bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Expression Aberrances and Genetic Polymorphisms of Lysyl Oxidase with Areca-Associated Oral Tumorigenesis
Authors: Shieh Tzong-Ming , Lin Shu-Chun , Liu Chung-Ji , Chang Shu-Shin , Ku Ti-Hsuan , Chang Kuo-Wei 
Published: August 2007

Abstract
Purpose: Areca nut use is the major cause of oral squamous cell carcinoma (OSCC) in Southern Asians. Areca nut contains a high level of free copper ions. Lysyl oxidase (LOX) is a copper-activated enzyme critical for extracellular matrix organization. Contradictory evidence has been put forward to suggest that LOX may be either an oncogenic or a suppressive element. This study investigated the oncogenic significance of LOX in areca-associated OSCC.
Experimental Design: The expression assays and polymorphism analysis were done to know the clinicopathologic implications of LOX status in OSCC. Knockdown and overexpression experiments were conducted to know the phenotypic effects of LOX on OSCC cells.
Results: Up-regulation of LOX mRNA and LOX protein expression in OSCCs relative to adjacent oral mucosa was found. Precancerous lesions had the highest LOX mRNA expression. Areca nut extract up-regulated LOX expression in oral epithelial cells. Knockdown of LOX induced cellular migration and invasion, but it reduced the anchorage-independent growth and xenographic tumorigenesis of OSCC cells. The reduction of migration and invasion by LOX overexpression was partially rescued by blockage of LOX activity. The Arg158Gln polymorphism was associated with earlier clinical stage of OSCC. Wild-type LOX overexpression induced anchorage-independent growth in OSCC cells, but this was not for LOXArg158Gln overexpression.
Conclusion: LOX exerts oncogenic roles in areca-associated OSCC. This potential could be affected by the existence of LOX propeptide domain or genetic polymorphism.
Sex Chromosome Alterations Associate with Tumor Progression in Sporadic Colorectal Carcinomas
Authors: Bottarelli Lorena , Azzoni Cinzia , Necchi Francesca , Lagrasta Costanza , Tamburini Elisa , D'Adda Tiziana , Pizzi Silvia , Sarli Leopoldo , Rindi Guido , Bordi Cesare 
Published: August 2007

Abstract
Purpose: The X and Y chromosomes have been associated with malignancy in different types of human tumors. This study attempts to determine the involvement of X chromosome and pseudoautosomal regions (PAR) in sporadic colorectal carcinogenesis.
Experimental Design: An allelotyping of X chromosome in 20 premalignant and 22 malignant sporadic colorectal tumors (CRC) from female patients and an analysis of losses [loss of heterozygosity (LOH)] on PARs from 44 CRCs and 12 adenomas of male patients were carried out. In male tumors, a fluorescence in situ hybridization analysis was done to identify which sex chromosome was possibly lost.
Results: The LOH frequency in female CRCs was 46% with higher incidence in patients with tumor recurrence than in those who were disease-free (P &lt; 0.01) and with a significant difference from adenomas (11%; P &lt; 0.0001). The LOH rate of PARs in male CRCs was 37% with a frequency significantly higher in patients with recurrence (P &lt; 0.03). These results were maintained also when data from PARs of all 66 male and female patients were cumulated (P &lt; 0.05). LOH in PARs was significantly correlated with LOH at 5q (P &lt; 0.01) and 18q (P &lt; 0.01), early and late events, respectively, in colorectal carcinogenesis. Fluorescence in situ hybridization analysis in male patients with extensive PAR LOH revealed a preferential loss of the Y chromosome.
Conclusions: Our data suggest a role for sex chromosome deletions in the malignant progression of sporadic CRCs and support the presence in the PARs of putative tumor suppressor genes involved in the progression of human sporadic CRCs.
Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma
Authors: Kato Yukihiko , Yoshimura Kiyoshi , Shin Tahiro , Verheul Henk , Hammers Hans , Sanni Tolib B. , Salumbides Brenda C. , Van Erp Karen , Schulick Richard , Pili Roberto 
Published: August 2007

