bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis
Authors: Bennett Kristi L. , Romigh Todd , Eng Charis 
Published: November 2009

Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis and improve outcome, early detection markers (e.g., DNA methylation) are crucial for timely cancer diagnosis. In a recent publication, an epigenome-wide screen revealed a set of genes that are commonly methylated and downregulated in head and neck cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, and IRX1). Interestingly, these candidates are potentially involved in the transforming growth factor-β (TGF-β) signaling pathway, which is often disrupted in HNSCC. Therefore, we sought to determine coordinated epigenetic silencing of these candidate genes in HNSCC as potential key disruptors of TGF-β signaling, which could ultimately result in HNSCC progression. Through immunoprecipitation studies, all five of the investigated candidate genes were found to interact with components of the TGF-β pathway. Overexpression of SLC5A8, EBF3, and IRX1 resulted in decreased mitotic activity and increased apoptosis. In addition, EBF3 was found to increase p21 promoter activity, and SMAD2 significantly increased IRX1 promoter activity. These findings are significant because they reveal a set of genes that interact with components of the TGF-β pathway, and their silencing via methylation in HNSCC results in coordinated decrease in apoptosis, increased proliferation, and decreased differentiation. [Cancer Res 2009;69(24):9301–5]
Signaling in Malignant Astrocytomas: Role of Neural Stem Cells and Its Therapeutic Implications
Authors: Alcantara Llaguno Sheila R. , Chen Jian , Parada Luis F. 
Published: November 2009

Abstract
Malignant astrocytomas are infiltrative and aggressive brain tumors. Conventional forms of therapy have not been effective in controlling this incurable disease. Recent advances in understanding the molecular biology of these tumors have revealed potential mechanisms by which astrocytoma cells undergo tumor initiation, progression, and maintenance, as well as possible avenues for targeted therapeutics. Studies on the role of neural stem cells as cells of origin and tumor-propagating cells have also greatly increased our understanding of the biology and clinical behavior of these tumors. An integrated view of the genetics, signal transduction, and cell biology of astrocytomas, as well as clinical data from patients, will provide a more useful approach in designing novel therapies for this devastating disease. (Clin Cancer Res 2009;15(23):7124–9)
Antiangiogenic Tetrathiomolybdate Protects against Her2/neu-Induced Breast Carcinoma by Hypoplastic Remodeling of the Mammary Gland
Authors: Pan Quintin , Rosenthal Devin T. , Bao Liwei , Kleer Celina G. , Merajver Sofia D. 
Published: November 2009

Abstract
Purpose: The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent.
Experimental Design: Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice.
Results: At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and &gt;460 days for TM-treated mice (P &lt; 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 ± 6.2% and 50.9 ± 4.5% (P &lt; 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase–positive mammary stem cells in Her2/neu and FVB mammary glands.
Conclusion: Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment. (Clin Cancer Res 2009;15(23):7441–6)
Combination of hTERT Knockdown and IFN-γ Treatment Inhibited Angiogenesis and Tumor Progression in Glioblastoma
Authors: George Joseph , Banik Naren L. , Ray Swapan K. 
Published: November 2009

