bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses
Authors: Ebi Hiromichi , Tomida Shuta , Takeuchi Toshiyuki , Arima Chinatsu , Sato Takahiko , Mitsudomi Tetsuya , Yatabe Yasushi , Osada Hirotaka , Takahashi Takashi 
Published: April 2009

Abstract
There is marked disparity with a slight overlap among prognosis-predictive signatures reported thus far for lung cancers. In this study, we aimed at linking poor prognosis with particular pathways and/or functions of the gene sets involved to better understand the underlying molecular characteristics associated with the prognosis of lung adenocarcinomas. Gene set enrichment analysis identified a gene set down-regulated by rapamycin as the most significant, whereas several others responsive to withdrawal of glucose or amino acids, which are related to signaling converging onto mammalian target of rapamycin (mTOR), were also shown to be significantly associated, in addition to those related to DNA damage response and cell cycle progression. We also used connectivity map (C-MAP) analysis, an independent bioinformatics approach, to search for Food and Drug Administration–approved drugs that potentially transform an unfavorable signature to a favorable one. Those results identified inhibitors of phosphatidylinositol 3-kinase (PI3K) and mTOR, as well as unexpected drugs such as phenothiazine antipsychotics and resveratrol as potential candidates. Experimental validation revealed that the latter unexpected agents also inhibited signaling converging onto mTOR and exhibited antitumor activities. In addition, deregulation of multiple signaling converging onto mTOR was shown to be significantly associated with sensitivity to PI-103, a dual specificity PI3K/mTOR inhibitor that is not contained in the C-MAP database, lending further support for the connection. Our results clearly show the existence of gene set–definable, intrinsic heterogeneities in lung adenocarcinomas, which seem to be related to both clinical behavior and sensitivity to agents affecting the identified pathways. [Cancer Res 2009;69(9):4027–35]
eIF4E Activation Is Commonly Elevated in Advanced Human Prostate Cancers and Significantly Related to Reduced Patient Survival
Authors: Graff Jeremy R. , Konicek Bruce W. , Lynch Rebecca L. , Dumstorf Chad A. , Dowless Michele S. , McNulty Ann M. , Parsons Stephen H. , Brail Leslie H. , Colligan Bruce M. , Koop Jonathan W. , Hurst Bernadette M. , Deddens James A. , Neubauer Blake L. , Stancato Louis F. , Carter Harry W. , Douglass Larry E. , Carter Julia H. 
Published: April 2009

Abstract
Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy. [Cancer Res 2009;69(9):3866–73]
Expansion of Highly Cytotoxic Human Natural Killer Cells for Cancer Cell Therapy
Authors: Fujisaki Hiroyuki , Kakuda Harumi , Shimasaki Noriko , Imai Chihaya , Ma Jing , Lockey Timothy , Eldridge Paul , Leung Wing H. , Campana Dario 
Published: April 2009

AbstractInfusions of natural killer (NK) cells are an emerging tool for cancer immunotherapy. The development of clinically applicable methods to produce large numbers of fully functional NK cells is a critical step to maximize the potential of this approach. We determined the capacity of the leukemia cell line K562 modified to express a membrane-bound form of interleukin (IL)-15 and 41BB ligand (K562-mb15-41BBL) to generate human NK cells with enhanced cytotoxicity. Seven-day coculture with irradiated K562-mb15-41BBL induced a median 21.6-fold expansion of CD56+CD3- NK cells from peripheral blood (range, 5.1- to 86.6-fold; n = 50), which was considerably superior to that produced by stimulation with IL-2, IL-12, IL-15, and/or IL-21 and caused no proliferation of CD3+ lymphocytes. Similar expansions could also be obtained from the peripheral blood of patients with acute leukemia undergoing therapy (n = 11). Comparisons of the gene expression profiles of the expanded NK cells and their unstimulated or IL-2–stimulated counterparts showed marked differences. The expanded NK cells were significantly more potent than unstimulated or IL-2–stimulated NK cells against acute myeloid leukemia cells in vitro. They could be detected for &gt;1 month when injected into immunodeficient mice and could eradicate leukemia in murine models of acute myeloid leukemia. We therefore adapted the K562-mb15-41BBL stimulation method to large-scale clinical-grade conditions, generating large numbers of highly cytotoxic NK cells. The results that we report here provide rationale and practical platform for clinical testing of expanded and activated NK cells for cell therapy of cancer. [Cancer Res 2009;69(9):4010–7]
FOXP3 Defines Regulatory T Cells in Human Tumor and Autoimmune Disease
Authors: Kryczek Ilona , Liu Rebecca , Wang Guobin , Wu Ke , Shu Xiaogong , Szeliga Wojciech , Vatan Linhua , Finlayson Emily , Huang Emina , Simeone Diane , Redman Bruce , Welling Theodore H. , Chang Alfred , Zou Weiping 
Published: April 2009

