bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of Peptidyl-Prolyl Isomerase-Like 1 Is Associated with the Growth of Colon Cancer Cells
Authors: Obama Kazutaka , Kato Tatsushi , Hasegawa Suguru , Satoh Seiji , Nakamura Yusuke , Furukawa Yoichi 
Published: March 2006

Abstract
Purpose and Experimental Design: To discover novel therapeutic targets for colon cancers, we previously surveyed expression patterns among 23,000 genes in colon cancer tissues using a cDNA microarray. Among the genes that were up-regulated in the tumors, we selected for this study peptidyl-prolyl isomerase-like 1 (PPIL1) encoding PPIL1, a cyclophilin-related protein.
Results: Western blot analysis and immunohistochemical staining using PPIL1-specific antibody showed that PPIL1 protein was frequently overexpressed in colon cancer cells compared with noncancerous epithelial cells of the colon mucosa. Colony formation assay showed a growth-promoting effect of wild-type PPIL1 on NIH3T3 and HEK293 cells. Consistently, transfection of short-interfering RNA specific to PPIL1 into SNUC4 and SNUC5 cells effectively reduced expression of the gene and retarded growth of the colon cancer cells. We further identified two PPIL1-interacting proteins, SNW1/SKIP (SKI-binding protein) and stathmin. SNW1/SKIP is involved in the regulation of transcription and mRNA splicing, whereas stathmin is involved in stabilization of microtubules. Therefore, elevated expression of PPIL1 may play an important role in proliferation of cancer cells through the control of SNW1/SKIP and/or stathmin.
Conclusion: The findings reported here may offer new insight into colonic carcinogenesis and contribute to the development of new molecular strategies for treatment of human colorectal tumors.
Adaptive Signature Design: An Adaptive Clinical Trial Design for Generating and Prospectively Testing A Gene Expression Signature for Sensitive Patients
Authors: Freidlin Boris , Simon Richard 
Published: March 2006

Abstract
Purpose: A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation. Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional, broad-eligibility approach to randomized clinical trials. Thus, there is a need for development of novel statistical methodology for rapid evaluation of these agents.
Experimental Design: We propose a new adaptive design for randomized clinical trials of targeted agents in settings where an assay or signature that identifies sensitive patients is not available at the outset of the study. The design combines prospective development of a gene expression–based classifier to select sensitive patients with a properly powered test for overall effect.
Results: Performance of the adaptive design, relative to the more traditional design, is evaluated in a simulation study. It is shown that when the proportion of patients sensitive to the new drug is low, the adaptive design substantially reduces the chance of false rejection of effective new treatments. When the new treatment is broadly effective, the adaptive design has power to detect the overall effect similar to the traditional design. Formulas are provided to determine the situations in which the new design is advantageous.
Conclusion: Development of a gene expression–based classifier to identify the subset of sensitive patients can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect.
Intraperitoneal Pretarget Radioimmunotherapy with CC49 Fusion Protein
Authors: Buchsbaum Donald J. , Khazaeli M.B. , Axworthy Donald B. , Schultz Jody , Chaudhuri Tandra R. , Zinn Kurt R. , Carpenter Mark , LoBuglio Albert F. 
Published: March 2006

Abstract
Purpose: This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T).
Experimental Design: The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti–tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin conjugated to the chelating agent 7,10-tetra-azacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) complexed with 111In-, 90Y-, or 177Lu-DOTA-biotin was injected.
Results: Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with 111In- or 177Lu-DOTA-biotin. Tumor localization of 111In-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with 90Y-DOTA-biotin at doses of 400 to 600 μCi or 177Lu-DOTA-biotin at doses of 600 to 800 μCi produced significant prolongation of survival compared with controls (P = 0.03 and P &lt; 0.01).
Conclusions: Pretarget radioimmunotherapy using regional administration of CC49 fusion protein and i.p. 90Y- or 177Lu-DOTA-biotin represents a successful therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.
Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell–Depleted Severe Combined Immunodeficient Mice
Authors: Yano Seiji , Muguruma Hiroaki , Matsumori Yuka , Goto Hisatsugu , Nakataki Emiko , Edakuni Nobutaka , Tomimoto Hideki , Kakiuchi Soji , Yamamoto Akihiko , Uehara Hisanori , Ryan Anderson , Sone Saburo 
Published: March 2006

