bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Interspersed Nuclear Element 1 Hypomethylation Is a Marker of Poor Prognosis in Stage IA Non–Small Cell Lung Cancer
Authors: Saito Kenichiro , Kawakami Kazuyuki , Matsumoto Isao , Oda Makoto , Watanabe Go , Minamoto Toshinari 
Published: April 2010

Abstract
Purpose: Global hypomethylation and the hypermethylation of gene promoter regions are common events in tumor DNA. The aim of this study was to evaluate the prognostic significance of both global hypomethylation and gene promoter hypermethylation in DNA from non–small cell lung cancer (NSCLC).
Experimental Design: Genomic DNA was obtained from the tumor tissue of 379 NSCLC patients who underwent surgery. Methylation levels were measured by real-time PCR following bisulfite modification of DNA and were correlated with clinicopathologic parameters and patient prognosis. Methylation of long interspersed nuclear element 1 (LINE-1) was used as a surrogate marker for global methylation. Hypermethylation of the APC, CDH13, and RASSF1 promoter regions was also evaluated.
Results: Tumor tissue showed significantly higher CDH13 and RASSF1 methylation levels compared with normal lung tissue, but lower LINE-1 methylation levels. APC, RASSF1, and LINE-1 methylation levels were significant prognostic factors in univariate analysis of an initial cohort of 234 cases. APC and LINE-1 methylation remained significant prognostic factors in multivariate analysis that included age, gender, smoking history, histologic type, and pathologic stage. LINE-1 methylation showed marginally significant prognostic value in stage IA and IB disease. Expansion of the study cohort to 364 cases revealed that LINE-1 methylation had significant prognostic value for stage IA NSCLC patients in multivariate analysis.
Conclusions: LINE-1 hypomethylation was an independent marker of poor prognosis in stage IA NSCLC. Validation of this finding in additional tumor cohorts could have clinical relevance for the management of early-stage NSCLC. Clin Cancer Res; 16(8); 2418–26. ©2010 AACR.
Targeted Cytosine Deaminase-Uracil Phosphoribosyl Transferase Suicide Gene Therapy Induces Small Cell Lung Cancer–Specific Cytotoxicity and Tumor Growth Delay
Authors: Christensen Camilla L. , Gjetting Torben , Poulsen Thomas T. , Cramer Frederik , Roth Jack A. , Poulsen Hans S. 
Published: April 2010

Abstract
Purpose: Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug.
Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery.
Results: INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts.
Conclusions: The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo. Clin Cancer Res; 16(8); 2308–19. ©2010 AACR.
Antitumor Efficacy Profile of PKI-402, a Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor
Authors: Mallon Robert , Hollander Irwin , Feldberg Larry , Lucas Judy , Soloveva Veronica , Venkatesan Aranapakam , Dehnhardt Christoph , Delos Santos Efren , Chen Zecheng , dos Santos Osvaldo , Ayral-Kaloustian Semiramis , Gibbons Jay 
Published: April 2010

Abstract
PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-α mutants, and mammalian target of rapamycin (mTOR; IC50 versus PI3K-α = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non–small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2+ and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm3 to 129 mm3 and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976–84. ©2010 AACR.
SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2
Authors: Peck Barrie , Chen Chun-Yuan , Ho Ka-Kei , Di Fruscia Paolo , Myatt Stephen S. , Coombes R. Charles , Fuchter Matthew J. , Hsiao Chwan-Deng , Lam Eric W.-F. 
Published: April 2010

Abstract
SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermide-induced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844–55. ©2010 AACR.
Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells
Authors: Rao Rekha , Nalluri Srilatha , Kolhe Ravindra , Yang Yonghua , Fiskus Warren , Chen Jianguang , Ha Kyungsoo , Buckley Kathleen M. , Balusu Ramesh , Coothankandaswamy Veena , Joshi Atul , Atadja Peter , Bhalla Kapil N. 
Published: April 2010