Abstract
Activated T cells may express FOXP3. It is thought that FOXP3 is not a specific marker to determine regulatory T cells (Treg) in humans. Here, we examined the functional phenotype and cytokine profile of the in vitro induced FOXP3+ T cells, primary FOXP3+ and FOXP3- T cells in patients with ulcerative colitis and tumors including colon carcinoma, melanoma, hepatic carcinoma, ovarian carcinoma, pancreatic cancer, and renal cell carcinoma. We observed similar levels of suppressive capacity of primary FOXP3+ T cells in blood, tumors, and colitic tissues. Compared with primary FOXP3- T cells in the same microenvironment, these primary FOXP3+ T cells expressed minimal levels of effector cytokines, negligible amount of cytotoxic molecule granzyme B, and levels of suppressive molecules interleukin-10 and PD-1. Although the in vitro activated T cells expressed FOXP3, these induced FOXP3+ T cells expressed high levels of multiple effector cytokines and were not functionally suppressive. The data reinforce the fact that FOXP3 remains an accurate marker to define primary Tregs in patients with cancer and autoimmune disease. We suggest that the combination of FOXP3 and cytokine profile is useful for further functionally distinguishing primary Tregs from activated conventional T cells. [Cancer Res 2009;69(9):3995–4000]
Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas
Authors: Kuo Kuan-Ting , Guan Bin , Feng Yuanjian , Mao Tsui-Lien , Chen Xu , Jinawath Natini , Wang Yue , Kurman Robert J. , Shih Ie-Ming , Wang Tian-Li 
Published: April 2009

Abstract
Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, is thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations, whereas low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain unknown. In addition, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG, and HG tumors using high-density 250K single nucleotide polymorphism arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions, including homozygous deletions, were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4%, and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except for the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profile in HG serous carcinomas, which can serve as a molecular foundation to study tumor suppressors in ovarian cancer. [Cancer Res 2009;69(9):4036–42]
Identification of Smyd4 as a Potential Tumor Suppressor Gene Involved in Breast Cancer Development
Authors: Hu Liping , Zhu Yiwei Tony , Qi Chao , Zhu Yi-Jun 
Published: April 2009

Abstract
To identify genes involved in breast tumorigenesis, we applied the retroviral LoxP-Cre system to a nontumorigenic mouse mammary epithelial cell line NOG8 to create random chromosome deletion/translocation. We found that the disruption of one allele of Smyd4 (SET and MYND domain containing 4) gene through chromosome translocation led to tumorigenesis. The expression of Smyd4 was markedly decreased in tumor cells. Re-expression of Smyd4 resulted in growth suppression of tumor cells and inhibition of tumor formation in nude mice. Furthermore, the RNA interference–mediated suppression of Smyd4 expression in human MCF10A mammary epithelial cells caused their growth in soft agar. Microarray studies revealed that platelet-derived growth factor receptor α polypeptide (Pdgfr-α) was highly expressed in tumor cells compared with NOG8 cells. Re-expression of Smyd4 significantly reduced the expression of Pdgfr-α in tumor cells. In human breast cancers, reverse transcription-PCR results revealed that Smyd4 expression was totally silenced in 2 of 10 specimens. These findings indicate that Smyd4, as a potential tumor suppressor, plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfr-α, and could be a novel target for improving treatment of breast cancer. [Cancer Res 2009;69(9):4067–72]
CD38/CD31, the CCL3 and CCL4 Chemokines, and CD49d/Vascular Cell Adhesion Molecule-1 Are Interchained by Sequential Events Sustaining Chronic Lymphocytic Leukemia Cell Survival
Authors: Zucchetto Antonella , Benedetti Dania , Tripodo Claudio , Bomben Riccardo , Dal Bo Michele , Marconi Daniela , Bossi Fleur , Lorenzon Debora , Degan Massimo , Rossi Francesca Maria , Rossi Davide , Bulian Pietro , Franco Vito , Del Poeta Giovanni , Deaglio Silvia , Gaidano Gianluca , Tedesco Francesco , Malavasi Fabio , Gattei Valter 
Published: April 2009