AbstractBackground: Small-cell lung cancer is often characterized by rapid growth and metastatic spread. Because tumor growth and metastasis are angiogenesis dependent, there is great interest in therapeutic strategies that aim to inhibit tumor angiogenesis.Methods: The effect of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor tyrosine kinases, was studied in experimental multiple-organ metastasis models with human small-cell lung cancer cell lines (SBC-3 or SBC-5) in natural killer cell–depleted severe combined immunodeficient mice.Results: Intravenously inoculated SBC-5 cells produced experimental metastases in the liver, lung, and bone whereas SBC-3 cells produced the metastases in the liver, systemic lymph nodes, and kidneys. Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (&gt;3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions. ZD6474 treatment did not significantly reduce the frequency of small (&lt;2-3 mm) metastatic lesions found in the lung (SBC-5) or kidney (SBC-3), consistent with an antiangiogenic mechanism of action. Immunohistochemical analysis of SBC-5 metastatic deposits in the liver showed that ZD6474 treatment inhibited VEGFR-2 activation and induced apoptosis of tumor-associated endothelial cells, resulting in decreasing tumor microvessel density. ZD6474 treatment was also associated with a decrease in tumor cell proliferation and an increase in tumor cell apoptosis. The antitumor effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib, a small-molecule inhibitor of epidermal growth factor receptor tyrosine kinase, was inactive in these models.Conclusions: These results suggest that ZD6474 may be of potential therapeutic value in inhibiting the growth of metastatic small-cell lung cancer in humans. Phase II trials with ZD6474 are currently ongoing in a range of solid tumors.
The Role of Cyclooxygenase-2 in Mediating the Effects of Histamine on Cell Proliferation and Vascular Endothelial Growth Factor Production in Colorectal Cancer
Authors: Cianchi Fabio , Cortesini Camillo , Schiavone Nicola , Perna Federico , Magnelli Lucia , Fanti Elena , Bani Daniele , Messerini Luca , Fabbroni Valentina , Perigli Giuliano , Capaccioli Sergio , Masini Emanuela 
Published: March 2006

AbstractPurpose: Activity of histidine decarboxylase, the key enzyme in the synthesis of histamine, has been shown to be increased in several types of human tumors. We attempted to establish whether the possible involvement of histidine decarboxylase and histamine in colorectal carcinogenesis might be mediated by the activation of the cyclooxygenase-2 (COX-2) pathway.Experimental Design: Expression/activity of histidine decarboxylase, histamine content, and prostaglandin E2 (PGE2) production were analyzed in 33 colorectal cancer samples and in the HT29, Caco-2, and HCT116 colon cancer cell lines. The effects of histamine, celecoxib, and H1, H2, and H4 receptor antagonists on COX-2 expression/activity, cell proliferation, and vascular endothelial growth factor (VEGF) production were assessed in the three colon cancer lines that showed different constitutive COX-2 expression.Results: We showed the up-regulation of histidine decarboxylase protein expression and activity in the tumor specimens when compared with normal colonic mucosa. Histidine decarboxylase activity and histamine content were also significantly higher in metastatic tumors than in nonmetastatic ones. These variables significantly correlated with tumor PGE2 production. The administration of histamine increased COX-2 expression/activity, cell proliferation, and VEGF production in the COX-2-positive HT29 and Caco-2 cells. Treatment with either H2/H4 receptor antagonists or celecoxib prevented these effects. Histamine had no effect on both the COX-2 pathway and VEGF production in the COX-2-negative HCT116 cells.Conclusions: Our data showed that histamine exerts both a proproliferative and a proangiogenic effect via H2/H4 receptor activation. These effects are likely to be mediated by increasing COX-2-related PGE2 production in COX-2-expressing colon cancer cells.
Identification of Peptide Vaccine Candidates for Prostate Cancer Patients with HLA-A3 Supertype Alleles
Authors: Matsueda Satoko , Takedatsu Hiroko , Yao Akihisa , Tanaka Masahiro , Noguchi Masanori , Itoh Kyogo , Harada Mamoru 
Published: March 2006