Abstract
Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1α, which results in the adaptive unfolded protein response (UPR). In the present studies, we determined that histone deacetylase-6 (HDAC6) binds and deacetylates GRP78. Following treatment with the pan-histone deacetylase inhibitor panobinostat (Novartis Pharmaceuticals), or knockdown of HDAC6 by short hairpin RNA, GRP78 is acetylated in 11 lysine residues, which dissociates GRP78 from PERK. This is associated with the activation of a lethal UPR in human breast cancer cells. Coimmunoprecipitation studies showed that binding of HDAC6 to GRP78 requires the second catalytic and COOH-terminal BUZ domains of HDAC6. Treatment with panobinostat increased the levels of phosphorylated-eukaryotic translation initiation factor (p-eIF2α), ATF4, and CAAT/enhancer binding protein homologous protein (CHOP). Panobinostat treatment also increased the proapoptotic BIK, BIM, BAX, and BAK levels, as well as increased the activity of caspase-7. Knockdown of GRP78 sensitized MCF-7 cells to bortezomib and panobinostat-induced UPR and cell death. These findings indicate that enforced acetylation and decreased binding of GRP78 to PERK is mechanistically linked to panobinostat-induced UPR and cell death of breast cancer cells. Mol Cancer Ther; 9(4); 942–52. ©2010 AACR.
Organic Cation Transporters Modulate the Uptake and Cytotoxicity of Picoplatin, a Third-Generation Platinum Analogue
Authors: More Swati S. , Li Shuanglian , Yee Sook Wah , Chen Ligong , Xu Zhidong , Jablons David M. , Giacomini Kathleen M. 
Published: April 2010

AbstractPicoplatin, a third-generation platinum agent, is efficacious against lung cancers that are otherwise resistant or become refractory during platinum treatment. This effort was aimed at the determination of the influence of organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and their genetic variants on cellular uptake of picoplatin and on the individual components of the ensuing cytotoxicity such as DNA adduct formation. The effect of OCT1 on picoplatin pharmacokinetics and antitumor efficacy was determined using OCT knockout mice and HEK293 xenografts stably expressing OCT1. The uptake and DNA adduct formation of picoplatin were found to be significantly enhanced by the expression of the OCTs. Expression of OCT1 and OCT2, but not OCT3, significantly enhanced picoplatin cytotoxicity, which was reduced in the presence of an OCT inhibitor. Common reduced functional variants of OCT1 and OCT2 led to reduction in uptake and DNA adduct formation of picoplatin in comparison with the reference OCT1 and OCT2. Pharmacokinetic parameters of picoplatin in Oct1−/− and Oct1+/+ mice were not significantly different, suggesting that the transporters do not influence the disposition of the drug. In contrast, the volume of OCT1-expressing xenografts in mice was significantly reduced by picoplatin treatment, suggesting that OCT1 may enhance the antitumor efficacy of picoplatin. These studies provide a basis for follow-up clinical studies that would seek to examine the relationship between the anticancer efficacy of picoplatin and expression levels of OCTs and their genetic variants in tumors. Mol Cancer Ther; 9(4); 1058–69. ©2010 AACR.
Garcinol Potentiates TRAIL-Induced Apoptosis through Modulation of Death Receptors and Antiapoptotic Proteins
Authors: Prasad Sahdeo , Ravindran Jayaraj , Sung Bokyung , Pandey Manoj K. , Aggarwal Bharat B. 
Published: April 2010

Abstract
Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH2-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856–68. ©2010 AACR.
Nutlin-3a Induces Cytoskeletal Rearrangement and Inhibits the Migration and Invasion Capacity of p53 Wild-Type Cancer Cells
Authors: Moran Diarmuid M. , Maki Carl G. 
Published: April 2010

Abstract
MDM2 is an E3 ubiquitin ligase that binds and ubiquitinates the tumor suppressor protein p53, leading to its proteasomal degradation. Nutlin-3a (Nutlin) is a preclinical drug that binds MDM2 and prevents the interaction between MDM2 and p53, leading to p53 stabilization and activation of p53 signaling events. Previous studies have reported that Nutlin promotes growth arrest and/or apoptosis in cancer cells that express wild-type p53. In the current study, Nutlin treatment caused a cytoskeletal rearrangement in p53 wild-type human cancer cells from multiple etiologies. Specifically, Nutlin decreased actin stress fibers and reduced the size and number of focal adhesions in treated cells. This process was dependent on p53 expression but was independent of p21 expression and growth arrest. Consistent with this, Nutlin-treated cells failed to form filamentous actin–based motility structures (lamellipodia) and displayed significantly decreased directional persistence in response to migratory cues. Finally, chemotactic assays showed a p53-dependent/p21-independent decrease in migratory and invasive capacity of Nutlin-treated cells. Taken together, these findings reveal that Nutlin treatment can inhibit the migration and invasion capacity of p53 wild-type cells, adding to the potential therapeutic benefit of Nutlin and other small molecule MDM2 inhibitors. Mol Cancer Ther; 9(4); 895–905. ©2010 AACR.
Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800
Authors: Massey Andrew J. , Schoepfer Joseph , Brough Paul A. , Brueggen Josef , Chène Patrick , Drysdale Martin J. , Pfaar Ulrike , Radimerski Thomas , Ruetz Stephan , Schweitzer Alain , Wood Mike , Garcia-Echeverria Carlos , Jensen Michael Rugaard 
Published: April 2010

