bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agglomerative Epigenetic Aberrations Are a Common Event in Human Breast Cancer
Authors: Novak Petr , Jensen Taylor , Oshiro Marc M. , Watts George S. , Kim Christina J. , Futscher Bernard W. 
Published: October 2008

Abstract
Changes in DNA methylation patterns are a common characteristic of cancer cells. Recent studies suggest that DNA methylation affects not only discrete genes, but it can also affect large chromosomal regions, potentially leading to LRES. It is unclear whether such long-range epigenetic events are relatively rare or frequent occurrences in cancer. Here, we use a high-resolution promoter tiling array approach to analyze DNA methylation in breast cancer specimens and normal breast tissue to address this question. We identified 3,506 cancer-specific differentially methylated regions (DMR) in human breast cancer with 2,033 being hypermethylation events and 1,473 hypomethylation events. Most of these DMRs are recurrent in breast cancer; 90% of the identified DMRs occurred in at least 33% of the samples. Interestingly, we found a nonrandom spatial distribution of aberrantly methylated regions across the genome that showed a tendency to concentrate in relatively small genomic regions. Such agglomerates of hypermethylated and hypomethylated DMRs spanned up to several hundred kilobases and were frequently found at gene family clusters. The hypermethylation events usually occurred in the proximity of the transcription start site in CpG island promoters, whereas hypomethylation events were frequently found in regions of segmental duplication. One example of a newly discovered agglomerate of hypermethylated DMRs associated with gene silencing in breast cancer that we examined in greater detail involved the protocadherin gene family clusters on chromosome 5 (PCDHA, PCDHB, and PCDHG). Taken together, our results suggest that agglomerative epigenetic aberrations are frequent events in human breast cancer. [Cancer Res 2008;68(20):8616–25]
Natural Killer Cell Accumulation in Tumors Is Dependent on IFN-γ and CXCR3 Ligands
Authors: Wendel Marco , Galani Ioanna E. , Suri-Payer Elisabeth , Cerwenka Adelheid 
Published: October 2008

Abstract
Several studies have correlated high numbers of tumor-infiltrating natural killer (NK) cells with a good prognosis for cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the tumors in IFN-γ receptor knockout (IFN-γR−/−) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of IFN-γ in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27high NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the tumor tissue. Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3−/− mice, and the capacity of adoptively transferred CXCR3−/− NK cells to accumulate in the tumor was severely impaired. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell–dependent survival. Our results identify IFN-γ and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors. Exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. [Cancer Res 2008;68(20):8437–45]
Balancing between Antitumor Efficacy and Autoimmune Pathology in T-Cell–Mediated Targeting of Carcinoembryonic Antigen
Authors: Bos Rinke , van Duikeren Suzanne , Morreau Hans , Franken Kees , Schumacher Ton N.M. , Haanen John B. , van der Burg Sjoerd H. , Melief Cornelis J.M. , Offringa Rienk 
Published: October 2008

AbstractCarcinoembryonic antigen (CEA) is intensively studied as a potential target for immunotherapy of colorectal cancers. Although overexpressed by tumors, CEA is also expressed in normal tissues, raising questions about the feasibility and safety of CEA-targeted immunotherapy. We investigated these issues in transgenic mice in which the expression of human CEA in normal tissues closely resembles that in man. Our data show that the T-cell response against CEA in these mice is blunted by both thymic and peripheral tolerance. Consequently, effective tumor targeting is only achieved by adoptive transfer of T cells from nontolerant donors in combination with interventions that eliminate peripheral immune regulatory mechanisms. However, such treatments can result in severe intestinal autoimmune pathology associated with weight loss and mortality. Interestingly, preconditioning of recipient mice by depletion of T-regulatory cells results in immune-mediated tumor control in the absence of toxicity. In this setting, CEA-specific T-cell responses are lower than those induced by toxic regimens and accompanied by additional T-cell responses against non-self antigen. These findings illustrate the importance of testing adoptive immunotherapies targeting self antigens such as CEA in preclinical in vivo models and show that the choice of immune intervention regimen critically determines the balance between therapeutic efficacy and toxicity. [Cancer Res 2008;68(20):8446–55]
Transient Nutlin-3a Treatment Promotes Endoreduplication and the Generation of Therapy-Resistant Tetraploid Cells
Authors: Shen Hong , Moran Diarmuid M. , Maki Carl G. 
Published: October 2008