Abstract
Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration–approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model.
Experimental Design: RENCA luciferase–expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection.
Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (&gt;80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (&gt;90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4+CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination.
Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.
The Role of the DNA Damage Checkpoint Pathway in Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Miyasaka Yoshihiro , Nagai Eishi , Yamaguchi Hiroshi , Fujii Kei , Inoue Takahiro , Ohuchida Kenoki , Yamada Tomomi , Mizumoto Kazuhiro , Tanaka Masao , Tsuneyoshi Masazumi 
Published: August 2007

Abstract
Purpose: Intraductal papillary mucinous neoplasms (IPMN) are known to show a transition from adenoma to carcinoma accompanied by several molecular abnormalities. ATM-Chk2-p53 DNA damage checkpoint activation, which is involved in prevention of the progression of several tumors, was analyzed to evaluate the role of the DNA damage checkpoint in the progression of IPMNs.
Experimental Design: One hundred and twenty-eight IPMNs were classified into four groups (intraductal papillary mucinous adenoma, borderline IPMN, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma) and stained immunohistochemically using antibody for Thr68-phosphorylated Chk2. Expression of ATM, Chk2, and p21WAF1 and accumulation of p53 were also analyzed.
Results: Chk2 phosphorylation was shown in all adenomas and showed a significant decreasing trend with the progression of atypia (P &lt; 0.0001 by the Cochran-Armitage test for trend). Expression of p21WAF1 also exhibited a decreasing tendency (P &lt; 0.0001), reflecting DNA damage checkpoint inactivation. p53 accumulation was mostly detected in malignant IPMNs. It was suggested that the DNA damage checkpoint provides a selective pressure for p53 mutation.
Conclusion: Our findings indicate that DNA damage checkpoint activation occurs in the early stage of IPMNs and prevents their progression. It is suggested that disturbance of the DNA damage checkpoint pathway due to Chk2 inactivation or p53 mutation contributes to the carcinogenesis of IPMNs.
Molecular Pathways for Cancer Angioprevention
Authors: Albini Adriana , Noonan Douglas M. , Ferrari Nicoletta 
Published: August 2007

Abstract
By analogy to the success of cardiovascular medicine in reducing mortality through preventive measures, cancer chemoprevention has the potential to significantly reduce incidence and mortality due to tumors. Angiogenesis is an event inhibited by most of the promising cancer chemoprevention compounds, a concept we termed “angioprevention.” Here, we review the signaling pathways that are targeted by diverse angioprevention compounds in endothelial cells. We highlight diverse mechanisms of action, implying that combination angioprevention approaches could further improve efficacy and be transferred to clinical practice.
Emmprin and Survivin Predict Response and Survival following Cisplatin-Containing Chemotherapy in Patients with Advanced Bladder Cancer
Authors: Als Anne B. , Dyrskjøt Lars , von der Maase Hans , Koed Karen , Mansilla Francisco , Toldbod Helle E. , Jensen Jens L. , Ulhøi Benedicte P. , Sengeløv Lisa , Jensen Klaus M.E. , Ørntoft Torben F. 
Published: August 2007