Abstract
Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH2-terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-RafV600E, Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development. Mol Cancer Ther; 9(4); 906–19. ©2010 AACR.
Adhesive Interactions Regulate Transcriptional Diversity in Malignant B Cells
Authors: Nadav-Dagan Liat , Shay Tal , Dezorella Nili , Naparstek Elizabeth , Domany Eytan , Katz Ben-Zion , Geiger Benjamin 
Published: April 2010

Abstract
The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated “type A” cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo (“type F” cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated “AF cells”) were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)–associated genes. The highly adherent type A cells expressed higher levels of NFκB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM. Mol Cancer Res; 8(4); 482–93. ©2010 AACR.
Southern Shaanxi Offcials in Early Nineteeth-Century China
Authors: McMahon Daniel 
Published: April 2010

AbstractThis essay examines an influential group of lower and middle level Qing administrators who served in southern Shaanxi in the early nineteenth century. These officials distinguished themselves pacifying the 1796-1804 White Lotus revolt, were promoted during the 1799-1805 Jiaqing reforms, and then were retained up to two decades in southern Shaanxi on the basis of their local expertise and effective administration. Accounts of rebel pacification, water management, and temple construction show that this cadre of field officials possessed considerable bureaucratic backing, regional prestige, and exibility in local action. These assets strengthened their ability to mobilize, supervise, restrain, and instruct increasingly self-managed local communities and aided the post-war restoration of southern Shaanxi. Their long tenure and regional authority likewise foreshadowed the rise of provincial "strongmen" in mid-nineteenth century China. Cet article est consacré à un groupe influent d'administrateurs Qing de rang inférieur ou moyen en poste dans le sud du Shaanxi au début du xixe siècle. Ces fonctionnaires s'étaient distingués pendant la pacification de la révolte du Lotus Blanc (1796-1804) et avaient bénéficié de promotions au moment des réformes de Jiaqing (1799-1805); ils furent maintenus en fonctions dans la même région, jusqu'à deux décennies durant, sur la base de leur expertise locale et de l'effcacité de leur administration. Comme on verra à partir d'épisodes concernant la répression des mouvements de rébellion, la gestion de l'irrigation et la construction de temples, ce cadre d'administrateurs locaux pouvait se prévaloir de considérables appuis bureaucratiques, d'un indéniable prestige régional et d'une grande souplesse d'initiative. Ils n'en étaient que mieux placés pour mobiliser, superviser et éduquer des communautés locales de plus en plus autonomes dans leur gestion et pour contribuer à la reconstruction du Sud-Shaanxi après la guerre. La durée de leurs périodes de service et leur autorité régionale pré gurent l'émergence des "hommes forts" provinciaux au milieu du xixe siècle.
The infinitivus pro imperativo in Ancient Greek. The Imperatival Infinitive as an Expression of Proper Procedural Action
Authors: Allan Rutger J. 
Published: April 2010

AbstractIn this paper, it is argued that the use of the imperatival infinitive (or, infinitivus pro imperativo) can be explained by means of the notion of procedure. The imperatival infinitive refers to the appropriate action that is to be carried out as part of a practical or conventional social procedure (script, frame) which is evoked in the discourse or by the extra-linguistic situation of the interlocutors. Unlike the imperative proper, the imperatival infinitive does not involve a direct appeal of the speaker to the hearer. As its directive force depends on the appropriateness of the action within a particular procedure, the imperatival infinitive can be seen as a more indirect type of directive expression.The functional differences between the imperative and the imperatival infinitive can be clarified by reference to the notions of finiteness and grounding. As imperatival infinitives are not finite, they do not invoke the ground (i.e. the speech event, its participants, and its immediate circumstances), but merely designate a type of action which is not epistemically located with respect to time or reality. Unlike the imperative, therefore, the directive force of the imperatival infinitive is not anchored in the ground, but, instead, it is pragmatically implicated by the procedure at hand.