bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Neural Stem Cells Target Experimental Intracranial Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor Regression
Authors: Kim Seung-Ki , Kim Seung U. , Park In Ho , Bang Jung Hee , Aboody Karen S. , Wang Kyu-Chang , Cho Byung-Kyu , Kim Manho , Menon Lata G. , Black Peter M. , Carroll Rona S. 
Published: September 2006

Abstract
Purpose: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system.
Experimental Design: The migratory ability of HB1.F3 cells (an immortalized, clonal human NSC line) to medulloblastoma was studied both in vitro and in vivo. As proof-of-concept, we used HB1.F3 cells engineered to secrete the prodrug activating enzyme cytosine deaminase. We investigated the potential of human NSCs to deliver a therapeutic gene and reduce tumor growth.
Results: The migratory capacity of HB1.F3 cells was confirmed by an in vitro migration assay, and corroborated in vivo by injecting chloromethylbenzamido-Dil–labeled HB1.F3 cells into the hemisphere contralateral to established medulloblastoma in nude mice. In vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy cells in coculture experiments. In vitro therapeutic studies were conducted in which animals bearing intracranial medulloblastoma were injected ipsilaterally with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. Histologic analyses showed that human NSCs migrate to the tumor bed and its boundary, resulting in a 76% reduction of tumor volume in the treatment group (P &lt; 0.01).
Conclusion: These studies show for the first time the potential of human NSCs as an effective delivery system to target and disseminate therapeutic agents to medulloblastoma.
Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Authors: Sabbatini Paul , Dupont Jakob , Aghajanian Carol , Derosa Felicia , Poynor Elizabeth , Anderson Sybil , Hensley Martee , Livingston Phillip , Iasonos Alexia , Spriggs David , McGuire William , Reinartz Silke , Schneider Sally , Grande Cathy , Lele Shashikant , Rodabaugh Kerry , Kepner James , Ferrone Soldano , Odunsi Kunle 
Published: September 2006

AbstractPurpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response.Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade &gt;2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL).Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.
Twist Overexpression Correlates with Hepatocellular Carcinoma Metastasis through Induction of Epithelial-Mesenchymal Transition
Authors: Lee Terence K. , Poon Ronnie T.P. , Yuen Anthony P. , Ling Ming Tat , Kwok Wei Kei , Wang Xiang Hong , Wong Yong Chuan , Guan Xin Yuan , Man Kwan , Chau King Lok , Fan Sheung Tat 
Published: September 2006

Abstract
Purpose: Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a high propensity for vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, Twist has been identified to play an important role in EMT-mediated metastasis through the regulation of E-cadherin expression. However, the actual role of Twist in tumor invasiveness remains unclear. The purpose of this study is to investigate the expression and possible role of Twist in HCC.
Experimental Design: We evaluated Twist and E-cadherin expression in HCC tissue microarray of paired primary and metastatic HCC by immunohistochemical staining. The role of Twist in EMT-mediated invasiveness was also evaluated in vitro in HCC cell lines.
Results: We first showed that overexpression of Twist was correlated with HCC metastasis (P = 0.001) and its expression was negatively correlated with E-cadherin expression (P = 0.001, r = −0.443) by tissue microarray. A significant increase of Twist at the mRNA level was also found in metastatic HCC cell lines MHCC-97H, MHCC-97L, and H2M when compared with nonmetastatic Huh-7, H2P, and PLC cell lines. The MHCC-97H cell line, which has a higher metastatic ability, was found to have a higher level of Twist than MHCC-97L. Accompanied with increased Twist expression in the metastatic HCC cell lines when compared with the nonmetastatic primary ones, we found decreased E-cadherin mRNA expression in the metastatic HCC cell lines. By ectopic transfection of Twist into PLC cells, Twist was able to suppress E-cadherin expression and induce EMT changes, which was correlated with increased HCC cell invasiveness.
Conclusion: This study shows that Twist overexpression was correlated with HCC metastasis through induction of EMT changes and HCC cell invasiveness.
Interleukin 6, a Nuclear Factor-κB Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-κB Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity
Authors: Domingo-Domenech Josep , Oliva Cristina , Rovira Ana , Codony-Servat Jordi , Bosch Marta , Filella Xavier , Montagut Clara , Tapia Marian , Campás Clara , Dang Lenny , Rolfe Mark , Ross Jeffrey S. , Gascon Pere , Albanell Joan , Mellado Begoña 
Published: September 2006

