bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Antibody Targeting the Type I Insulin-like Growth Factor Receptor Enhances the Castration-Induced Response in Androgen-Dependent Prostate Cancer
Authors: Plymate Stephen R. , Haugk Kathy , Coleman Ilsa , Woodke Lillie , Vessella Robert , Nelson Peter , Montgomery R. Bruce , Ludwig Dale L. , Wu Jennifer D. 
Published: November 2007

Abstract
Purpose: To determine the effect of inhibition of insulin-like growth factor-IR (IGF-IR) signaling with an antibody to the IGF-IR, A12, in conjunction with androgen withdrawal on prostate cancer progression in a human prostate xenograft model, LuCaP 35.
Experimental Design: LuCaP 35 was implanted s.c. in severe combined immunodeficient mice. At the time of castration, mice were randomized to one of three groups. Group 1 was castrate only; group 2 received A12 40 mg/kg i.p. for 2 weeks beginning 1 week after castration; and group 3 received A12 40 mg/kg i.p. for 2 weeks beginning 2 weeks after castration.
Results: In group 1, tumor volume decreased to 60% of the starting volume 4 weeks post-castration. In groups 2 and 3, tumor volumes nadired 6 weeks after castration at &lt;10% of the volume at time of castration (P &lt; 0.01). Tumor regrowth was not seen in groups 2 or 3 until 15 weeks after castration. Androgen receptor (AR) localization in tumors showed a decrease in nuclear staining in groups 2 and 3 compared with group 1 (P &lt; 0.001). Tumor volume correlated with nuclear AR intensity. AR-regulated genes increased early in group 1, but did not increase in groups 2 and 3. Thus, tumor-specific survival was prolonged by the addition of A12 to castration.
Conclusions: This study shows that the inhibition of IGF-IR enhances the effects of castration in prostate cancer. These effects are associated with a decrease in AR signaling and nuclear AR localization, and recurrence is associated with an increase in AR-regulated gene expression.
Buccal Mucosa Cells as In vivo Model to Evaluate Gefitinib Activity in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Loprevite Maura , Tiseo Marcello , Chiaramondia Maurizio , Capelletti Marzia , Bozzetti Cecilia , Bortesi Beatrice , Naldi Nadia , Nizzoli Rita , Dadati Patrizia , Kunkl Annalisa , Zennaro Daniela , Lagrasta Costanza , Campanini Nicoletta , Spiritelli Elena , Camisa Roberta , Grossi Francesco , Rindi Guido , Franciosi Vittorio , Ardizzoni Andrea 
Published: November 2007

Abstract
Purpose: To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non–small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed.
Experimental Design: Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response.
Results: Fifty-eight patients with pretreated advanced non–small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P &lt; 0.001).
Conclusions: Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.
Expression of Prenylated Rab Acceptor 1 Domain Family, Member 2 (PRAF2) in Neuroblastoma: Correlation with Clinical Features, Cellular Localization, and Cerulenin-Mediated Apoptosis Regulation
Authors: Geerts Dirk , Wallick Christopher J. , Koomoa Dana-Lynn T. , Koster Jan , Versteeg Rogier , Go Ramon Christopher V. , Bachmann André S. 
Published: November 2007

Abstract
Purpose: Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein that has recently been implicated in human cancer. In the present study, we analyzed for the first time PRAF2 mRNA expression in a large set of human tumors. The high expression in neuroblastic tumors prompted us to analyze PRAF2 expression correlations with genetic and clinical features of these tumors. In addition, we determined the localization of PRAF2 protein in neuroblastoma cells and studied its regulation in apoptosis.
Experimental Design: Affymetrix microarray analysis was done with a set of 41 different tumor types (1,426 samples) in the public domain, a set of three different neuroblastic tumor types (110 samples), and a panel of 25 neuroblastoma cell lines. The subcellular localization of endogenous PRAF2 in neuroblastoma cells was identified by immunofluorescence microscopy and apoptosis detected by Annexin V staining and poly(ADP-ribose) polymerase cleavage.
Results: PRAF2 mRNA was detected in 970 of 1,426 samples in the public data set. All 110 neuroblastic tumors expressed PRAF2 at higher levels than any other tumor examined. Importantly, PRAF2 expression levels significantly correlated with the following clinical features: patient age at diagnosis (P = 6.19 × 10−5), survival (P = 1.32 × 10−3), International Neuroblastoma Staging System stage (P = 2.86 × 10−4), and MYCN amplification (P = 3.74 × 10−3). PRAF2 localized in bright cytoplasmic punctae and protein levels increased in neuroblastoma cells that underwent cerulenin-induced apoptosis.
Conclusions: Elevated PRAF2 expression levels correlated with unfavorable genetic and clinical features, suggesting PRAF2 as a candidate prognostic marker of neuroblastoma.
Prognostic Value of LISCH7 mRNA in Plasma and Tumor of Colon Cancer Patients
Authors: García José M. , Peña Cristina , García Vanesa , Domínguez Gemma , Muñoz Concepción , Silva Javier , Millán Isabel , Diaz Raquel , Lorenzo Yolanda , Rodriguez Rufo , Bonilla Félix 
Published: November 2007