AbstractPurpose: The limitless invasive and proliferative capacities of tumor cells are associated with telomerase and expression of its catalytic component, human telomerase reverse transcriptase (hTERT). IFN-γ modulates several cellular activities, including signaling pathways and cell cycle, through transcriptional regulation.Experimental Design: Using a recombinant plasmid with hTERT siRNA cDNA, we downregulated hTERT during IFN-γ treatment in human glioblastoma SNB-19 and LN-18 cell lines and examined whether such a combination could inhibit angiogenesis and tumor growth in nude mice. In vitro angiogenesis assay was done using coculture of tumor cells with human microvascular endothelial cells. In vivo angiogenesis assay was done using diffusion chambers under the dorsal skin of nude mice. In vivo imaging of intracerebral tumorigenesis and longitudinal solid tumor development studies were conducted in nude mice.Results: In vitro and in vivo angiogenesis assays showed inhibition of capillary-like network formation of microvascular endothelial cells and neovascularization under dorsal skin of nude mice, respectively. We observed inhibition of intracerebral tumorigenesis and s.c. solid tumor formation in nude mice after treatment with combination of hTERT siRNA and IFN-γ. Western blotting of solid tumor samples showed significant downregulation of the molecules that regulate cell invasion, angiogenesis, and tumor progression.Conclusions: Our study showed that the combination of hTERT siRNA and IFN-γ effectively inhibited angiogenesis and tumor progression through the downregulation of molecules involved in these processes. Therefore, the combination of hTERT siRNA and IFN-γ is a promising therapeutic strategy for controlling the growth of human glioblastoma. (Clin Cancer Res 2009;15(23):7186–95)
Phase I Study of Flavopiridol with Oxaliplatin and Fluorouracil/Leucovorin in Advanced Solid Tumors
Authors: Rathkopf Dana , Dickson Mark A. , Feldman Darren R. , Carvajal Richard D. , Shah Manish A. , Wu Nian , Lefkowitz Robert , Gonen Mithat , Cane Lauren M. , Dials Heather J. , Winkelmann Jennifer L. , Bosl George J. , Schwartz Gary K. 
Published: November 2009

Abstract
Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)–induced apoptosis in a sequence-dependent manner.
Experimental Design: We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.
Results: Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m2) and 5FU (2,400 mg/m2), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m2 flavopiridol, 85 mg/m2 oxaliplatin, and 1,800 mg/m2 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (&gt;30% positive cells) for responders and p53 wild-type for nonresponders.
Conclusions: Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual. (Clin Cancer Res 2009;15(23):7405–11)
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
Authors: Wolchok Jedd D. , Hoos Axel , O'Day Steven , Weber Jeffrey S. , Hamid Omid , Lebbé Celeste , Maio Michele , Binder Michael , Bohnsack Oliver , Nichol Geoffrey , Humphrey Rachel , Hodi F. Stephen 
Published: November 2009

Abstract
Purpose: Immunotherapeutic agents produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes. Resulting clinical response patterns extend beyond those of cytotoxic agents and can manifest after an initial increase in tumor burden or the appearance of new lesions (progressive disease). Response Evaluation Criteria in Solid Tumors or WHO criteria, designed to detect early effects of cytotoxic agents, may not provide a complete assessment of immunotherapeutic agents. Novel criteria for the evaluation of antitumor responses with immunotherapeutic agents are required.
Experimental Design: The phase II clinical trial program with ipilimumab, an antibody that blocks CTL antigen-4, represents the most comprehensive data set available to date for an immunotherapeutic agent. Novel immune therapy response criteria proposed, based on the shared experience from community workshops and several investigators, were evaluated using data from ipilimumab phase II clinical trials in patients with advanced melanoma.
Results: Ipilimumab monotherapy resulted in four distinct response patterns: (a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions. All patterns were associated with favorable survival.
Conclusion: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria. Further prospective evaluations of the immune-related response criteria, particularly their association with overall survival, are warranted. (Clin Cancer Res 2009;15(23):7412–20)
Telomeres: The Long and Short of Developing Non-Hodgkin Lymphoma
Authors: Noy Ariela 
Published: November 2009

Abstract
Chromosomal integrity is vital to the life span of the dividing cell. Telomeres are tandem sequences at chromosome ends that provide protection for the genetic coding material. Erosion of those ends leads to cell death. Does stabilization promote cancer? (Clin Cancer Res 2009;15(23):7114–5)
Targeting Histone Demethylases in Cancer Therapy
Authors: Grant Steven 
Published: November 2009