Abstract
p53 activity is controlled in large part by MDM2, an E3 ubiquitin ligase that binds p53 and promotes its degradation. The MDM2 antagonist Nutlin-3a stabilizes p53 by blocking its interaction with MDM2. Several studies have supported the potential use of Nutlin-3a in cancer therapy. Two different p53 wild-type cancer cell lines (U2OS and HCT116) treated with Nutlin-3a for 24 hours accumulated 2N and 4N DNA content, suggestive of G1 and G2 phase cell cycle arrest. This coincided with increased p53 and p21 expression, hypophosphorylation of pRb, and depletion of Cyclin B1, Cyclin A, and CDC2. Upon removal of Nutlin-3a, 4N cells entered S phase and re-replicated their DNA without an intervening mitotic division, a process known as endoreduplication. p53-p21 pathway activation was required for the depletion of Cyclin B1, Cyclin A, and CDC2 in Nutlin-3a–treated cells and for endoreduplication after Nutlin-3a removal. Stable tetraploid clones could be isolated from Nutlin-3a treated cells, and these tetraploid clones were more resistant to ionizing radiation and cisplatin-induced apoptosis than diploid counterparts. These data indicate that transient Nutlin-3a treatment of p53 wild-type cancer cells can promote endoreduplication and the generation of therapy-resistant tetraploid cells. These findings have important implications regarding the use of Nutlin-3a in cancer therapy.[Cancer Res 2008;68(20):8260–8]
Small Molecule Targeting the Hec1/Nek2 Mitotic Pathway Suppresses Tumor Cell Growth in Culture and in Animal
Authors: Wu Guikai , Qiu Xiao-Long , Zhou Longen , Zhu Jiewen , Chamberlin Richard , Lau Johnson , Chen Phang-Lang , Lee Wen-Hwa 
Published: October 2008

Abstract
Hec1 is a conserved mitotic regulator critical for spindle checkpoint control, kinetochore functionality, and cell survival. Overexpression of Hec1 has been detected in a variety of human cancers and is linked to poor prognosis of primary breast cancers. Through a chemical genetic screening, we have identified a small molecule, N-(4-[2,4-dimethyl-phenyl]-thiazol-2-yl)-benzamide (INH1), which specifically disrupts the Hec1/Nek2 interaction via direct Hec1 binding. Treating cells with INH1 triggered reduction of kinetochore-bound Hec1 as well as global Nek2 protein level, consequently leading to metaphase chromosome misalignment, spindle aberrancy, and eventual cell death. INH1 effectively inhibited the proliferation of multiple human breast cancer cell lines in culture (GI50, 10–21 μmol/L). Furthermore, treatment with INH1 retarded tumor growth in a nude mouse model bearing xenografts derived from the human breast cancer line MDA-MB-468, with no apparent side effects. This study suggests that the Hec1/Nek2 pathway may serve as a novel mitotic target for cancer intervention by small compounds. [Cancer Res 2008;68(20):8393–9]
The Thioredoxin System Mediates Redox-Induced Cell Death in Human Colon Cancer Cells: Implications for the Mechanism of Action of Anticancer Agents
Authors: Sun Yu , Rigas Basil 
Published: October 2008

AbstractAnticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide–donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC50, 10–90 μmol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H2O2, superoxide anion, and peroxynitirte), induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). Nuclear factor-κB and mitogen-activated protein kinases were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by small interfering RNA abrogated cell death induced by them. These compounds also inhibited the activity of Trx reductase that reduces oxidized Trx-1, whereas the Trx reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacologic control of cancer. [Cancer Res 2008;68(20):8269–77]
Roles of Idiotype-Specific T Cells in Myeloma Cell Growth and Survival: Th1 and CTL Cells Are Tumoricidal while Th2 Cells Promote Tumor Growth
Authors: Hong Sungyoul , Qian Jianfei , Yang Jing , Li Haiyan , Kwak Larry W. , Yi Qing 
Published: October 2008

