Orsenigo Marta , Lagonigro M. Stefania , Gronchi Alessandro , Fiore Marco , Casali Paolo G. , Bertulli Rossella , Carbone Antonino , Pierotti Marco A. , Tamborini Elena , Pilotti Silvana 
Published: April 2007

Abstract
Purpose: To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment.
Experimental Design: We investigated 132 tumor samples obtained from 35 patients with advanced disease who underwent resective surgery after imatinib treatment according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group protocol. On the basis of imaging findings, 27 patients were responders and 8 progressors, and retaining this radiological subdivision, we analyzed posttreatment morphologic changes correlating them with molecular, biochemical, and cytogenetic analyses.
Results: On the basis of morphology (residual viable cellularity/proliferation markers), three subgroups were identified showing high, moderate, or low response. All of the progressing cases clustered in the low-response subgroup, whereas the responding cases were distributed in all three subgroups. The correlation between morphology and the molecular findings showed that secondary mutations segregated with the low-response subgroup, whereas c-Kit primary resistance mutations were randomly distributed in the three subgroups. Fluorescence in situ hybridization analysis of c-Kit/PDGFRA genes showed that all of the progressing cases were disomic. Referring to morphology, among the responding cases, a disomic pattern was mainly restricted to the high responders, whereas the moderate and low responders were aneusomic. Comparison of post-imatinib genomic profiles with the 23 available primary tumors showed that 17 cases carried the same cytogenetic pattern. Overall, 12 of the 27 primary tumors presented a gain/loss of c-Kit/PDGFRA gene copy number.
Conclusions: Our findings show that c-Kit/PDGFRA genomic alterations were present at disease onset in 1/3 of the examined cases. They therefore represent an early event possibly related to primary imatinib resistance in GISTs.
Cholecystokinin Down-Regulation by RNA Interference Impairs Ewing Tumor Growth
Authors: Carrillo Jaime , García-Aragoncillo Eva , Azorín Daniel , Agra Noelia , Sastre Ana , González-Mediero Imelda , García-Miguel Purificación , Pestaña Ángel , Gallego Soledad , Segura Dolores , Alonso Javier 
Published: April 2007

Abstract
Purpose: Tumors of the Ewing family are characterized by chromosomal translocations that yield chimeric transcription factors, such as EWS/FLI1, which regulate the expression of specific genes that contribute to the malignant phenotype. In the present study, we show that cholecystokinin (CCK) is a new target of the EWS/FLI1 oncoprotein and assess its functional role in Ewing tumor pathogenesis.
Experimental Design: Relevant EWS/FLI1 targets were identified using a combination of cell systems with inducible EWS/FLI1 expression, Ewing tumors and cell lines, microarrays, and RNA interference with doxycycline-inducible small hairpin RNA (shRNA) vectors. A doxycycline-inducible CCK-shRNA vector was stably transfected in A673 and SK-PN-DW Ewing cell lines to assess the role of CCK in cell proliferation and tumor growth.
Results: Microarray analysis revealed that CCK was up-regulated by EWS/FLI1 in HeLa cells. CCK was overexpressed in Ewing tumors as compared with other pediatric malignancies such as rhabdomyosarcoma and neuroblastoma, with levels close to those detected in normal tissues expressing the highest levels of CCK. Furthermore, EWS/FLI1 knockdown in A673 and SK-PN-DW Ewing cells using two different doxycycline-inducible EWS/FLI1-specific shRNA vectors down-regulated CCK mRNA expression and diminished the levels of secreted CCK, showing that CCK is a EWS/FLI1 specific target gene in Ewing cells. A doxycycline-inducible CCK-specific shRNA vector successfully down-regulated CCK expression, reduced the levels of secreted CCK in Ewing cell lines, and inhibited cell growth and proliferation in vitro and in vivo. Finally, we show that Ewing cell lines and tumors express CCK receptors and that the growth inhibition produced by CCK silencing can be rescued by culturing the cells with medium containing CCK.
Conclusions: Our data support the hypothesis that CCK acts as an autocrine growth factor stimulating the proliferation of Ewing cells and suggest that therapies targeting CCK could be promising in the treatment of Ewing tumors.
ADAM-17 Expression in Breast Cancer Correlates with Variables of Tumor Progression
Authors: McGowan Patricia M. , Ryan Bríd M. , Hill Arnold D.K. , McDermott Enda , O'Higgins Niall , Duffy Michael J. 
Published: April 2007