Abstract
A novel oligoamine analog inhibitor of histone demethylases blocks colon tumor cell growth in association with histone methylation and gene re-expression. It also markedly potentiates the activity of hypomethylating agents in vitro and in vivo, suggesting that histone demethylase inhibitors may represent a valuable addition to the armamentarium of epigenetic agents. (Clin Cancer Res 2009;15(23):7111–3)
Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1α/Sp4
Authors: Tsai Wen-Bin , Aiba Isamu , Lee Soo-yong , Feun Lynn , Savaraj Niramol , Kuo Macus Tien 
Published: November 2009

Abstract
Arginine deiminase (ADI)–based arginine depletion is a novel strategy under clinical trials for the treatment of malignant melanoma with promising results. The sensitivity of melanoma to ADI treatment is based on its auxotrophy for arginine due to a lack of argininosuccinate synthetase (AS) expression, the rate-limiting enzyme for the de novo biosynthesis of arginine. We show here that AS expression can be transcriptionally induced by ADI in melanoma cell lines A2058 and SK-MEL-2 but not in A375 cells, and this inducibility was correlated with resistance to ADI treatment. The proximal region of the AS promoter contains an E-box that is recognized by c-Myc and HIF-1α and a GC-box by Sp4. Through ChIP assays, we showed that under noninduced conditions, the E-box was bound by HIF-1α in all the three melanoma cell lines. Under arginine depletion conditions, HIF-1α was replaced by c-Myc in A2058 and SK-MEL-2 cells but not in A375 cells. Sp4 was constitutively bound to the GC-box regardless of arginine availability in all three cell lines. Overexpressing c-Myc by transfection upregulated AS expression in A2058 and SK-MEL-2 cells, whereas cotransfection with HIF-1α suppressed c-Myc–induced AS expression. These results suggest that regulation of AS expression involves interplay among positive transcriptional regulators c-Myc and Sp4, and negative regulator HIF-1α that confers resistance to ADI treatment in A2058 and SK-MEL-2 cells. Inability of AS induction in A375 cells under arginine depletion conditions was correlated by the failure of c-Myc to interact with the AS promoter. [Mol Cancer Ther 2009;8(12):3223–33]
Celastrol Synergistically Enhances Temozolomide Cytotoxicity in Melanoma Cells
Authors: Chen Ming , Rose Amy E. , Doudican Nicole , Osman Iman , Orlow Seth J. 
Published: November 2009

Abstract
Efforts to improve melanoma response rates to temozolomide (TMZ) have thus far been unsuccessful. We screened a library of 2,000 marketed drugs and natural products to identify agents with the potential to sensitize melanoma cells to the effects of TMZ. Celastrol (CEL), a natural compound found in the Thunder of God vine, was identified based on its ability to enhance cell death in TMZ-resistant melanoma cells. A cell proliferation assay was used to compare the growth-inhibitory effects of TMZ alone versus TMZ/CEL combination treatment. Cytotoxic synergy was assessed using combination-index methods. The expression of nuclear factor-κB (NF-κB), IκB, mitogen-activated protein kinase, and ubiquitinated proteins were examined using Western blotting, and the localization of NF-κB in CEL-treated melanoma cells was evaluated using immunofluorescence microscopy. The CEL/TMZ combination synergistically inhibited cell proliferation in melanoma cells. CEL treatment increased the levels of ubiquitinated proteins, reduced the levels of tumor necrosis factor-α–induced IκB phosphorylation, and blocked NF-κB translocation to the nucleus. Inhibition of NF-κB with small interfering RNA mimicked the ability of CEL to sensitize melanoma cells to TMZ, suggesting that inhibition of NF-κB may play a role in TMZ/CEL-induced cytotoxicity. The TMZ/CEL combination induced the phosphorylation of c-Jun NH2-terminal kinase, implicating the mitogen-activated protein kinase pathway in the treatment effects. Our data suggest that CEL may be effective in sensitizing resistant melanoma cells to the effects of TMZ. (Mol Cancer Res 2009;7(12):1946–53)
p57KIP2: “Kip”ing the Cell under Control
Authors: Pateras Ioannis S. , Apostolopoulou Kalliopi , Niforou Katerina , Kotsinas Athanassios , Gorgoulis Vassilis G. 
Published: November 2009

