bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays
Authors: Stark Mitchell , Hayward Nicholas 
Published: March 2007

Abstract
Although a number of genes related to melanoma development have been identified through candidate gene screening approaches, few studies have attempted to conduct such analyses on a genome-wide scale. Here we use Illumina 317K whole-genome single-nucleotide polymorphism arrays to define a comprehensive allelotype of melanoma based on loss of heterozygosity (LOH) and copy number changes in a panel of 76 melanoma cell lines. In keeping with previous reports, we found frequent LOH on chromosome arms 9p (72%), 10p (55%), 10q (55%), 9q (49%), 6q (43%), 11q (43%), and 17p (41%). Tumor suppressor genes (TSGs) can be identified through homozygous deletion (HD). We detected 174 HDs, the most common of which targeted CDKN2A (n = 33). The second highest frequency of HD occurred in PTEN (n = 8), another well known melanoma TSG. HDs were also common for PTPRD (n = 7) and HDAC4 (n = 3), TSGs recently found to be mutated or deleted in other cancer types. Analysis of other HDs and regions of LOH that we have identified might lead to the characterization of further melanoma TSGs. We noted 197 regional amplifications, including some centered on the melanoma oncogenes MITF (n = 9), NRAS (n = 3), BRAF (n = 3), and CCND1 (n = 3). Other amplifications potentially target novel oncogenes important in the development of a subset of melanomas. The numerous focal amplifications and HDs we have documented here are the first step toward identifying a comprehensive catalog of genes involved in melanoma development, some of which may be useful prognostic markers or targets for therapies to treat this disease. [Cancer Res 2007;67(6):2632–42]
Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer
Authors: Hosokawa Masayo , Takehara Akio , Matsuda Koichi , Eguchi Hidetoshi , Ohigashi Hiroaki , Ishikawa Osamu , Shinomura Yasuhisa , Imai Kohzoh , Nakamura Yusuke , Nakagawa Hidewaki 
Published: March 2007

Abstract
To isolate novel diagnostic markers and therapeutic targets for pancreatic cancer, we earlier did expression profile analysis of pancreatic cancer cells using a genome-wide cDNA microarray combined with microdissection. Among dozens of trans-activated genes in pancreatic cancer cells, this study focused on KIAA0101 whose overexpression in pancreatic cancer cells was validated by immunohistochemical analysis. KIAA0101 was previously identified as p15PAF [proliferating cell nuclear antigen (PCNA)–associated factor] to bind with PCNA; however, its function remains unknown. To investigate for the biological significance of KIAA0101 overexpression in cancer cells, we knocked down KIAA0101 by small interfering RNA (siRNA) in pancreatic cancer cells and found that the reduced expression by siRNA caused drastic attenuation of their proliferation as well as significant decrease in DNA replication rate. Concordantly, exogenous overexpression of KIAA0101 enhanced cancer cell growth, and NIH3T3 derivative cells expressing KIAA0101 revealed in vivo tumor formation, implying its growth-promoting and oncogenic property. We also showed that the expression of KIAA0101 was regulated tightly by the p53-p21 pathway. To consider the KIAA0101/PCNA interaction as a therapeutic target, we designed the cell-permeable 20-amino-acid dominant-negative peptide and found that it could effectively inhibit the KIAA0101/PCNA interaction and resulted in the significant growth suppression of cancer cells. Our results clearly implicated that suppression of the KIAA0101 and PCNA oncogenic activity, or the inhibition of KIAA0101/PCNA interaction, is likely to be a promising strategy to develop novel cancer therapeutic drugs. [Cancer Res 2007;67(6)2568–76]
Metallothionein Expression Is Suppressed in Primary Human Hepatocellular Carcinomas and Is Mediated through Inactivation of CCAAT/Enhancer Binding Protein α by Phosphatidylinositol 3-Kinase Signaling Cascade
Authors: Datta Jharna , Majumder Sarmila , Kutay Huban , Motiwala Tasneem , Frankel Wendy , Costa Robert , Cha Hyuk C. , MacDougald Ormond A. , Jacob Samson T. , Ghoshal Kalpana 
Published: March 2007