Abstract
The ADAMs are a family of membrane proteins possessing a disintegrin and metalloprotease domain. One of their main functions is shedding of membrane proteins. The aim of this study was to test the hypothesis that ADAM-17 (also known as tumor necrosis factor-α converting enzyme) is involved in breast cancer progression. Overexpression of ADAM-17 in MCF-7 breast cancer cells increased in vitro invasion and proliferation, whereas down-regulation of ADAM-17 expression in MDA-MB-435 cells decreased invasion and proliferation. At both mRNA and protein levels, ADAM-17 expression was significantly up-regulated in breast cancer compared with normal breast tissue. Using Western blotting, ADAM-17 protein in breast cancer was shown to exist in two forms migrating with approximate molecular masses of 100 and 120 kDa. Based on their known molecular mass, these bands were taken to represent the active and precursor forms of ADAM-17, respectively. The proportion of active to total ADAM-17 increased progressively from normal breast tissue to primary breast cancer to lymph node metastases (P = 0.017, Kruskal-Wallis test). In primary cancers, the active form was expressed more frequently in node-positive compared with node-negative tumors (P = 0.034, χ2 test). Furthermore, in primary carcinomas, both forms of ADAM-17 correlated significantly (Spearman correlation analysis) with levels of urokinase plasminogen activator (precursor form: r = 0.246, P = 0.032, n = 83 and active form: r = 0.428, P = 0.0001, n = 83) and proliferating cell nuclear antigen (precursor form: r = 0.524, P &lt; 0.0001, n = 73 and active form: r = 0.365, P = 0.002, n = 73). Our results support the hypothesis that ADAM-17 is involved in breast cancer progression.
Reciprocal Regulation of SOCS 1 and SOCS3 Enhances Resistance to Ionizing Radiation in Glioblastoma Multiforme
Authors: Zhou Hong , Miki Rika , Eeva Mervi , Fike Francesca M. , Seligson David , Yang Lu , Yoshimura Akihiko , Teitell Michael A. , Jamieson Christina A.M. , Cacalano Nicholas A. 
Published: April 2007

AbstractPurpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance.Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay.Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells.Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.
A Novel Chromogranin-A Promoter-Driven Oncolytic Adenovirus for Midgut Carcinoid Therapy
Authors: Leja Justyna , Dzojic Helena , Gustafson Elisabet , Öberg Kjell , Giandomenico Valeria , Essand Magnus 
Published: April 2007

Abstract
Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene.
Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases.
Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes.
Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.
Silencing of Hypoxia Inducible Factor-1α by RNA Interference Attenuates Human Glioma Cell GrowthIn vivo
Authors: Gillespie David L. , Whang Kum , Ragel Brian T. , Flynn Jeannette R. , Kelly David A. , Jensen Randy L. 
Published: April 2007

AbstractPurpose: Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which, in turn, is regulated by cellular oxygen tension. Hypoxia inducible factor-1α (HIF-1α) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas.Experimental Design: We investigated the role of HIF-1α in glioma growth in vivo using RNA interference (RNAi) in U251, U87, and U373 glioma cells.Results: We found that RNAi can be used to significantly attenuate glioma growth by reducing HIF-1α levels constitutively using short hairpin RNAs and transiently using small interfering RNAs (siRNA). HIF-1α levels on average were reduced 55% in normoxia and 71% in hypoxia. Vascular endothelial growth factor and GLUT-1 levels were reduced 81% and 71%, respectively, in the stable HIF-1α–reduced clones. These clones showed significant growth attenuation (up to 73%) compared with negative controls when grown in vivo in mouse flanks. Cellular proliferation was also reduced significantly, as determined by MIB-1 staining. Treating gliomas grown in mouse flank transiently with siRNA against HIF-1α by intratumoral injection resulted in a significant reduction of HIF-1α activity. This activity was followed using a hypoxia-responsive luciferase construct that enabled hypoxia imaging in vivo. Tumor volume in these siRNA injection experiments was reduced by 50% over the negative controls.Conclusions: These results indicate that transient RNAi directed against HIF-1α can effectively curb glioma growth in vivo.
Ursodeoxycholic Acid versus Sulfasalazine in Colitis-Related Colon Carcinogenesis in Mice
Authors: Kohno Hiroyuki , Suzuki Rikako , Yasui Yumiko , Miyamoto Shingo , Wakabayashi Keiji , Tanaka Takuji 
Published: April 2007