Abstract
Purpose: LISCH7 is a gene potentially regulated by p53 that is up-regulated in metastasis development. Our hypothesis was that the expression of LISCH7 in primary colorectal tumors determined certain characteristics of the tumors, as well as their behavior, and that its identification in plasma could serve as a prognostic marker.
Experimental Design: We tested this hypothesis in a series of 115 tumors and normal tissues and in 83 plasmas from patients with sporadic colorectal carcinomas, as well as in 20 healthy control plasmas in which the expression levels of the gene were measured by real-time PCR. The expression data were contrasted with clinicopathologic variables.
Results: Although LISCH7 expression was not detected in any control plasma samples, it was positive in 25 (30.1%) plasmas from patients (P = 0.002). LISCH7 mRNA in plasma was significantly associated with the pathologic stage (P = 0.019), with lymph node metastasis (P = 0.008) and with vascular invasion (P = 0.005). Expression was not detected in any normal tissues but was detected in 80 tumor tissues, with a clear association found with vascular invasion (P = 0.027). Moreover, we show that LISCH7 was specifically expressed by the epithelial tumor cells. The adjusted overall survival study showed independent prognostic values for LISCH7 expression levels in tumor tissues (hazard ratio, 3.45; 95% confidence interval, 1.19-9.98).
Conclusions: Our results suggest that LISCH7 is a good tumor marker whose expression levels could be considered as a poor prognosis factor in human colon cancer. Furthermore, plasma is suggested as a feasible source of nucleic acids for subsequent noninvasive prognostic studies.
A Bispecific Recombinant Cytotoxin (DTEGF13) Targeting Human Interleukin-13 and Epidermal Growth Factor Receptors in a Mouse Xenograft Model of Prostate Cancer
Authors: Stish Brad J. , Chen Hua , Shu Yanqun , Panoskaltsis-Mortari Angela , Vallera Daniel A. 
Published: November 2007

AbstractPurpose: Overexpressed cytokine receptors are considered valid targets for new biologicals targeting prostate cancer. However, current reagents are limited in efficacy. Our goal was to determine the advantages of simultaneously targeting two established targets, epidermal growth factor receptor and interleukin-13 (IL-13) receptor, with a new bispecific cytotoxin in which both EGF and IL-13 cytokines were cloned onto the same single-chain molecule with truncated diphtheria toxin (DT390).Experimental Design: In vitro experiments measured the potency of bispecific DTEGF13 and compared its activity to its monospecific counterparts, DTEGF and DTIL13. We determined whether the presence of both cytokine ligands on the same molecule was responsible for its superior activity. In vivo, DTEGF13 was given i.t. to athymic nude mice with established PC-3 human prostate cancer tumor xenografts on their flanks.Results: In vitro, DTEGF13 was more potent than the monospecific cytotoxins against human prostate cancer lines. Enhanced activity was related to the presence of both cytokines on the same single-chain molecule and was not attributed to enhanced binding capacity. Killing was receptor specific. Cytotoxicity could be blocked with anti-EGF and anti–IL-13 antibodies. In vivo, DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established PC-3 tumors in nude mice (P &lt; 0.0001).Conclusions: These data show for the first time that simultaneous targeting of cytokine receptors with two ligands on the same molecule has pronounced anticancer advantages. In an animal model in which human DTEGF13 is cross-reactive with mouse, DTEGF13 was highly effective in checking aggressive prostate tumor progression and was reasonably tolerated.
A Self-Quenched Galactosamine-Serum Albumin-RhodamineX Conjugate: A “Smart” Fluorescent Molecular Imaging Probe Synthesized with Clinically Applicable Material for Detecting Peritoneal Ovarian Cancer Metastases
Authors: Hama Yukihiro , Urano Yasuteru , Koyama Yoshinori , Gunn Andrew J. , Choyke Peter L. , Kobayashi Hisataka 
Published: November 2007