AbstractPurpose: The peptide vaccine candidates identified to date have been focused on the HLA-A2 and HLA-A24 alleles. The HLA-A11, HLA-A31, and HLA-A33 alleles share binding motifs and belong to an HLA-A3 supertype family. In this study, we attempted to identify CTL-directed peptide candidates, derived from prostate-related antigens and shared by HLA-A11+, HLA-A31+, and HLA-A33+ prostate cancer patients.Experimental Design: Based on the binding motif to the HLA-A3 supertype alleles, 42 peptides were prepared from prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostatic acid phosphatase (PAP). These peptides were first screened for their ability to be recognized by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific and prostate cancer–reactive CTLs from peripheral blood mononuclear cells (PBMC) of cancer patients with the HLA-A11, HLA-A31, and HLA-A33 alleles.Results: Five peptide candidates, including the PSA16-24, PAP155-163, PAP248-257, PSMA207-215, and PSMA431-440 peptides, were frequently recognized by IgGs of prostate cancer patients. These peptides efficiently induced peptide-specific and prostate cancer–reactive CTLs from PBMCs of cancer patients with the HLA-A11, HLA-A31, and HLA-A33 alleles. Antibody blocking and cold inhibition experiments revealed that the HLA-A3 supertype–restricted cytotoxicity against prostate cancer cells could be ascribed to peptide-specific and CD8+ T cells.Conclusions: We identified prostate-related antigen-derived new peptide candidates for HLA-A11-, HLA-A31-, and HLA-A33-positive prostate cancer patients. This information could facilitate the development of a peptide-based anticancer vaccine for patients with alleles other than HLA-A2 and HLA-A24.
Novel Genes Associated with Malignant Melanoma but not Benign Melanocytic Lesions
Authors: Talantov Dmitri , Mazumder Abhijit , Yu Jack X. , Briggs Thomas , Jiang Yuqiu , Backus John , Atkins David , Wang Yixin 
Published: March 2006

Abstract
Purpose: Cutaneous melanoma is a common, aggressive cancer with increasing incidence. The identification of melanoma-specific deregulated genes could provide molecular markers for lymph node staging assays and further insight into melanoma tumorigenesis.
Experimental Design: Total RNA isolated from 45 primary melanoma, 18 benign skin nevi, and 7 normal skin tissue specimens were analyzed on an Affymetrix Hu133A microarray containing 22,000 probe sets.
Results: Hierarchical clustering revealed a distinct separation of the melanoma samples from the benign and normal specimens. Novel genes associated with malignant melanoma were identified. Differential gene expression of two melanoma-specific genes, PLAB and L1CAM, were tested by a one-step quantitative reverse transcription-PCR assay on primary malignant melanoma, benign nevi, and normal skin samples, as well as on malignant melanoma lymph node metastasis and melanoma-free lymph nodes. The performance of the markers was compared with conventional melanoma markers such as tyrosinase, gp100, and MART1.
Conclusion: Our study systematically identified novel melanoma-specific genes and showed the feasibility of using a combination of PLAB and L1CAM in a reverse transcription-PCR assay to differentiate clinically relevant samples containing benign or malignant melanocytes.
Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib
Authors: Théou Nathalie , Gil Sophie , Devocelle Anne , Julié Catherine , Lavergne-Slove Anne , Beauchet Alain , Callard Patrice , Farinotti Robert , Le Cesne Axel , Lemoine Antoinette , Faivre-Bonhomme Laurence , Emile Jean-François 
Published: March 2006

Abstract
Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.
The Role of S100A6 in Pancreatic Cancer Development and Its Clinical Implication as a Diagnostic Marker and Therapeutic Target
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Ishikawa Nami , Fujii Kei , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao 
Published: March 2006