Abstract
Purpose: Inflammation influences carcinogenesis. In the current study, we investigated whether ursodeoxycholic acid (UDCA) can inhibit colitis-related mouse colon carcinogenesis and compared it with the effects of sulfasalazine.
Experimental Design: Male CD-1 mice were given a single i.p. injection of azoxymethane followed by 1-week oral exposure of 1% dextran sodium sulfate in drinking water. They are then maintained on a basal diet mixed with UDCA (0.016%, 0.08%, or 0.4%) or sulfasalazine (0.05%) for 17 weeks. At week 20, the tumor-inhibitory effects of both chemicals were assessed by counting the incidence and multiplicity of colonic neoplasms. The immunohistochemical expression of the proliferating cell nuclear antigen labeling index in colonic epithelial malignancies was also assessed. Finally, at week 5, the mRNA expressions for cyclooxygenase-2, inducible nitric oxide synthase, peroxisome proliferator-activated receptor-γ, and tumor necrosis factor-α were measured in nontumorous mucosa.
Results: Feeding the mice with UDCA at all doses significantly inhibited the multiplicity of colonic adenocarcinoma. The treatment also significantly lowered the proliferating cell nuclear antigen labeling index in the colonic malignancies. UDCA feeding reduced the expression of inducible nitric oxide synthase and tumor necrosis factor-α mRNA in the colonic mucosa, while not significantly affecting the expression of cyclooxygenase-2 mRNA and peroxisome proliferator-activated receptor-γ mRNA. Sulfasalazine caused a nonsignificant reduction in the incidence and multiplicity of colonic neoplasia and did not affect these mRNA expression.
Conclusions: Our findings suggest that UDCA rather than sulfasalazine could serve as an effective suppressing agent in colitis-related colon cancer development in mice.
Higher Frequency of Diploidy in Young-Onset Microsatellite-Stable Colorectal Cancer
Authors: Boardman Lisa A. , Johnson Ruth A. , Petersen Gloria M. , Oberg Ann L. , Kabat Brian F. , Slusser Joshua P. , Wang Liang , Morlan Bruce W. , French Amy J. , Smyrk Thomas C. , Lindor Noralane M. , Thibodeau Stephen N. 
Published: April 2007

AbstractPurpose: Colorectal carcinoma (CRC) can be divided into two nonoverlapping groups: those that are chromosomally unstable but microsatellite stable (MSS CIN+) and those that are chromosomally stable but microsatellite unstable (MSI CIN−). However, a third group with neither chromosome nor microsatellite instability (MSS CIN−) makes a substantial contribution to the total CRC burden. The clinicopathologic features of MSS CIN− CRC are not well delineated. We assessed the relationship between age and chromosomal instability (CIN) status as measured by ploidy and allelic imbalance in a series of MSS tumors.Experimental Design: We studied a prospectively collected series of CRC patients at Mayo Clinic Rochester. A total of 84 samples of MSS CRC in patients ≤50 years old were identified between 1994 and 1997. A consecutive series of 90 MSS CRC in patients ≥65 years old served as a comparison group. CIN status was assessed using two techniques: ploidy analysis by flow cytometry and small chromosome changes as measured by genomewide fractional allelic imbalance.Results: CRC in the young-onset group was more likely to involve the rectum and to be high stage. MSS tumors in the young-onset group were more often diploid (46%) than those in older patients (26%; P = 0.006). This difference was maintained in the subset of MSS CRC that were high stage (42% versus 18%; P = 0.02) and in rectal cancers (50% versus 23%; P = 0.04).Conclusion: A greater proportion of young patients with MSS CRC has diploid tumors than patients who develop MSS CRC over age 65.
Improving Simulations of Convective Systems from TRMM LBA: Easterly and Westerly Regimes
Authors: Lang S. , Tao W-K. , Simpson J. , Cifelli R. , Rutledge S. , Olson W. , Halverson J. 
Published: April 2007