Abstract
Purpose: Fluorophore activation after cellular internalization of a targeted fluorescently labeled conjugate is an effective molecular imaging strategy to increase target-to-background ratios. The d-galactose receptor on ovarian cancer cells has been used to target self-quenched avidin-rhodamineX conjugates in which the avidin component binds to d-galactose receptor and the rhodamines are optically activated by dequenching only after cellular internalization. As a nonimmunogenic alternative of avidin, galactosamine-conjugated serum albumin (GmSA) targets the d-galactose receptor with higher binding affinity and has more conjugation sites available for rhodamineX than avidin.
Experimental Design: GmSA was conjugated with 20 rhodamineX molecules (GmSA-20ROX) to create a self-quenching complex, which was compared with a conjugate consisting of GmSA and a single rhodamineX (GmSA-1ROX) in ex vivo chemical activation characteristics, intracellular activation, and in vivo molecular imaging for detecting peritoneal micrometastases of SHIN3 ovarian cancer.
Results: GmSA-20ROX was five times brighter than GmSA-1ROX when incubated with SHIN3 ovarian cancer cells for 3 h. Submillimeter SHIN3 ovarian cancer implants in the peritoneal cavity were clearly visualized in vivo with spectral fluorescence imaging due to the high tumor-to-background ratio. The sensitivity and specificity of GmSA-20ROX for implant detection were determined by colocalization of the rhodamineX emission with red fluorescent protein expressed constitutively in the SHIN3 tumor implants. Among 336 lesions, sensitivity and specificity were 99%/99%, respectively, for GmSA-20ROX, whereas the results for GmSA-1ROX were only 24%/100% (n = 388), respectively, for lesions ∼0.8 mm or greater in diameter.
Conclusion: Self-quenched GmSA-20ROX is more efficient than previous d-galactose–targeted fluorescent conjugates.
MCP-1 Promoter Polymorphism at −2518 Is Associated with Metastasis of Nasopharyngeal Carcinoma after Treatment
Authors: Tse Ka-Po , Tsang Nang-Ming , Chen Kung-Den , Li Hsin-Pai , Liang Ying , Hsueh Chuen , Chang Kai-Ping , Yu Jau-Song , Hao Sheng-Po , Hsieh Ling-Ling , Chang Yu-Sun 
Published: November 2007

Abstract
Purpose: We herein examined whether the single nucleotide polymorphism (SNP) at −2518 of the MCP-1 gene promoter region influences clinical outcomes among nasopharyngeal carcinoma (NPC) patients.
Experimental Design: The study population consisted of 411 NPC patients without metastasis at diagnosis. All patients were treated at the Chang Gung Memorial Hospital from March 1994 to November 2004. The MCP-1 SNP−2518 genotype of each patient was determined by TaqMan genotyping kit. Statistical analyses were conducted to compare disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) of patients according to genotype. MCP-1 expression in tumor biopsies was examined by immunohistochemistry.
Results: Among 411 NPC patients, carriers of AA and AG genotypes were prone to distant metastasis than that of GG genotype (hazard ratio, 2.21; P = 0.017, and hazard ratio, 2.23; P = 0.005, for AA and AG genotype, respectively) after initial radiotherapy. No genotype-specific significant difference was found in DSS, PFS, and LRFS. Furthermore, immunohistochemistry revealed that MCP-1 expression level was higher in NPC tumor cells from GG carriers compared with those from AA and AG carriers.
Conclusions: MCP-1 SNP−2518 may be a valuable genetic marker for assessing the risk of developing distant metastasis after the radiotherapy in NPC patients. Carriers of A allele may require more aggressive chemotherapy implicating a potential marker for personalized medicine. We speculate that a regulatory SNP may be associated with the distant metastasis of NPC. Validation studies are warranted.
Investigation of Two Dosing Schedules of Vandetanib (ZD6474), an Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, in Combination with Irinotecan in a Human Colon Cancer Xenograft Model
Authors: Troiani Teresa , Serkova Natalie J. , Gustafson Daniel L. , Henthorn Thomas K. , Lockerbie Owen , Merz Andrea , Long Michael , Morrow Mark , Ciardiello Fortunato , Eckhardt S. Gail 
Published: November 2007

AbstractPurpose: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer.Experimental Design: HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib.Results: The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group.Conclusions: These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.
Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1α Autocrine Loop, and Reduces Orthotopic Tumor Growth
Authors: Lang Sven A. , Moser Christian , Gaumann Andreas , Klein Dagmar , Glockzin Gabriel , Popp Felix C. , Dahlke Marc H. , Piso Pompiliu , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver 
Published: November 2007