Abstract
Purpose: To investigate whether nuclear factor κB (NF-κB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-κB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-κB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients.
Experimental Design: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-κB inhibitor PS-1145 (an inhibitor of IκB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-κB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter.
Results: PC-3 and DU-145 cells had higher NF-κB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-κB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-κB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8 ± 9.5 pg/mL in PSA responders versus 36.7 ± 20.8 pg/mL (P = 0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P = 0.0007). On multivariate analysis, pretreatment IL-6 (P = 0.05) was an independent prognostic factor for time to disease progression and survival.
Conclusions: Inhibition of NF-κB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.
EWS-CREB1: A Recurrent Variant Fusion in Clear Cell Sarcoma—Association with Gastrointestinal Location and Absence of Melanocytic Differentiation
Authors: Antonescu Cristina R. , Nafa Khedoudja , Segal Neil H. , Dal Cin Paola , Ladanyi Marc 
Published: September 2006

Abstract
Purpose: Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP–responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined.
Experimental Design: We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR.
Results: Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin.
Conclusions: EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.
Human Regulatory T Cells Control Xenogeneic Graft-versus-Host Disease Induced by Autologous T Cells in RAG2−/−γc−/− Immunodeficient Mice
Authors: Mutis Tuna , van Rijn Rozemarijn S. , Simonetti Elles R. , Aarts-Riemens Tineke , Emmelot Maarten E. , van Bloois Louis , Martens Anton , Verdonck Leo F. , Ebeling Saskia B. 
Published: September 2006

AbstractPurpose: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell–dependent xenogeneic (x)-GvHD in a new model where x-GvHD is induced in RAG2−/−γc−/− mice by i.v. administration of human peripheral blood mononuclear cells (PBMC).Experimental Design: Human PBMC, depleted of or supplemented with autologous CD25+ Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals.Results: Depletion of CD25+ cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25+ cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4+ and CD8+ T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-γ, suggesting the de novo development of TR1 cells.Conclusions: These results show, for the first time, the potent in vivo capacity of naturally occurring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.
Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors
Authors: Moosmayer Dieter , Berndorff Dietmar , Chang Chien-Hsing , Sharkey Robert M. , Rother Axel , Borkowski Sandra , Rossi Edmund A. , McBride William J. , Cardillo Thomas M. , Goldenberg David M. , Dinkelborg Ludger M. 
Published: September 2006

Abstract
Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).
Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the 111In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted 111In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. 111In and 125I were used as surrogate marker for the therapeutic radioisotopes 90Y/177Lu and 131I, respectively.
Results: Tumor uptake of the pretargeted 111In-labeled peptide was significantly higher than 125I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach.
Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by &gt;3-fold compared with directly radiolabeled 131I-L19-SIP.
S100A11, A Putative Tumor Suppressor Gene, Is Overexpressed in Pancreatic Carcinogenesis
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Ohhashi Seiji , Yamaguchi Hiroshi , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao 
Published: September 2006

AbstractPurpose: Recent microarray analyses revealed that expression of S100A11 is up-regulated in pancreatic cancer. The aim of the present study was to evaluate the association of S100A11 with pancreatic carcinogenesis.Experimental Design: We measured S100A11 mRNA expression in various clinical samples related to pancreatic cancer and its precursor lesions, intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia, by quantitative reverse transcription-PCR.Results: Levels of S100A11 were significantly higher in pancreatic cancer (n = 22) and IPMN (n = 18) bulk tissues than in nonneoplastic bulk tissues (n = 22; P &lt; 0.0001 for both). Levels of S100A11 did not differ between pancreatic cancer and IPMN bulk tissues. In microdissection analyses, however, IPMN cells (n = 21) expressed significantly higher levels of S100A11 than did cancer cells (n = 23; P = 0.003). The median level of S100A11 expression was higher in pancreatic intraepithelial neoplasia cells (n = 6) than in cancer cells. In pancreatic juice analyses, cancer-related (n = 24; P = 0.004) and IPMN-related (n = 18; P = 0.001) juice expressed significantly higher levels of S100A11 than did chronic pancreatitis–related juice (n = 23).Conclusions: The present data suggest that expression of S100A11, a putative tumor suppressor gene, is increased in the early stage of pancreatic carcinogenesis and decreased during subsequent progression to cancer. Analysis of the S100A11 level in pancreatic juice may be an effective tool for screening of patients with high-risk lesions that could progress to pancreatic cancer or detecting early-stage pancreatic cancer.
Matrix Metalloproteinase Polymorphisms and Survival in Stage I Non–Small Cell Lung Cancer
Authors: Heist Rebecca Suk , Marshall Ariela L. , Liu Geoffrey , Zhou Wei , Su Li , Neuberg Donna , Lynch Thomas J. , Wain John , Christiani David C. 
Published: September 2006