Abstractp57KIP2 is an imprinted gene located at the chromosomal locus 11p15.5. It is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family, which includes additionally p21CIP1/WAF1 and p27KIP1. It is the least studied CIP/KIP member and has a unique role in embryogenesis. p57KIP2 regulates the cell cycle, although novel functions have been attributed to this protein including cytoskeletal organization. Molecular analysis of animal models and patients with Beckwith-Wiedemann Syndrome have shown its nodal implication in the pathogenesis of this syndrome. p57KIP2 is frequently down-regulated in many common human malignancies through several mechanisms, denoting its anti-oncogenic function. This review is a thorough analysis of data available on p57KIP2, in relation to p21CIP1/WAF1 and p27KIP1, on gene and protein structure, its transcriptional and translational regulation, and its role in human physiology and pathology, focusing on cancer development. (Mol Cancer Res 2009;7(12):1902–19)
Lack of Evidence for Green Tea Polyphenols as DNA Methylation Inhibitors in Murine Prostate
Authors: Morey Kinney Shannon R. , Zhang Wa , Pascual Marien , Greally John M. , Gillard Bryan M. , Karasik Ellen , Foster Barbara A. , Karpf Adam R. 
Published: November 2009

Abstract
Green tea polyphenols (GTP) have been reported to inhibit DNA methylation in cultured cells. Here, we tested whether oral consumption of GTPs affects normal or cancer-specific DNA methylation in vivo, using mice. Wild-type (WT) and transgenic adenocarcinoma of mouse prostate (TRAMP) mice were given 0.3% GTPs in drinking water beginning at 4 weeks of age. To monitor DNA methylation, we measured 5-methyl-deoxycytidine (5mdC) levels, methylation of the B1 repetitive element, and methylation of the Mage-a8 gene. Each of these parameters were unchanged in prostate, gut, and liver from WT mice at both 12 and 24 weeks of age, with the single exception of a decrease of 5mdC in the liver at 12 weeks. In GTP-treated TRAMP mice, 5mdC levels and the methylation status of four loci hypermethylated during tumor progression were unaltered in TRAMP prostates at 12 or 24 weeks. Quite surprisingly, GTP treatment did not inhibit tumor progression in TRAMP mice, although known pharmacodynamic markers of GTPs were altered in both WT and TRAMP prostates. We also administered 0.1%, 0.3%, or 0.6% GTPs to TRAMP mice for 12 weeks and measured 5mdC levels and methylation of B1 and Mage-a8 in prostate, gut, and liver tissues. No dose-dependent alterations in DNA methylation status were observed. Genome-wide DNA methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR assay also revealed no significant hypomethylating effect of GTP. These data indicate that oral administration of GTPs does not affect normal or cancer-specific DNA methylation in the murine prostate.
Dietary Tricin Suppresses Inflammation-Related Colon Carcinogenesis in Male Crj: CD-1 Mice
Authors: Oyama Takeru , Yasui Yumiko , Sugie Shigeyuki , Koketsu Mamoru , Watanabe Kunitomo , Tanaka Takuji 
Published: November 2009