AbstractIdiotype (Id) protein, secreted by myeloma cells, is a tumor-specific antigen. Id-based immunotherapy has been explored in patients with myeloma, and results were disappointing. Although previous studies have shown that Id-specific CTLs are able to lyse myeloma cells, it is unclear whether other types of Id-specific T cells, such as type-1 T-helper (Th1) and type-2 T-helper (Th2) cells, are also able to suppress or kill myeloma cells. Using a 5T murine myeloma model, we generated T-cell clones of different subsets and examined their function in the context of myeloma cells. Id-specific CTLs specifically lysed myeloma cells via MHC class I, perforin, and Fas ligand (FasL), and Th1, but not Th2, cells lysed the myeloma cells by FasL–Fas interaction. CTL and Th1 cells also suppressed the growth and function of myeloma cells, whereas Th2 cells promoted the proliferation and enhanced the secretion of Id protein and cytokines by myeloma cells. CTL and Th1, but not Th2, cells were able to eradicate established myeloma in vivo after adoptive transfer. These results show that Id-specific CTL and Th1 are promising effector cells, whereas Th2 provide no protection and may even promote tumor progression in vivo. [Cancer Res 2008;68(20):8456–64]
A Dietary Anthocyanidin Delphinidin Induces Apoptosis of Human Prostate Cancer PC3 Cells In vitro and In vivo: Involvement of Nuclear Factor-κB Signaling
Authors: Hafeez Bilal Bin , Siddiqui Imtiaz Ahmad , Asim Mohammad , Malik Arshi , Afaq Farrukh , Adhami Vaqar Mustafa , Saleem Mohammad , Din Maria , Mukhtar Hasan 
Published: October 2008

Abstract
Delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, possesses antioxidant, anti-inflammatory, and antiangiogenic properties. In this study, we provide evidence that it could be developed as a novel agent against human prostate cancer (PCa). We observed that delphinidin treatment to human PCa LNCaP, C4-2, 22Rν1, and PC3 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human prostate epithelial cells. We selected PC3 cells as a test model system because of their highly aggressive proliferative nature. Delphinidin treatment of cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G2-M phase. This induction of apoptosis seems to be mediated via activation of caspases because N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluromethylketone significantly reduced apoptosis induced by delphinidin. We also observed that delphinidin treatment of cells resulted in a dose-dependent decrease in (a) phosphorylation of IκB kinase γ (NEMO), (b) phosphorylation of nuclear factor-κB (NF-κB) inhibitory protein IκBα, (c) phosphorylation of NF-κB/p65 at Ser536 and NF-κB/p50 at Ser529, (d) NF-κB/p65 nuclear translocation, and (e) NF-κB DNA binding activity. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells resulted in a significant inhibition of tumor growth. Analysis of tumors from delphinidin-treated mice showed significant decrease in the expression of NF-κB/p65, Bcl2, Ki67, and PCNA. Taken together, our data suggest that delphinidin could be developed as an agent against human PCa. [Cancer Res 2008;68(20):8564–72]
Toll-Like Receptor 9 Mediates CpG Oligonucleotide–Induced Cellular Invasion
Authors: Ilvesaro Joanna M. , Merrell Melinda A. , Li Li , Wakchoure Savita , Graves David , Brooks Sonja , Rahko Eeva , Jukkola-Vuorinen Arja , Vuopala Katri S. , Harris Kevin W. , Selander Katri S. 
Published: October 2008

AbstractToll-like receptor 9 (TLR9) belongs to the innate immune system and recognizes microbial and vertebrate DNA. We showed previously that treatment with the TLR9-agonistic ODN M362 (a CpG sequence containing oligonucleotide) induces matrix metalloproteinase-13–mediated invasion in TLR9-expressing human cancer cell lines. Here, we further characterized the role of the TLR9 pathway in this process. We show that CpG oligonucleotides induce invasion in macrophages from wild-type C57/B6 and MyD88 knockout mice and in human MDA-MB-231 breast cancer cells lacking MyD88 expression. This effect was significantly inhibited in macrophages from TLR9 knockout mice and in human MDA-MB-231 breast cancer cells stably expressing TLR9 small interfering RNA or dominant-negative tumor necrosis factor receptor-associated factor 6 (TRAF6). Sequence modifications to the CpG oligonucleotides that targeted the stem loop and other secondary structures were shown to influence the invasion-inducing effect in MDA-MB-231 cells. In contrast, methylation of the cytosine residues of the parent CpG oligonucleotide did not affect the TLR9-mediated invasion compared with the unmethylated parent CpG oligonucleotide. Finally, expression of TLR9 was studied in clinical breast cancer samples and normal breast epithelium with immunohistochemistry. TLR9 staining localized in epithelial cells in both cancer and normal samples. The mean TLR9 staining intensity was significantly increased in the breast cancer cells compared with normal breast epithelial cells. In conclusion, our results suggest that TLR9 expression is increased in breast cancer and CpG oligonucleotide–induced cellular invasion is mediated via TLR9 and TRAF6, independent of MyD88. Further, our findings suggest that the structure and/or stability of DNA may influence the induction of TLR9-mediated invasion in breast cancer. (Mol Cancer Res 2008;6(10):1534–43)
Induction of Antiproliferative Connective Tissue Growth Factor Expression in Wilms' Tumor Cells by Sphingosine-1-Phosphate Receptor 2
Authors: Li Mei-Hong , Sanchez Teresa , Pappalardo Anna , Lynch Kevin R. , Hla Timothy , Ferrer Fernando 
Published: October 2008