AbstractPurpose: The matrix metalloproteinases (MMP) are a family of enzymes that can degrade extracellular matrix and facilitate invasion through the basement membrane. Several polymorphisms in MMP-1, MMP-2, MMP-3, and MMP-12 have been described, some of which lead to differential transcription. We hypothesized that polymorphisms in these MMP genes may be associated with survival outcomes in early-stage non–small cell lung cancer (NSCLC).Experimental Design: We evaluated the relationship between MMP-1, MMP-2, MMP-3, and MMP-12 polymorphisms and both recurrence-free survival (RFS) and overall survival (OS) among 382 patients with stage I NSCLC. Analyses of genotype associations with survival outcomes were done using Cox proportional hazards models and Kaplan-Meier methods and the log-rank test.Results: Patients carrying the variant G allele of the MMP-12 1082A/G polymorphism had significantly worse outcomes [crude hazard ratio (HR) for OS 1.74; 95% confidence interval (95% CI), 1.18-2.58, P = 0.006; crude HR for RFS, 1.53; 95% CI, 1.05-2.23, P = 0.03]. After adjusting for age, sex, stage, pack-years of smoking, and histologic subtype, the MMP-12 1082A/G polymorphism remained significantly associated with survival outcomes [adjusted HR (AHR) for OS, 1.94; 95% CI, 1.28-2.97, P = 0.002; AHR for RFS, 1.61; 95% CI, 1.07-2.41, P = 0.02]. None of the other MMP polymorphisms was significantly associated with survival.Conclusions: Our results show that patients with stage I NSCLC carrying the variant G allele of the MMP-12 1082A/G polymorphism have worse survival.
S100P Is an Early Developmental Marker of Pancreatic Carcinogenesis
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Egami Takuya , Yamaguchi Hiroshi , Fujii Kei , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao 
Published: September 2006

Abstract
Purpose: Our goal was to clarify the involvement and clinical significance of S100P in pancreatic carcinogenesis.
Experimental Design: We examined S100P expression in 45 bulk pancreatic tissues; in microdissected cells, including invasive ductal carcinoma (IDC) cells (20 sections), pancreatic intraepithelial neoplasia (PanIN) cells (12 sections), intraductal papillary mucinous neoplasm (IPMN) cells (19 sections), and normal epithelial cells (11 sections); and in pancreatic juice samples from 99 patients with pancreatic diseases (32 cancer, 35 IPMN, and 32 chronic pancreatitis samples). We used quantitative real-time reverse transcription-PCR with gene-specific priming to measure S100P in these various types of samples.
Results: In bulk tissue analyses, pancreatic cancer and IPMN expressed significantly higher levels of S100P than did nonneoplastic pancreas (P &lt; 0.017 and P = 0.0013, respectively). Microdissection analyses revealed that IPMN expressed significantly higher levels of S100P than did IDC (P &lt; 0.0001) and PanIN (P = 0.0031), although S100P expression did not differ between IDC and PanIN (P = 0.077). In pancreatic juice analyses, cancer and IPMN juice expressed significantly higher levels of S100P than did pancreatitis juice (both P &lt; 0.0001). Receiver operating characteristic curve analyses revealed that measurement of S100P in pancreatic juice was useful for discriminating neoplastic disease from chronic pancreatitis (area under the curve = 0.837; 95% confidence interval, 0.749-0.903).
Conclusion: S100P may be an early developmental marker of pancreatic carcinogenesis, and measurement of S100P in pancreatic juice may be useful for early detection of pancreatic cancer or screening of early pancreatic carcinogenesis.
Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients
Authors: Largillier Rémy , Etienne-Grimaldi Marie-Christine , Formento Jean-Louis , Ciccolini Joseph , Nebbia Jean-François , Ginot Aurélie , Francoual Mireille , Renée Nicole , Ferrero Jean-Marc , Foa Cyril , Namer Moïse , Lacarelle Bruno , Milano Gérard 
Published: September 2006

Abstract
Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).
Experimental design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3′ region and 28 bp repeats, including G&gt;C mutation in the 5′ region), MTHFR (677C&gt;T and 1298A&gt;C), and DPD (IVS14 + 1G&gt;A) were determined in 105 consecutive patients.
Results: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P = 0.064). The sole patient bearing the DPD IVS14 + 1G&gt;A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P = 0.037).
Conclusions: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.