AbstractReactive oxygen species (ROS) resulting from chronic inflammation cause liver injury leading to transformation of regenerating hepatocytes. Metallothioneins (MT), induced at high levels by oxidative stress, are potent scavengers of ROS. Here, we report that the levels of MT-1 and MT-2A are drastically reduced in primary human hepatocellular carcinomas (HCCs) and in diethylnitrosamine-induced liver tumors in mice, which is primarily due to transcriptional repression. Expression of the transcription factor, MTF-1, essential for MT expression, and its target gene Zn-T1 that encodes the zinc transporter-1 was not significantly altered in HCCs. Inhibitors of both phosphatidylinositol 3-kinase (PI3K) and its downstream target AKT increased expression of MT genes in HCC cells but not in liver epithelial cells. Suppression of MT-1 and MT-2A by ectopic expression of the constitutively active PI3K or AKT and their up-regulation by dominant-negative PI3K or AKT mutant confirmed negative regulation of MT expression by PI3K/AKT signaling pathway. Further, treatment of cells with a specific inhibitor of glycogen synthase kinase-3 (GSK-3), a downstream effector of PI3K/AKT, inhibited MT expression specifically in HCC cells. Short interfering RNA–mediated depletion of CCAAT/enhancer binding protein α (C/EBPα), a target of GSK-3, impeded MT expression, which could not be reversed by PI3K inhibitors. DNA binding activity of C/EBPα and its phosphorylation at T222 and T226 by GSK-3 are required for MT expression. MTF-1 and C/EBPα act in concert to increase MT-2A expression, which probably explains the high level of MT expression in the liver. This study shows the role of PI3K/AKT signaling pathway and C/EBPα in regulation of MT expression in hepatocarcinogenesis. [Cancer Res 2007;67(6):2736–46]
The Synthetic Triterpenoids CDDO-Methyl Ester and CDDO-Ethyl Amide Prevent Lung Cancer Induced by Vinyl Carbamate in A/J Mice
Authors: Liby Karen , Royce Darlene B. , Williams Charlotte R. , Risingsong Renee , Yore Mark M. , Honda Tadashi , Gribble Gordon W. , Dmitrovsky Ethan , Sporn Thomas A. , Sporn Michael B. 
Published: March 2007

Abstract
We report the first use of new synthetic triterpenoids to prevent lung cancer in experimental animals. Female A/J mice were treated with the mutagenic carcinogen vinyl carbamate, which induces adenocarcinoma of the lung in all animals within 16 weeks. If mice were fed either the methyl ester or the ethyl amide derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-ME and CDDO-EA, respectively), beginning 1 week after dosing with carcinogen, the number, size, and severity of lung carcinomas were markedly reduced. The mechanisms of action of CDDO-ME and CDDO-EA that are germane to these in vivo findings are the following results shown here in cell culture: (a) suppression of the ability of IFN-γ to induce de novo formation of nitric oxide synthase in a macrophage-like cell line RAW264.7, (b) induction of heme oxygenase-1 in these RAW cells, and (c) suppression of phosphorylation of the transcription factor signal transducers and activators of transcription 3 as well as induction of apoptosis in human lung cancer cell lines. [Cancer Res 2007;67(6):2414–9]
A Randomized Phase II Pharmacokinetic and Pharmacodynamic Study of Indisulam as Second-Line Therapy in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Talbot Denis C. , von Pawel Joachim , Cattell Emma , Yule S. Murray , Johnston Claire , Zandvliet Anthe S. , Huitema Alwin D.R. , Norbury Chris J. , Ellis Paul , Bosquee Leon , Reck Martin 
Published: March 2007

AbstractPurpose: The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non–small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile.Experimental Design: Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m2 on day one (dx1) or 130 mg/m2 given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy.Results: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels.Conclusions: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non–small cell lung cancer.
Monoclonal Antibody 4C5 Immunostains Human Melanomas and Inhibits Melanoma Cell Invasion and Metastasis
Authors: Stellas Dimitris , Karameris Andreas , Patsavoudi Evangelia 
Published: March 2007

Abstract
Purpose: Tumor cell metastasis constitutes a major problem in the treatment of cancer. Because the cure rate of metastatic tumors is very low, new therapeutic approaches are needed. Heat shock protein 90 (HSP90) is a molecular chaperone that is recognized as a new target for the treatment of cancer. Here, we examine the value of a monoclonal antibody (mAb) against HSP90, mAb 4C5, as a potential marker in malignant melanomas. Moreover, we investigate the possibility to use mAb 4C5 as an inhibitor of melanoma cell invasion and metastasis.
Experimental Design: Paraffin blocks of formalin-fixed human melanoma tumor tissues were used to prepare tissue microarrays. The B16 F10 melanoma cell line was used in all the in vitro experiments. To assess melanoma cell invasion, the wound-healing assay and the Matrigel invasion assay were applied. To evaluate the effect of mAb 4C5 on tumor metastasis, we used an experimental model of metastatic melanoma.
Results: Immunohistochemical studies done on a panel of malignant melanomas showed positive immunostaining with mAb 4C5 in all cases. mAb 4C5 inhibits B16 F10 cell invasion by binding to surface HSP90 because it is not internalized. mAb 4C5 significantly inhibits melanoma metastasis in C57BL/6 mice inoculated with B16 F10 cells.
Conclusions: mAb 4C5 could be potentially used as a novel specific marker for malignant melanomas. mAb 4C5 inhibits melanoma cell invasion in vitro by binding to cell surface HSP90 expressed on B16 F10 melanoma cells. Finally, this antibody significantly inhibits melanoma metastasis, thus rendering it a potential therapeutic agent for the treatment of cancer metastasis.
Clinical Implications of Fibroblast Activation Protein in Patients with Colon Cancer
Authors: Henry Leonard R. , Lee Hyung-Ok , Lee John S. , Klein-Szanto Andres , Watts Perry , Ross Eric A. , Chen Wen-Tien , Cheng Jonathan D. 
Published: March 2007