Abstract
Purpose: Cisplatin-containing chemotherapy is the standard of care for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The response rate is ∼50% and tumor-derived molecular prognostic markers are desirable for improved estimation of response and survival.
Experimental Design: Affymetrix GeneChip expression profiling was carried out using tumor material from 30 patients. A set of genes with an expression highly correlated to survival time after chemotherapy was identified. Two genes were selected for validation by immunohistochemistry in an independent material of 124 patients receiving cisplatin-containing therapy.
Results: Fifty-five differentially expressed genes correlated significantly to survival time. Two of the protein products (emmprin and survivin) were validated using immunohistochemistry. Multivariate analysis identified emmprin expression (hazard ratio, 2.23; P &lt; 0.0001) and survivin expression (hazard ratio, 2.46; P &lt; 0.0001) as independent prognostic markers for poor outcome, together with the presence of visceral metastases (hazard ratio, 2.62; P &lt; 0.0001). In the clinical good prognostic group of patients without visceral metastases, both markers showed significant discriminating power as supplemental risk factors (P &lt; 0.0001). Within this group of patients, the subgroups of patients with no positive, one positive, or two positive immunohistochemistry scores (emmprin and survivin) had estimated 5-year survival rates of 44.0%, 21.1%, and 0%, respectively. Response to chemotherapy could also be predicted with an odds ratio of 4.41 (95% confidence interval, 1.91-10.1) and 2.48 (95% confidence interval, 1.1-5.5) for emmprin and survivin, respectively.
Conclusions: Emmprin and survivin proteins were identified as strong independent prognostic factors for response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer.
Highly Efficient Gene Delivery for Bladder Cancers by Intravesically Administered Replication-Competent Retroviral Vectors
Authors: Kikuchi Eiji , Menendez Silvia , Ozu Choichiro , Ohori Makoto , Cordon-Cardo Carlos , Logg Christopher R. , Kasahara Noriyuki , Bochner Bernard H. 
Published: August 2007

Abstract
Purpose: In an attempt to improve viral delivery of potentially therapeutic genes via an intravesical route, we have recently developed murine leukemia virus-based replication-competent retrovirus (RCR) vectors.
Experimental Design: We evaluated the transduction efficiency of intravesically administered RCR vectors to bladder tumor using orthotopic animal models to determine their potential as delivery vectors for bladder cancer.
Results: The RCR vector containing green fluorescent protein (GFP) marker gene achieved efficient in vitro transmission of the GFP transgene. Murine bladder tumor-2 mouse bladder tumors exposed to intravesically administered RCR vectors exhibited 0%, 9.2 ± 2.9%, and 30.0 ± 6.2% of GFP expression at 9, 18, and 27 days after exposure in the orthotopic model, respectively. Orthotopic KU-19-19 human bladder tumors exposed to intravesically administered RCR vectors exhibited 3%, 85 ± 1.0%, and 100% of GFP expression at 7, 21, and 35 days after exposure, respectively. GFP staining was observed only in the tumor cells in the bladder. No detectable PCR products of GFP gene could be observed in distant organs. Treatment with RCR vectors containing yeast cytosine deaminase (CD) gene plus 5-fluorocytosine (5-FC) dramatically inhibited the growth of preestablished murine bladder tumor-2 tumors. A single course of 5-FC treatment resulted in a 50% animal survival in mice exposed to RCR-CD compared with a 0% survival in all controls over a 70-day follow-up period.
Conclusions: Intravesically administered RCR vectors can efficiently deliver genes to orthotopic bladder tumor without viral spread in distant organs. RCR-CD/5-FC suicide gene therapy promises to be a novel and potentially therapeutic modality for bladder cancer.
Antagonism of Platelet-Derived Growth Factor Receptor in Non–Small Cell Lung Cancer: Rationale and Investigations
Authors: Bauman Julie E. , Eaton Keith D. , Martins Renato G. 
Published: August 2007