AbstractCD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ versus CD38−CD49d− CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38−CD49d− cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor α overproduction. These effects were apparent in BMB from CD38+CD49d+ CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells. [Cancer Res 2009;69(9):4001–9]
The Steroid Receptor Coactivator-1 Regulates Twist Expression and Promotes Breast Cancer Metastasis
Authors: Qin Li , Liu Zhaoliang , Chen Hongwu , Xu Jianming 
Published: April 2009

Abstract
In breast cancer, steroid receptor coactivator-1 (SRC-1) expression positively correlates with HER2 expression and poor prognosis. In mouse mammary tumor virus–polyoma middle T (PyMT) breast cancer mouse model, SRC-1 strongly promotes mammary tumor metastasis. However, the molecular targets and mechanisms that mediate the role of SRC-1 in metastasis are unknown. In this study, SRC-1 wild-type (WT) and knockout (KO) cell lines were developed from the mammary tumors of WT/PyMT and KO/PyMT mice. WT cells exhibited strong migration and invasion capabilities, reduced E-cadherin and β-catenin epithelial markers, gained N-cadherin and vimentin mesenchymal markers, and formed undifferentiated invasive structures in three-dimensional culture. In contrast, KO cells showed slow migration and invasion, retained E-cadherin, had less N-cadherin and vimentin, and developed partially differentiated three-dimensional structures. Importantly, WT cells expressed Twist, a master regulator of metastasis, at significantly higher levels versus KO cells. SRC-1 knockdown in WT cells reduced Twist expression, whereas SRC-1 restoration in KO cells also rescued Twist expression. Furthermore, SRC-1 was found to coactivate Twist transcription through physical interaction with the transcription factor PEA3 at the proximal Twist promoter. Accordingly, Twist knockdown in WT cells increased E-cadherin and reduced cell invasion and metastasis, and Twist expression in KO cells decreased E-cadherin and increased cell invasion. SRC-1 knockdown in human breast cancer cells also decreased Twist, cell migration, and invasion. Therefore, SRC-1 promotes breast cancer invasiveness and metastasis by coactivating PEA3-mediated Twist expression. Intervention of SRC-1 function may provide new strategies to inhibit breast cancer metastasis. [Cancer Res 2009;69(9):3819–27]
Development of a Multiplex Quantitative PCR Signature to Predict Progression in Non–Muscle-Invasive Bladder Cancer
Authors: Wang Rou , Morris David S. , Tomlins Scott A. , Lonigro Robert J. , Tsodikov Alexander , Mehra Rohit , Giordano Thomas J. , Kunju L. Priya , Lee Cheryl T. , Weizer Alon Z. , Chinnaiyan Arul M. 
Published: April 2009

Abstract
In bladder cancer, clinical grade and stage fail to capture outcome. We developed a clinically applicable quantitative PCR (QPCR) gene signature to predict progression in non–muscle-invasive bladder cancer. Comparative metaprofiling of 12 DNA microarray data sets (comprising 631 samples and 241,298 probe sets) identified 96 genes, which showed differential expression in seven clinical outcome categories, or were identified as outliers, historic markers, or housekeeping genes. QPCR was done to determine mRNA expression from 96 bladder tumors. Fifty-seven genes differentiated T2 from non-T2 tumors (P &lt; 0.05). Principal components analysis and Cox regression models were used to predict probability of T2 progression for non-T2 patients, placing them into high- and low-risk groups based on their gene expression. At 2 years, high-risk patients exhibited greater T2 progression (45% for high-risk patients versus 12% for low-risk patients; P = 0.003, log-rank test). This difference remained significant within T1 tumors (61% for high-risk patients versus 22% for low-risk patients; P = 0.02) and Ta tumors (29% for high-risk patients versus 0% for low-risk patients; P = 0.03). The best multivariate Cox model included stage and gender, and this signature provided predictive improvement over both (P = 0.002, likelihood ratio test). Immunohistochemistry was done for two genes in the signature not previously described in bladder cancer, ACTN1 and CDC25B, corroborating their up-regulation at the protein level with disease progression. Thus, we identified a 57-gene QPCR panel to help predict progression of non–muscle-invasive bladder cancers and delineate a systematic, generalizable approach to converting microarray data into a multiplex assay for cancer progression. [Cancer Res 2009;69(9):3810–8]
Transcription Inhibition of Heat Shock Proteins: A Strategy for Combination of 17-Allylamino-17-Demethoxygeldanamycin and Actinomycin D
Authors: Cervantes-Gomez Fabiola , Nimmanapalli Ramadevi , Gandhi Varsha 
Published: April 2009