Abstract
Purpose: Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty.
Experimental Design: Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models.
Results: One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in &gt;93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, −0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival.
Conclusion: Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.
A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma
Authors: Berenson James R. , Matous Jeffrey , Swift Regina A. , Mapes Russell , Morrison Blake , Yeh Howard S. 
Published: March 2007

Abstract
Purpose: This multicenter, open-label, phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma.
Experimental Design: Enrolled in six cohorts, patients were given arsenic trioxide (0.125 or 0.250 mg/kg), bortezomib (0.7, 1.0, or 1.3 mg/m2), and a fixed dose of ascorbic acid (1 g) i.v. on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles. The primary end point was safety/tolerability of the ABC regimen.
Results: Twenty-two patients (median age, 63 years) were enrolled, having failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One patient had asymptomatic arrhythmia and withdrew from the study. Objective responses were observed in 6 (27%) patients, including two partial responses and four minor responses. Median progression-free survival was 5 months (95% confidence interval, 2-9 months), and median overall survival had not been reached. The 12-month progression-free survival and overall survival rates were 34% and 74%, respectively. One (minor response) of six patients receiving the lowest dose of bortezomib (0.7 mg/m2) and 5 (2 partial responses and 3 minor responses) of 16 patients receiving the higher doses (1.0 or 1.3 mg/m2) responded.
Conclusions: The ABC regimen was well tolerated by most patients, and it produced preliminary signs of efficacy with an objective response rate of 27% in this heavily pretreated study population. These findings warrant further clinical evaluation of the ABC combination for treatment of relapsed/refractory multiple myeloma.
Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer
Authors: Solit David B. , Ivy S. Percy , Kopil Catherine , Sikorski Rachel , Morris Michael J. , Slovin Susan F. , Kelly W. Kevin , DeLaCruz Anthony , Curley Tracy , Heller Glenn , Larson Steven , Schwartz Lawrence , Egorin Merrill J. , Rosen Neal , Scher Howard I. 
Published: March 2007

Abstract
Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules.
Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies.
Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies.
Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.
Phase I Pharmacokinetic and Pharmacodynamic Study of 17-N-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study
Authors: Bagatell Rochelle , Gore Lia , Egorin Merrill J. , Ho Richard , Heller Glenn , Boucher Nichole , Zuhowski Eleanor G. , Whitlock James A. , Hunger Stephen P. , Narendran Aru , Katzenstein Howard M. , Arceci Robert J. , Boklan Jessica , Herzog Cynthia E. , Whitesell Luke , Ivy S. Percy , Trippett Tanya M. 
Published: March 2007

AbstractPurpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation.Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1.Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m2; 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m2. DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 ± 6.21 (mean ± SD) L/h/m2 and 2.6 ± 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels.Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
Long-Lived Antitumor CD8+ Lymphocytes for Adoptive Therapy Generated Using an Artificial Antigen-Presenting Cell
Authors: Butler Marcus O. , Lee Jeng-Shin , Ansén Sascha , Neuberg Donna , Hodi F. Stephen , Murray Andrew P. , Drury Linda , Berezovskaya Alla , Mulligan Richard C. , Nadler Lee M. , Hirano Naoto 
Published: March 2007

AbstractPurpose: Antitumor lymphocytes can be generated ex vivo unencumbered by immunoregulation found in vivo. Adoptive transfer of these cells is a promising therapeutic modality that could establish long-term antitumor immunity. However, the widespread use of adoptive therapy has been hampered by the difficulty of consistently generating potent antitumor lymphocytes in a timely manner for every patient. To overcome this, we sought to establish a clinical grade culture system that can reproducibly generate antigen-specific cytotoxic T lymphocytes (CTL).Experimental Design: We created an off-the-shelf, standardized, and renewable artificial antigen-presenting cell (aAPC) line that coexpresses HLA class I, CD54, CD58, CD80, and the dendritic cell maturation marker CD83. We tested the ability of aAPC to generate tumor antigen-specific CTL under optimal culture conditions. The number, phenotype, effector function, and in vitro longevity of generated CTL were determined.Results: Stimulation of CD8+ T cells with peptide-pulsed aAPC generated large numbers of functional CTL that recognized a variety of tumor antigens. These CTLs, which possess a phenotype consistent with in vivo persistence, survived ex vivo for prolonged periods of time. Clinical grade aAPC33, produced under current Good Manufacturing Practices guidelines, generated sufficient numbers of CTL within a short period of time. These CTL specifically lysed a variety of melanoma tumor lines naturally expressing a target melanoma antigen. Furthermore, antitumor CTL were easily generated in all melanoma patients examined.Conclusions: With clinical grade aAPC33 in hand, we are now poised for clinical translation of ex vivo generated antitumor CTL for adoptive cell transfer.