Abstract
Molecules that target growth and survival pathways in cancer cells have revolutionized the treatment of cancer. Imatinib mesylate is one such agent inhibiting the tyrosine kinase that results from the Bcr-Abl translocation. Imatinib is also a potent inhibitor of the platelet-derived growth factor receptor. The platelet-derived growth factor receptor is crucial in the regulation of interstitial fluid pressure, as well as in the function of pericytes. Increased interstitial fluid pressure is a common feature of solid tumors and is thought to impede transcapillary transport of chemotherapy. Preclinical data show that platelet-derived growth factor receptor antagonism decreases interstitial fluid pressure, augments intratumoral concentration of chemotherapy, and impairs tumor growth. Pericytes are important cells in the vascular support structure of tumors regulating endothelial cell survival and directing capillary growth. Preclinical data suggest that dual targeting of pericytes and endothelial cells is a more effective antiangiogenic strategy than antiendothelial monotherapy. Two phase II studies in advanced non–small cell lung cancer are currently under way with imatinib. The first trial evaluates the use of intermittent imatinib and weekly paclitaxel in elderly patients. The second trial evaluates a novel maintenance strategy of imatinib and the antivascular endothelial growth factor antibody bevacizumab after first-line chemotherapy with bevacizumab. These trials should indicate whether encouraging preclinical data can be translated into clinical benefit in non–small cell lung cancer.
A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations
Authors: Kiyoi Hitoshi , Shiotsu Yukimasa , Ozeki Kazutaka , Yamaji Satomi , Kosugi Hiroshi , Umehara Hiroshi , Shimizu Makiko , Arai Hitoshi , Ishii Kenichi , Akinaga Shiro , Naoe Tomoki 
Published: August 2007

Abstract
Purpose: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700.
Experimental Design: The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3–expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models.
Results: FI-700 showed a potent IC50 value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)–driven growth of Wt-FLT3–expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G1 arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C.
Conclusions: FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.
Incorporating Bortezomib into the Treatment of Lung Cancer
Authors: Davies Angela M. , Lara Primo N. , Mack Philip C. , Gandara David R. 
Published: August 2007

Abstract
Bortezomib, a small-molecule proteasome inhibitor, has activity in lung cancer both as a single agent and in combination with agents commonly used in lung cancer. The ability of bortezomib to favorably modulate the expression of apoptosis-associated proteins, along with its moderate toxicity as a single agent, provides the basis for its combination with cytotoxic agents in the treatment of lung cancer. In non–small cell lung cancer, bortezomib as a single agent has limited activity but in combination with chemotherapy has shown encouraging activity without significantly adding to toxicity. Bortezomib as a single agent has shown minimal activity in small cell lung cancer. Although the role of bortezomib in lung cancer is uncertain, it is likely to have its greatest clinical benefit when given in combination with other therapeutics. Ongoing studies are focused on optimizing the scheduling of bortezomib with chemotherapy, investigating its combination with targeted agents and radiation, and examining its efficacy in a specific subgroup, bronchioloalveolar carcinoma.
HKI-272 in Non–Small Cell Lung Cancer
Authors: Wong Kwok-Kin 
Published: August 2007

Abstract
Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene are found in ∼10% of lung adenocarcinomas sequenced in the United States and in ∼30% sequenced in Asia. These mutations are associated with sensitivity to the EGFR inhibitors gefitinib and erlotinib. Many patients who initially respond to erlotinib or gefitinib subsequently relapse. Studies have identified EGFR T790M mutations in tumors from patients who initially responded and then relapsed. The T790M mutation, when combined in vitro with treatment-sensitizing EGFR mutations, permits the continued growth of tumor cells in the presence of erlotinib and gefitinib. HKI-272 is an irreversible EGFR/HER/ErbB inhibitor that has been shown to inhibit the growth of T790M mutant cells in vitro in human lung cancer cell lines and in murine cells transfected with sensitizing EGFR mutations. A phase I HKI-272 monotherapy trial in patients with solid tumors is close to completion. Preliminary analyses of the trial, presented at the 2006 annual meeting of American Society of Clinical Oncology, showed that HKI-272 can achieve stable disease control for over 6 months in some patients with non–small cell lung cancer that has progressed after treatment with gefitinib or erlotinib. A phase II trial of HKI-272 in non–small cell lung cancer patients has been initiated. HKI-272 might offer benefits to non–small cell lung cancer patients who have relapsed after an initial response to erlotinib.
A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-β1 Mediates Suppression in the Tumor Microenvironment
Authors: Strauss Laura , Bergmann Christoph , Szczepanski Miroslaw , Gooding William , Johnson Jonas T. , Whiteside Theresa L. 
Published: August 2007