Abstract
The 3D Goddard Cumulus Ensemble model is used to simulate two convective events observed during the Tropical Rainfall Measuring Mission Large-Scale Biosphere–Atmosphere (TRMM LBA) experiment in Brazil. These two events epitomized the type of convective systems that formed in two distinctly different environments observed during TRMM LBA. The 26 January 1999 squall line formed within a sheared low-level easterly wind flow. On 23 February 1999, convection developed in weak low-level westerly flow, resulting in weakly organized, less intense convection. Initial simulations captured the basic organization and intensity of each event. However, improvements to the model resolution and microphysics produced better simulations as compared to observations. More realistic diurnal convective growth was achieved by lowering the horizontal grid spacing from 1000 to 250 m. This produced a gradual transition from shallow to deep convection that occurred over a span of hours as opposed to an abrupt appearance of deep convection. Eliminating the dry growth of graupel in the bulk microphysics scheme effectively removed the unrealistic presence of high-density ice in the simulated anvil. However, comparisons with radar reflectivity data using contoured-frequency-with-altitude diagrams (CFADs) revealed that the resulting snow contents were too large. The excessive snow was reduced primarily by lowering the collection efficiency of cloud water by snow and resulted in further agreement with the radar observations. The transfer of cloud-sized particles to precipitation-sized ice appears to be too efficient in the original scheme. Overall, these changes to the microphysics lead to more realistic precipitation ice contents in the model. However, artifacts due to the inability of the one-moment scheme to allow for size sorting, such as excessive low-level rain evaporation, were also found but could not be resolved without moving to a two-moment or bin scheme. As a result, model rainfall histograms underestimated the occurrence of high rain rates compared to radar-based histograms. Nevertheless, the improved precipitation-sized ice signature in the model simulations should lead to better latent heating retrievals as a result of both better convective–stratiform separation within the model as well as more physically realistic hydrometeor structures for radiance calculations.
New Multiscale Models and Self-Similarity in Tropical Convection
Authors: Majda Andrew J. 
Published: April 2007

Abstract
One of the unexplained striking features of tropical convection is the observed statistical self-similarity in clusters, superclusters, and intraseasonal oscillations through complex multiscale processes ranging from the mesoscales to the equatorial synoptic scales to the intraseasonal/planetary scales. Here new multispatial-scale, multitime-scale, simplified asymptotic models are derived systematically from the equatorial primitive equations on the range of scales from mesoscale to equatorial synoptic to planetary/intraseasonal, which provide a useful analytic framework for addressing these issues. New mesoscale equatorial synoptic dynamical (MESD) models and balanced MESD (BMESD) models are developed for the multitime, multispace interaction from mesoscales to equatorial synoptic scales; new multitime versions of the intraseasonal planetary equatorial synoptic dynamics (IPESD) models are developed for multiple spatiotemporal interactions on equatorial synoptic scales and planetary scales. The mathematical character derived below for all these simplified models explicitly demonstrates that the main nonlinear interactions across scales are quasi-linear where eddy flux divergences of momentum and temperature from nonlinear advection from the smaller-scale spatiotemporal flows as well as mean source effects accumulate in time and drive the waves on the successively larger spatiotemporal scales. Furthermore, these processes that transfer energy to the next larger, longer, spatiotemporal scales are self-similar in a suitable sense established here. On the other hand, the larger scales set the environment for this transport through processes such as mean advection of the smaller scales.
Virtualization
Authors: Bannon Peter R. 
Published: April 2007

AbstractThe virtual temperature of a moist air parcel is defined as the temperature of a dry air parcel having the same mass, volume, and pressure. It is shown here that a virtual air parcel can be formed diabatically by warming the parcel to its virtual temperature while replacing its water vapor with the equivalent mass of dry air under isobaric, isochoric conditions. Conversely a saturated virtual air parcel can be formed diabatically by cooling the parcel to its saturated virtual temperature while replacing some of its dry air with the equivalent mass of water vapor under isobaric, isochoric conditions. These processes of virtualization can be represented on a vapor pressure–temperature diagram. This diagram facilitates the comparison of the relative density of two moist air parcels at the same pressure. The effects of liquid and/or solid water can also be included.