Abstract
Connective tissue growth factor (CTGF), a member of the CCN family of secreted matricellular proteins, regulates fibrosis, angiogenesis, cell proliferation, apoptosis, tumor growth, and metastasis. However, the role of CTGF and its regulation mechanism in Wilms' tumor remains largely unknown. We found that the bioactive lipid sphingosine-1-phosphate (S1P) induced CTGF expression in a concentration- and time-dependent manner in a Wilms' tumor cell line (WiT49), whereas FTY720-phosphate, an S1P analogue that binds all S1P receptors except S1P2, did not. Further, the specific S1P2 antagonist JTE-013 completely inhibited S1P-induced CTGF expression, whereas the S1P1 antagonist VPC44116 did not, indicating that this effect was mediated by S1P2. This was confirmed by adenoviral transduction of S1P2 in WiT49 cells, which showed that overexpression of S1P2 increased the expression of CTGF. Induction of CTGF by S1P was sensitive to ROCK inhibitor Y-27632 and c-Jun NH2-terminal kinase inhibitor SP600125, suggesting the requirement of RhoA/ROCK and c-Jun NH2-terminal kinase pathways for S1P-induced CTGF expression. Interestingly, the expression levels of CTGF were decreased in 8 of 10 Wilms' tumor tissues compared with matched normal tissues by quantitative real-time PCR and Western blot analysis. In vitro, human recombinant CTGF significantly inhibited the proliferation of WiT49 cells. In addition, overexpression of CTGF resulted in significant inhibition of WiT49 cell growth. Taken together, these data suggest that CTGF protein induced by S1P2 might act as a growth inhibitor in Wilms' tumor. (Mol Cancer Res 2008;6(10):1649–56)
Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma
Authors: Yu Eun Jeong , Lee Young , Rha Sun Young , Kim Tae Soo , Chung Hyun Cheol , Oh Bong Kyeong , Yang Woo Ick , Noh Sung Hoon , Jeung Hei-Cheul 
Published: October 2008

Abstract
We investigated the biological role of thymidine phosphorylase (TP), an angiogenic factor, in gastric cancer cell migration and invasion and explored a therapeutic approach for high TP-expressing tumors using TP enzymatic inhibitor (TPI) and rapamycin. We established TP cDNA overexpressing gastric cancer cell lines (MKN-45/TP and YCC-3/TP) and did invasion and adhesion assays with Matrigel-coated transwell membranes. The related signal pathway using recombinant human TP (rhTP), deoxy-d-ribose (D-dRib), and signal pathway inhibitors (wortmannin, LY294002, and rapamycin) was investigated. First, AGS and MKN-1 gastric cancer cell lines showed dose-dependent up-regulation of invasiveness through Matrigel following treatment with rhTP or D-dRib. TP-overexpressing cancer cell lines displayed increased migration and invasion activity, which doubled with rhTP and D-dRib treatment. This activity depended on the enzymatic activity of TP, and TP stimulated the adhesion of cancer cells onto Matrigel and induced actin filament remodeling. Finally, we showed that this activity is related to increased phosphatidylinositol 3-kinase activity in TP-overexpressing cells and that combination treatment with rapamycin and TP enzymatic inhibitor produces an additive effect to abrogate TP-induced invasion. Taken together, TP increases the migration and invasion of gastric cancer cells, especially in TP-expressing cells. Therapies targeting TP might diminish the propensity for invasion and metastasis in gastric cancer. (Mol Cancer Res 2008;6(10):1554–66)
Potentiation of Temozolomide Cytotoxicity by Poly(ADP)Ribose Polymerase Inhibitor ABT-888 Requires a Conversion of Single-Stranded DNA Damages to Double-Stranded DNA Breaks
Authors: Liu Xuesong , Shi Yan , Guan Ran , Donawho Cherrie , Luo Yanping , Palma Joann , Zhu Gui-dong , Johnson Eric F. , Rodriguez Luis E. , Ghoreishi-Haack Nayereh , Jarvis Ken , Hradil Vincent P. , Colon-Lopez Milagros , Cox Bryan F. , Klinghofer Vered , Penning Thomas , Rosenberg Saul H. , Frost David , Giranda Vincent L. , Luo Yan 
Published: October 2008

