bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies
Authors: Schimmer Aaron D. , O'Brien Susan , Kantarjian Hagop , Brandwein Joseph , Cheson Bruce D. , Minden Mark D. , Yee Karen , Ravandi Farhad , Giles Francis , Schuh Andre , Gupta Vikas , Andreeff Michael , Koller Charles , Chang Hong , Kamel-Reid Suzanne , Berger Mark , Viallet Jean , Borthakur Gautam 
Published: December 2008

Abstract
Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.
Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.
Results: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.
Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
Advances in Breast Cancer: Pathways to Personalized Medicine
Authors: Olopade Olufunmilayo I. , Grushko Tatyana A. , Nanda Rita , Huo Dezheng 
Published: December 2008

Abstract
Breast cancer is a complex disease caused by the progressive accumulation of multiple gene mutations combined with epigenetic dysregulation of critical genes and protein pathways. There is substantial interindividual variability in both the age at diagnosis and phenotypic expression of the disease. With an estimated 1,152,161 new breast cancer cases diagnosed worldwide per year, cancer control efforts in the postgenome era should be focused at both population and individual levels to develop novel risk assessment and treatment strategies that will further reduce the morbidity and mortality associated with the disease. The discovery that mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers has radically transformed our understanding of the genetic basis of breast cancer, leading to improved management of high-risk women. A better understanding of tumor host biology has led to improvements in the multidisciplinary management of breast cancer, and traditional pathologic evaluation is being complemented by more sophisticated genomic approaches. A number of genomic biomarkers have been developed for clinical use, and increasingly, pharmacogenetic end points are being incorporated into clinical trial design. For women diagnosed with breast cancer, prognostic or predictive information is most useful when coupled with targeted therapeutic approaches, very few of which exist for women with triple-negative breast cancer or those with tumors resistant to chemotherapy. The immediate challenge is to learn how to use the molecular characteristics of an individual and their tumor to improve detection and treatment, and ultimately to prevent the development of breast cancer. The five articles in this edition of CCR Focus highlight recent advances and future directions on the pathway to individualized approaches for the early detection, treatment, and prevention of breast cancer.
DNA Copy-Number Alterations Underlie Gene Expression Differences between Microsatellite Stable and Unstable Colorectal Cancers
Authors: Jorissen Robert N. , Lipton Lara , Gibbs Peter , Chapman Matthew , Desai Jayesh , Jones Ian T. , Yeatman Timothy J. , East Philip , Tomlinson Ian P.M. , Verspaget Hein W. , Aaltonen Lauri A. , Kruhøffer Mogens , Ørntoft Torben F. , Andersen Claus Lindbjerg , Sieber Oliver M. 
Published: December 2008

Abstract
Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression.
Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training samples and validated as MSI classifier using test samples. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data.
Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P &lt; 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of individual samples predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P &lt; 0.001).
Conclusions: Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.
Nuclear Factor-κB p65/relA Silencing Induces Apoptosis and Increases Gemcitabine Effectiveness in a Subset of Pancreatic Cancer Cells
Authors: Pan Xue , Arumugam Thiruvengadam , Yamamoto Tameyoshi , Levin Pavel A. , Ramachandran Vijaya , Ji Baoan , Lopez-Berestein Gabriel , Vivas-Mejia Pablo E. , Sood Anil K. , McConkey David J. , Logsdon Craig D. 
Published: December 2008

Abstract
Purpose: Nuclear factor κB (NFκB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFκB activity may be prognostic, and inhibition of NFκB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFκB activity and the effects of inhibiting NFκB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine.
Experimental Design: The gemcitabine sensitivity of pancreatic cancer cell lines BxPC-3, L3.6pl, CFPAC-1, MPanc-96, PANC-1, and MIA PaCa-2 were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting assays. NFκB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFκB activity were determined in vitro and in vivo. NFκB was inhibited by silencing of the p65/relA subunit using small interfering RNA in vitro and by neutral liposomal delivery of small interfering RNA in vivo, and the effects were evaluated on gemcitabine sensitivity.
Results: The cell lines L3.6pl, BxPC-3, and CFPAC-1 were sensitive, whereas MPanc-96, PANC-1, and MIA PaCa-2 were resistant to gemcitabine. No significant correlation was observed between basal NFκB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFκB either in vitro or in vivo. Silencing of p65/relA induced apoptosis and increased gemcitabine killing of all gemcitabine-sensitive pancreatic cancer cells. No significant effects, however, were observed on gemcitabine-resistant pancreatic cancer cell lines either in vitro or in vivo.
Conclusions: NFκB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFκB may be a useful therapeutic target for a subset of pancreatic cancers.
Cyclooxygenase-2 Expression Is an Independent Predictor of Poor Prognosis in Colon Cancer
Authors: Ogino Shuji , Kirkner Gregory J. , Nosho Katsuhiko , Irahara Natsumi , Kure Shoko , Shima Kaori , Hazra Aditi , Chan Andrew T. , Dehari Reiko , Giovannucci Edward L. , Fuchs Charles S. 
Published: December 2008