Abstract
The flavone 4′,5,7-trihydroxy-3′,5′-dimethoxyflavone (tricin) present in rice, oats, barley, and wheat exhibits antigrowth activity in several human cancer cell lines and anti-inflammatory potential. However, the chemopreventive activity has not yet been elucidated in preclinical animal models of colorectal cancer. This study was designed to determine whether dietary tricin exerts inflammation-associated colon carcinogenesis induced by azoxymethane and dextran sulfate sodium in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (10 mg/kg body weight) and followed by a 1-week exposure to dextran sulfate sodium (1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the experimental diet containing 50 or 250 ppm tricin. The experiment was terminated at week 18 to determine the chemopreventive efficacy of tricin. In addition, the effects of dietary tricin on the expression of several inflammatory cytokines, including tumor necrosis factor (TNF)-α, were assayed. The development of colonic adenomas and adenocarcinomas was significantly reduced by feeding with 50 and 250 ppm tricin, respectively. Dietary tricin also significantly reduced the proliferation of adenocarcinoma cells as well as the numbers of mitoses/anaphase bridging in adenocarcinoma cells. The dietary administration with tricin significantly inhibited the expression of TNF-α in the nonlesional cypts. Our findings that dietary tricin inhibits inflammation-related mouse colon carcinogenesis by suppressing the expression of TNF-α in the nonlesional cyrpts and the proliferation of adenocarcinomas suggest a potential use of tricin for clinical trials of colorectal cancer chemoprevention.
EphA2 in the Early Pathogenesis and Progression of Non–Small Cell Lung Cancer
Authors: Brannan Jennifer M. , Sen Banibrata , Saigal Babita , Prudkin Ludmila , Behrens Carmen , Solis Luisa , Dong Wenli , Bekele B. Nebiyou , Wistuba Ignacio , Johnson Faye M. 
Published: November 2009

AbstractOverexpression of the receptor tyrosine kinase EphA2 occurs in non–small cell lung cancer (NSCLC) and a number of other human cancers. This overexpression correlates with a poor prognosis, smoking, and the presence of Kirsten rat sarcoma (K-Ras) mutations in NSCLC. In other cancers, EphA2 has been implicated in migration and metastasis. To determine if EphA2 can promote NSCLC progression, we examined the relationship of EphA2 with proliferation and migration in cell lines and with metastases in patient tumors. We also examined potential mechanisms involving AKT, Src, focal adhesion kinase, Rho guanosine triphosphatases (GTPase), and extracellular signal–regulated kinase (ERK)-1/2. Knockdown of EphA2 in NSCLC cell lines decreased proliferation (colony size) by 20% to 70% in four of five cell lines (P &lt; 0. 04) and cell migration by 7% to 75% in five of six cell lines (P &lt; 0. 03). ERK1/2 activation correlated with effects on proliferation, and inhibition of ERK1/2 activation also suppressed proliferation. In accordance with the in vitro data, high tumor expression of EphA2 was an independent prognostic factor in time to recurrence (P = 0.057) and time to metastases (P = 0.046) of NSCLC patients. We also examined EphA2 expression in the putative premalignant lung lesion, atypical adenomatous hyperplasia, and the noninvasive bronchioloalveolar component of adenocarcinoma because K-Ras mutations occur in atypical adenomatous hyperplasia and are common in lung adenocarcinomas. Both preinvasive lesion types expressed EphA2, showing its expression in the early pathogenesis of lung adenocarcinoma. Our data suggest that EphA2 may be a promising target for treating and preventing NSCLC.
Preventive Effects of Bexarotene and Budesonide in a Genetically Engineered Mouse Model of Small Cell Lung Cancer
Authors: Wang Yian , Wen Weidong , Yi Yijun , Zhang Zhongqiu , Lubet Ronald A. , You Ming 
Published: November 2009

Abstract
In the present study, we examined the effect of bexarotene (Targretin) and budesonide in the chemoprevention of small cell lung carcinoma using a lung-specific knockout model of Rb1 and p53. Upon treatment with bexarotene, tumor incidence, number, and load were significantly reduced (P &lt; 0.05). Budesonide treatment trended to inhibition, but the effect was not statistically significant (P &gt; 0.05). Immunohistochemical staining indicated that bexarotene treatment decreased cell proliferation and increased apoptosis in tumors. The Rb1/p53 gene–targeted mouse seems to be a valuable model for chemopreventive studies on human small cell lung cancer. Our results indicate that the retinoid X receptor agonist bexarotene may be a potent chemopreventive agent in this cancer type.