Abstract
Purpose: Immunosuppression, including that mediated by CD4+CD25highFoxp3+ regulatory T cells (Treg), is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Tregs with a distinct phenotype in tumor-infiltrating lymphocytes (TIL) contribute to local immune suppression.
Experimental Design: The frequency and phenotype of Treg in TIL and/or peripheral blood mononuclear cells (PBMC) in 15 HNSCC patients and PBMC in 15 normal controls were compared. Single-cell sorted CD4+CD25high T cells were tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidyl ester–labeled and activated autologous CD4+CD25− responder T cells. Transwell inserts separating Treg from responders and neutralizing interleukin-10 (IL-10) or transforming growth factor-β1 (TGF-β1) antibodies were used to evaluate the mechanisms used by Treg to suppress responder cell proliferation.
Results: In TIL, CD25+ cells were enriched in the CD3+CD4+ subset (13 ± 3%) relative to circulating CD3+CD4+ T cells (3 ± 0.7%) in HNSCC patients (P ≤ 0.01) or normal controls (2 ± 1.5%; P ≤ 0.001). Among the CD3+CD4+ subset, CD25high Treg represented 3 ± 0.5% in TIL, 1 ± 0.3% in PBMC, and 0.4 ± 0.2% in normal controls. Tregs in TIL were GITR+, IL-10+, and TGF-β1+, although circulating Treg up-regulated CD62L and CCR7 but not GITR, IL-10, or TGF-β1. Treg in TIL mediated stronger suppression (P ≤ 0.001) than Treg in PBMC of HNSCC patients. The addition of neutralizing IL-10 and TGF-β antibodies almost completely abrogated suppression (5 ± 2.51%). Transwell inserts partly prevented suppression (60 ± 5% versus 95 ± 5%).
Conclusions: Suppression in the tumor microenvironment is mediated by a unique subset of Treg, which produce IL-10 and TGF-β1 and do not require cell-to-cell contact between Treg and responder cells for inhibition.
Enzastaurin, a Protein Kinase Cβ–Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer
Authors: Herbst Roy S. , Oh Yun , Wagle Asavari , Lahn Michael 
Published: August 2007

AbstractEnzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In contrast to previous PKC inhibitors, enzastaurin is very well tolerated with a favorable safety profile, allowing it to be dosed for extended durations. In the present review, we summarize the rationale for targeting PKC in cancer, the preclinical experience of enzastaurin, and the clinical findings of the current phase I and II studies. Based on the combined information, we present the rationale for its future assessment in the treatment of lung cancer.
Is There a Role for Cetuximab in Non–Small Cell Lung Cancer?
Authors: Morgensztern Daniel , Govindan Ramaswamy 
Published: August 2007

AbstractThe epidermal growth factor receptor (EGFR) is commonly overexpressed in non–small cell lung cancer (NSCLC). In addition, activating mutations in the EGFR tyrosine kinase domain have been described almost exclusively in NSCLC. Cetuximab, a monoclonal antibody against EGFR, has only modest single-agent activity in advanced NSCLC. A few phase II studies conducted in advanced NSCLC show no significant benefit from adding cetuximab to chemotherapy. However, in vitro observations of synergy between EGFR inhibitors and radiation therapy have been confirmed in the clinical setting of head and neck cancer. The addition of cetuximab to radiotherapy improves survival in patients with locally advanced unresectable squamous cell cancer of the head and neck compared with radiotherapy alone and this combination is being actively studied in locally advanced NSCLC. Research is also ongoing to define the role of cetuximab in combination with other targeted agents. This review will summarize the results of recently published studies on cetuximab and outline current research with this agent in NSCLC.