Abstract
Purpose: Cyclooxygenase-2 (COX-2; PTGS2) is considered to play an important role in colorectal carcinogenesis and is often up-regulated in colon cancers. However, previous data on the influence of COX-2 expression on patient outcome have been conflicting.
Experimental Design: Using 662 colon cancers (stage I-IV) in two independent prospective cohorts (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected COX-2 overexpression in 548 (83%) tumors by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related molecular events, including the CpG island methylation phenotype, microsatellite instability, and p53, CIMP, KRAS, and BRAF mutations.
Results: During follow-up of the 662 cases, there were 283 deaths, including 163 colon cancer-specific deaths. Patients with COX-2-positive tumors showed a trend towards an inferior colon cancer-specific mortality [HR, 1.37; 95% confidence interval (95% CI), 0.87-2.14], which became significant after adjusting for tumor stage and other predictors of clinical outcome (multivariate HR, 1.70; 95% CI, 1.06-2.74; P = 0.029). Notably, the prognostic effect of COX-2 expression might differ according to p53 status (Pinteraction = 0.04). Compared with tumors with both COX-2 and p53 negative, COX-2-positive tumors were significantly associated with an increased cancer-specific mortality (multivariate HR, 2.12; 95% CI, 1.23-3.65) regardless of p53 status. A similar trend was observed when overall mortality was used as an outcome.
Conclusion: COX-2 overexpression is associated with worse survival among colon cancer patients. The effect of COX-2 on clinical outcome may be modified by p53 status.
A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1α
Authors: Li Shan Hua , Shin Dong Hoon , Chun Yang-Sook , Lee Myung Kyu , Kim Myung-Suk , Park Jong-Wan 
Published: December 2008

Abstract
Hypoxia-inducible factor (HIF)-1 plays a key role in tumor promotion by inducing ∼60 genes required for tumor adaptation to hypoxia; thus, it is viewed as a target for cancer therapy. For this reason, YC-1, which down-regulates HIF-1α and HIF-2α at the post-translational level, is being developed as a novel anticancer drug. We here found that YC-1 acts in a novel manner to inhibit HIF-1. In the Gal4 reporter system, which is not degraded by YC-1, YC-1 was found to significantly inactivate the COOH-terminal transactivation domain (CAD) of HIF-1α, whereas it failed to inactivate CAD(N803A) mutant. In coimmunoprecipitation assays, YC-1 stimulated factor inhibiting HIF (FIH) binding to CAD even in hypoxia, whereas it failed to increase the cellular levels of hydroxylated Asn803 of CAD. It was also found that YC-1 prevented p300 recruitment by CAD in mammalian two-hybrid and coimmunoprecipitation assays. The involvement of FIH in YC-1-induced CAD inactivation was confirmed in EPO-enhancer and Gal4 reporter systems using FIH small interfering RNA and dimethyloxalylglycine FIH inhibitor. Indeed, FIH inhibition rescued HIF target gene expressions repressed by YC-1. In cancer cell lines other than Hep3B, YC-1 inhibits HIF-1α via the FIH-dependent CAD inactivation as well as via the protein down-regulation. Given these results, we suggest that the functional inactivation of HIF-α contributes to the YC-1-induced deregulation of hypoxia-induced genes. [Mol Cancer Ther 2008;7(12):3729–38]
In vivocharacterization of a polymeric nanoparticle platform with potential oral drug delivery capabilities
Authors: Bisht Savita , Feldmann Georg , Koorstra Jan-Bart M. , Mullendore Michael , Alvarez Hector , Karikari Collins , Rudek Michelle A. , Lee Carlton K. , Maitra Amarnath , Maitra Anirban 
Published: December 2008