Abstract
Poly(ADP-ribose) polymerase (PARP) senses DNA breaks and facilitates DNA repair via the polyADP-ribosylation of various DNA binding and repair proteins. We explored the mechanism of potentiation of temozolomide cytotoxicity by the PARP inhibitor ABT-888. We showed that cells treated with temozolomide need to be exposed to ABT-888 for at least 17 to 24 hours to achieve maximal cytotoxicity. The extent of cytotoxicity correlates with the level of double-stranded DNA breaks as indicated by γH2AX levels. In synchronized cells, damaging DNA with temozolomide in the presence of ABT-888 during the S phase generated high levels of double-stranded breaks, presumably because the single-stranded DNA breaks resulting from the cleavage of the methylated nucleotides were converted into double-stranded breaks through DNA replication. As a result, treatment of temozolomide and ABT-888 during the S phase leads to higher levels of cytotoxicity. ABT-888 inhibits poly(ADP-ribose) formation in vivo and enhances tumor growth inhibition by temozolomide in multiple models. ABT-888 is well tolerated in animal models. ABT-888 is currently in clinical trials in combination with temozolomide. (Mol Cancer Res 2008;6(10):1621–9)
RhoA Silencing Reverts the Resistance to Doxorubicin in Human Colon Cancer Cells
Authors: Doublier Sophie , Riganti Chiara , Voena Claudia , Costamagna Costanzo , Aldieri Elisabetta , Pescarmona Gianpiero , Ghigo Dario , Bosia Amalia 
Published: October 2008

AbstractThe efficacy of doxorubicin in the treatment of cancer is limited by its side effects and by the onset of drug resistance. Reverting such resistance could allow the decrease of the dose necessary to eradicate the tumor, thus diminishing the toxicity of the drug. We transfected doxorubicin-sensitive (HT29) and doxorubicin-resistant (HT29-dx) human colon cancer cells with RhoA small interfering RNA. The subsequent decrease of RhoA protein was associated with the increased sensitivity to doxorubicin in HT29 cells and the complete reversion of doxorubicin resistance in HT29-dx cells. RhoA silencing increased the activation of the nuclear factor-κB pathway, inducing the transcription and the activity of nitric oxide synthase. This led to the tyrosine nitration of the multidrug resistance protein 3 transporter (MRP3) and contributed to a reduced doxorubicin efflux. Moreover, RhoA silencing decreased the ATPase activity of P-glycoprotein (Pgp) in HT29 and HT29-dx cells as a consequence of the reduced expression of Pgp. RhoA silencing, by acting as an upstream controller of both MRP3 nitration and Pgp expression, was effective to revert the toxicity and accumulation of doxorubicin in both HT29 and HT29-dx cells. Therefore, we suggest that inactivating RhoA has potential clinical applications and might in the future become part of a gene therapy protocol. (Mol Cancer Res 2008;6(10):1607–20)
Employing Migrant Domestic Workers in Urban Yemen: A New Form of Social Distinction
Authors: de Regt Marina 
Published: October 2008

AbstractThis article argues that employing migrant domestic workers has become a new form of social distinction in urban Yemen. The rapid social, economic and political changes of the past forty years have altered Yemen's system of social stratification. Formerly, one's racial descent and economic background determined the work they performed. Manual and service professions had a very low status and were only performed by the lowest social status groups. Nowadays other forms of social distinction have emerged. Although the economic situation in Yemen has deteriorated since the 1990s, the demand for paid domestic labour has increased. Yemeni women are reluctant to take up paid work as domestics, and middle and upper middle class families in urban areas employ migrant and refugee women, in particular from the Horn of Africa.