Abstract
Purpose: Inhibitors of heat-shock protein 90 (Hsp90) may interfere with oncogenic signaling pathways, including Erk, Akt, and hypoxia-inducible factor-1α (HIF-1α). Because insulin-like growth factor-I receptor (IGF-IR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways are implicated in the progression of pancreatic cancer, we hypothesized that blocking Hsp90 with geldanamycin derivates [17-allylamino-geldanamycin (17-AAG), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)] would impair IGF-I– and interleukin-6–mediated signaling and thus reduce pancreatic tumor growth and angiogenesis in vivo.
Experimental Design: Human pancreatic cancer cells (HPAF-II, L3.6pl) were used for experiments. Changes in signaling pathway activation upon Hsp90 blockade were investigated by Western blotting. Effects of Hsp90 inhibition (17-AAG) on vascular endothelial growth factor were determined by ELISA and real-time PCR. Effects of 17-DMAG (25 mg/kg; thrice a week; i.p.) on tumor growth and vascularization were investigated in a s.c. xenograft model and in an orthotopic model of pancreatic cancer.
Results: 17-AAG inhibited IGF-IR signaling by down-regulating IGF-IRβ and directly impairing IGF-IR phosphorylation. Hypoxia- and IL-6–mediated activation of HIF-1α or STAT3/STAT5 were substantially inhibited by 17-AAG. Moreover, a novel IL-6/STAT3/HIF-1α autocrine loop was effectively disrupted by Hsp90 blockade. In vivo, 17-DMAG significantly reduced s.c. tumor growth and diminished STAT3 phosphorylation and IGF-IRβ expression in tumor tissues. In an orthotopic model, pancreatic tumor growth and vascularization were both significantly reduced upon Hsp90 inhibition, as reflected by final tumor weights and CD31 staining, respectively.
Conclusions: Blocking Hsp90 disrupts IGF-I and IL-6–induced proangiogenic signaling cascades by targeting IGF-IR and STAT3 in pancreatic cancer, leading to significant growth-inhibitory effects. Therefore, we suggest that Hsp90 inhibitors could prove to be valuable in the treatment of pancreatic cancer.
Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma
Authors: Voorhees Peter M. , Chen Qing , Kuhn Deborah J. , Small George W. , Hunsucker Sally A. , Strader John S. , Corringham Robert E. , Zaki Mohamed H. , Nemeth Jeffrey A. , Orlowski Robert Z. 
Published: November 2007

AbstractPurpose: Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance.Experimental Design: The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6–dependent and IL-6–independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples.Results: Treatment of IL-6–dependent and IL-6–independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138+ myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3.Conclusions: Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma.
Fluorine-18-α-Methyltyrosine Positron Emission Tomography for Diagnosis and Staging of Lung Cancer: A Clinicopathologic Study
Authors: Kaira Kyoichi , Oriuchi Noboru , Otani Yoshimi , Shimizu Kimihiro , Tanaka Shigebumi , Imai Hisao , Yanagitani Noriko , Sunaga Noriaki , Hisada Takeshi , Ishizuka Tamotsu , Dobashi Kunio , Kanai Yoshikatsu , Endou Hitoshi , Nakajima Takashi , Endo Keigo , Mori Masatomo 
Published: November 2007

Abstract
Purpose: l-[3-18F]-α-Methyltyrosine ([18F]FMT) is an amino acid tracer for positron emission tomography (PET). We evaluated the diagnostic usefulness of [18F]FMT PET in non–small-cell lung cancer (NSCLC) patients. Tumor uptake of [18F]FMT was compared with that of 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]FDG) and correlated with L-type amino acid transporter 1 (LAT1) expression.
Experimental Design: Fifty NSCLC patients were enrolled in this study, and a pair of PET study with [18F]FMT and [18F]FDG was done. LAT1 expression and Ki-67 labeling index of the resected tumors were analyzed by immunohistochemical staining.
Results: For the primary tumor detection, [18F]FMT PET exhibited a sensitivity of 90% whereas the sensitivity for [18F]FDG PET was 94%. For lymph node staging, the sensitivity and specificity of [18F]FMT PET were 57.8% and 100%, and those of [18F]FDG PET were 65.7% and 91%, respectively. The expression of LAT1 in squamous cell carcinoma and large cell carcinoma was significantly higher than that in adenocarcinoma. [18F]FMT uptake was also higher in squamous cell carcinoma and large cell carcinoma than in adenocarcinoma. Uptake of [18F]FMT in the tumor is closely correlated with LAT1 expression (ρ = 0.890).
Conclusion: [18F]FMT PET had no false-positives in the detection of primary tumor and lymph node metastasis and could improve the diagnostic performance in NSCLC. Uptake of [18F]FMT correlated with the expression of LAT1 that showed a significant association with cellular proliferation.