AbstractNanotechnology has enabled significant advances in the areas of cancer diagnosis and therapy. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic formulations of poorly water-soluble, yet potent anticancer drugs. Whereas a number of nanoparticle-drug combinations are at various stages of preclinical or clinical assessment, the overwhelming majorities of such systems are injectable formulations and are incapable of being partaken orally. The development of an oral nano-delivery system would have distinct advantages for cancer chemotherapy. We report the synthesis and physicochemical characterization of orally bioavailable polymeric nanoparticles composed of N-isopropylacrylamide, methylmethacrylate, and acrylic acid in the molar ratios of 60:20:20 (designated NMA622). Amphiphilic NMA622 nanoparticles show a size distribution of &lt;100 nm (mean diameter of 80 ± 34 nm) with low polydispersity and can readily encapsulate a number of poorly water-soluble drugs such as rapamycin within the hydrophobic core. No apparent systemic toxicities are observed in mice receiving as much as 500 mg/kg of the orally administered void NMA622 for 4 weeks. Using NMA622-encapsulated rapamycin (“nanorapamycin”) as a prototype for oral nano-drug delivery, we show favorable in vivo pharmacokinetics and therapeutic efficacy in a xenograft model of human pancreatic cancer. Oral nanorapamycin leads to robust inhibition of the mammalian target of rapamycin pathway in pancreatic cancer xenografts, which is accompanied by significant growth inhibition (P &lt; 0.01) compared with control tumors. These data indicate that NMA622 nanoparticles provide a suitable platform for oral delivery of water-insoluble drugs like rapamycin for cancer therapy. [Mol Cancer Ther 2008;7(12):3878–88]
Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ
Authors: Gasparri Anna Maria , Jachetti Elena , Colombo Barbara , Sacchi Angelina , Curnis Flavio , Rizzardi Gian-Paolo , Traversari Catia , Bellone Matteo , Corti Angelo 
Published: December 2008

AbstractTargeted delivery of IFNγ to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNγ-NGR) in animal models is greater than that of IFNγ, frequent administrations of IFNγ-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFNγ-NGR. The study was carried out in immunocompetent mice and in nu/nu mice bearing RMA lymphoma, B16F melanoma, or WEHI-164 fibrosarcoma and in vitro using cultured tumor cells. IDO activity was increased in lymphoma homogenates after multiple treatments with IFNγ-NGR but not after a single treatment. Coadministration of 1-methyl-tryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFNγ-NGR and 1-methyl-tryptophan was observed in vitro in tumor cell proliferation assays or in nu/nu tumor-bearing mice, suggesting that the antitumor effect was host mediated. We conclude that IDO is critically involved in tumor resistance to repeated treatments with IFNγ-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFNγ-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity. [Mol Cancer Ther 2008;7(12):3859–66]
Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol
Authors: Yang Zhen , Yang Sun , Misner Bobbye J. , Chiu Rita , Liu Feng , Meyskens Frank L. 
Published: December 2008

Abstract
It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially metastatic Lu1205 cells. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets [activator protein-1 (AP-1)/JunD, matrix metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)] by Western blot and reverse transcription-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/JunD by specific small interfering RNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastasis of melanoma cells. Resveratrol has been shown to be an APE/Ref-1 inhibitor and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant may be an appropriate choice for combining with other compounds that develop resistance by up-regulation of these molecules. [Mol Cancer Ther 2008;7(12):3751–60]
MicroRNAs and cancer: past, present, and potential future
Authors: Nelson Kristen M. , Weiss Glen J. 
Published: December 2008