Abstract
Recent microarray analyses showed that the S100 family contains members that are candidate diagnostic markers or therapeutic targets. In the present study, to evaluate the involvement of S100A6 in pancreatic cancer and its clinical usefulness for diagnosis, we examined S100A6 mRNA expression in pancreatic tissues and pancreatic juice from patients with different pancreatic diseases. To investigate the role of S100A6 in carcinogenesis of pancreatic cancer and the potential of S100A6 as a diagnostic marker for early detection of pancreatic cancer, we did immunohistochemistry and microdissection-based mRNA analysis of pancreatic normal ducts, pancreatic intraepithelial neoplasias, and invasive ductal carcinomas. We also used in vitro experiments and microarray analysis with RNA interference to evaluate the functional role of S100A6 and its potential as a therapeutic target for pancreatic cancer. S100A6 mRNA levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. In pancreatic juice, there was a significant difference in S100A6 expression between patients with carcinoma and those with nonneoplastic disease. Receiver operating characteristic curves revealed that S100A6 might be a useful marker for diagnosis of pancreatic cancer. Immunohistochemistry and microdissection-based analysis showed differential expression of S100A6 among normal ducts, pancreatic intraepithelial neoplasias, and invasive ductal carcinomas. In vitro data showed that inhibition of S100A6 decreased proliferation and invasiveness of cancer cells, and these findings were supported by microarray data. Our present results suggest that quantitation of S100A6 mRNA is a promising tool for diagnosis of pancreatic cancer, and that S100A6 may be a promising therapeutic target for pancreatic cancer.
Radioimmunotherapy of CD22-Expressing Daudi Tumors in Nude Mice with a 90Y-Labeled Anti-CD22 Monoclonal Antibody
Authors: Vallera Daniel A. , Brechbiel Martin W. , Burns Linda J. , Panoskaltsis-Mortari Angela , Dusenbery Katie E. , Clohisy Dennis R. , Vitetta Ellen S. 
Published: March 2006

Abstract
A study was undertaken to investigate the efficacy of a high affinity, rapidly internalizing anti-CD22 monoclonal antibody for selectively delivering high-energy 90Y radioactivity to B lymphoma cells in vivo. The antibody, RFB4, was readily labeled with 90Y using the highly stable chelate, 1B4M-diethylenetriaminepentaacetic acid. Labeled RFB4 selectively bound to the CD22+ Burkitt's lymphoma cell line Daudi, but not to CD22− control cells in vitro as compared with a control antibody, and was more significantly bound (P = 0.03) to Daudi solid tumors growing in athymic nude mice. Biodistribution data correlated well with the antitumor effect. The therapeutic effect of 90Y-labeled anti-CD22 (Y22) was dose-dependent, irreversible, and the best results were achieved in mice receiving a single i.p. dose of 196 μCi. These mice displayed a significantly better (P &lt; 0.01) antitumor response than control mice and survived &gt;200 days with no evidence of tumor. Histology studies showed no significant injury to kidney, liver, or small intestine. Importantly, tumor-bearing mice treated with Y22 had no radiologic bone marrow damage compared with tumor-bearing mice treated with the control-labeled antibody arguing that the presence of CD22+ tumor protected mice from bone marrow damage. When anti-CD22 radioimmunotherapy was compared to radioimmunotherapy with anti-CD19 and anti-CD45 antibodies, all three antibodies distributed significantly high levels of radioisotope to flank tumors in vivo compared with controls (P &lt; 0.05), induced complete remission, and produced long-term, tumor-free survivors. These findings indicate that anti-CD22 radioimmunotherapy with Y22 is highly effective in vivo against CD22-expressing malignancies and may be a useful therapy for drug-refractory B cell leukemia patients.
High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes
Authors: Woods Michael O. , Hyde Angela J. , Curtis Fiona K. , Stuckless Susan , Green Jane S. , Pollett Aaron F. , Robb J. Desmond , Green Roger C. , Croitoru Marina E. , Careen Amanda , Chaulk Jason A.W. , Jegathesan Jegan , McLaughlin John R. , Gallinger Steven S. , Younghusband H. Banfield , Bapat Bharati V. , Parfrey Patrick S. 
Published: March 2006

Abstract
Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland.
Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer–like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1.
Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings.
Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.
Intestinal microflora and digestive toxicity of irinotecan in mice.
Authors: Brandi Giovanni , Dabard Jean , Raibaud Pierre , Di Battista Monica , Bridonneau Chantal , Pisi Anna Maria , Morselli Labate Antonio Maria , Pantaleo Maria Abbondanza , De Vivo Antonello , Biasco Guido 
Published: March 2006

Abstract
PURPOSE: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. EXPERIMENTAL DESIGN: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with 100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80, 100, and 150 mg/kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. RESULTS: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and &gt; or =150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P &lt; 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P &lt; 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. CONCLUSIONS: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.