Abstract
MicroRNAs (miRNAs) are a class of small RNAs that have revealed a new level of gene regulation in the cell. After being processed by Drosha and Dicer RNase III endonucleases, mature miRNAs can inhibit the translation of mRNA by directing a RNA-induced silencing complex (RISC) to the target mRNA. miRNAs are making an impact in our understanding of cancer biology. Acting as either tumor suppressors or oncogenes, miRNAs regulate several genes known to play important roles in cancer. With the discovery of miRNAs comes the need for new techniques to study their activity. Bioinformatic tools can be used to predict mRNA targets of miRNA, but validation of miRNA regulation of predicted targets is imperative. miRNAs are differentially expressed in normal and tumor cells as well as between tumor subtypes. These differences may be useful as prognostic and predictive markers in cancer patients. The study of miRNAs holds much promise for improving diagnosis and treatment of cancer. [Mol Cancer Ther 2008;7(12):3655–60]
Monoclonal antibody 14C5 targets integrin αvβ5
Authors: Burvenich Ingrid , Schoonooghe Steve , Vervoort Liesbet , Dumolyn Caroline , Coene Elisabeth , Vanwalleghem Lieve , Van Huysse Jacques , Praet Marleen , Cuvelier Claude , Mertens Nico , De Vos Filip , Slegers Guido 
Published: December 2008

Abstract
This study identifies and characterizes the antigen recognized by monoclonal antibody (mAb) 14C5. We compared the expression of antigen 14C5 with the expression of eight integrin subunits (α1, α2, α3, αv, β1, β2, β3, and β4) and three integrin heterodimers (αvβ3, αvβ5, and α5β1) by flow cytometry. Antigen 14C5 showed a similar expression to αvβ5 in eight different epithelial cancer cell lines (A549, A2058, C32, Capan-2, Colo16, HT-1080, HT-29, and SKBR-3). Specific binding of P1F6, an anti-αvβ5 specific antibody, was blocked by mAb 14C5. After transient expression of αvβ5 in 14C5-negative Colo16 cells, mAb 14C5 was able to bind a subpopulation of αvβ5-positive cells. We evaluated the tissue distribution of the 14C5 antigen in colon (n = 20) and lung (n = 16) cancer tissues. The colon carcinoma cells stained positive for 14C5 in 50% of tumors analyzed, whereas bronchoalveolar lung carcinoma and typical carcinoid were not positive for the antigen. More common types of non–small cell lung cancer, i.e., squamous (n = 5) and adenocarcinoma (n = 3), stained positive in 2 of 5 squamous carcinomas and in 1 of 3 investigated adenocarcinoma. Colon (95%) and lung (50%) carcinoma tissues showed extensive expression of antigen 14C5 in the stroma surrounding the tumor cells and on the membrane of the adjacent fibroblasts. We show for the first time that mAb 14C5 binds the vascular integrin αvβ5, suggesting that mAb 14C5 can be used as a screening agent to select colon and lung cancer patients that are eligible for anti-αvβ5–based therapies. [Mol Cancer Ther 2008;7(12):3771–9]
Carbonic anhydrase IX has chaperone-like functions and is an immunoadjuvant
Authors: Wang Yanping , Wang Xiang-Yang , Subjeck John R. , Kim Hyung L. 
Published: December 2008

AbstractCarbonic anhydrase IX (CA9) is a hypoxia-regulated, transmembrane protein associated with neoplastic growth in a large spectrum of human tumors. CA9 is expressed in nearly all clear-cell renal tumors; levels of CA9 expression predict prognosis and response to interleukin-2 therapy. These observations may be explained by a novel chaperone-like function of CA9, which allows it to serve as an immunoadjuvant and stimulate an adaptive immune response against tumor antigens. Classic heat shock proteins (HSP) such as HSP110 and HSP70 are up-regulated in response to cellular stress and function to protect intracellular proteins from aggregation. Similarly, CA9 formed complexes with client proteins and inhibited heat-induced aggregation and enabled refolding of denatured client protein. HSP released from injured cells activate an immune response. CA9 bound dendritic cells in a receptor-specific manner. Bound CA9 was internalized by dendritic cells and processed primarily through the proteosomal pathway. In a murine melanoma model, a complex of CA9 and gp100 generated a gp100-specific antitumor response. A soluble form of CA9 shed from tumor cells had the same chaperone-like functions, providing renal tumors and hypoxic cells with a mechanism for stimulating an immune response against extracellular antigens. Interleukin-2 treatment of patient renal tumors in short-term culture increased CA9 shedding, suggesting a strategy for augmenting the immunogenicity of renal tumors. CA9 has chaperone-like functions and CA9 shed from tumors may play a direct role in stimulating an adaptive immune response. [Mol Cancer Ther 2008;7(12):3867–77]