Abstract
The heat shock protein (HSP) 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical trials because of its unique mechanism of action and antitumor activity. However, 17-AAG triggers the transcription and elevation of antiapoptotic HSP90, HSP70, and HSP27, which lead to chemoresistance in tumor cells. We hypothesized that inhibiting HSP90, HSP70, and HSP27 transcription may enhance 17-AAG–induced cell death in multiple myeloma cell lines. Actinomycin D (Act D), a clinically used agent and transcription inhibitor, was combined with 17-AAG. The concentrations for 17-AAG and Act D were selected based on the target actions and plasma levels during therapy. Inducible and constitutive HSP27, HSP70, and HSP90 mRNA and protein levels were measured by real-time reverse transcription-PCR and immunoblot assays. Compared with no treatment, Act D alone decreased HSP mRNA levels in MM.1S and RPMI-8226 cell lines. Combining Act D with 17-AAG did not attenuate 17-AAG–mediated increases in transcript levels of inducible HSP70; however, constitutive HSP mRNA levels were decreased. In contrast to its effect on mRNA levels, Act D was able to abrogate 17-AAG–mediated increases in all HSP protein levels. The cytotoxicity of combined Act D and 17-AAG was assessed. Treatment with Act D alone caused &lt;40% cell death, whereas the combination of 17-AAG and Act D resulted in an increase of cell death in both multiple myeloma cell lines. In conclusion, these results indicate that 17-AAG–mediated induction of HSP70 and HSP27 expression can be attenuated by Act D and therefore can potentially improve the clinical treatment of multiple myeloma. [Cancer Res 2009;69(9):3947–54]
Associations between α-Tocopherol, β-Carotene, and Retinol and Prostate Cancer Survival
Authors: Watters Joanne L. , Gail Mitchell H. , Weinstein Stephanie J. , Virtamo Jarmo , Albanes Demetrius 
Published: April 2009

Abstract
Previous studies suggest that carotenoids and tocopherols (vitamin E compounds) may be inversely associated with prostate cancer risk, yet little is known about how they affect prostate cancer progression and survival. We investigated whether serum α-tocopherol, β-carotene, and retinol concentrations, or the α-tocopherol and β-carotene trial supplementation, affected survival of men diagnosed with prostate cancer during the α-Tocopherol, β-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial testing the effects of β-carotene and α-tocopherol supplements on cancer incidence in adult male smokers in southwestern Finland (n = 29,133). Prostate cancer survival was examined using the Kaplan-Meier method with deaths from other causes treated as censoring, and using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CI) adjusted for family history of prostate cancer, age at randomization, benign prostatic hyperplasia, age and stage at diagnosis, height, body mass index, and serum cholesterol. As of April 2005, 1,891 men were diagnosed with prostate cancer and 395 died of their disease. Higher serum α-tocopherol at baseline was associated with improved prostate cancer survival (HR, 0.67; 95% CI, 0.45–1.00), especially among cases who had received the α-tocopherol intervention of the trial and who were in the highest quintile of α-tocopherol at baseline (HR, 0.51; 95% CI, 0.20–0.90) or at the 3-year follow-up measurement (HR, 0.26; 95% CI, 0.09–0.71). Serum β-carotene, serum retinol, and supplemental β-carotene had no apparent effects on survival. These findings suggest that higher α-tocopherol (and not β-carotene or retinol) status increases overall prostate cancer survival. Further investigations, possibly including randomized studies, are needed to confirm this observation. [Cancer Res 2009;69(9):3833–41]
Genetic Variation in B-Cell–Activating Factor Is Associated with an Increased Risk of Developing B-Cell Non–Hodgkin Lymphoma
Authors: Novak Anne J. , Slager Susan L. , Fredericksen Zachary S. , Wang Alice H. , Manske Michelle M. , Ziesmer Steven , Liebow Mark , Macon William R. , Dillon Stacey R. , Witzig Thomas E. , Cerhan James R. , Ansell Stephen M. 
Published: April 2009

Abstract
Elevated B-cell–activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non–Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P &lt; 0.05). When categorized into low-, moderate-, and high-risk groups based on risk alleles, we found the permutation-corrected odds ratio for the trend to be 1.43 (P = 0.0019) for risk of B-cell NHL, 1.69 (P = 0.0093) for diffuse large B-cell lymphoma, 1.43 (P = 0.029) for follicular lymphoma, and 1.06 (P = 0.21) for chronic lymphocytic leukemia/small lymphocytic lymphoma. The mean serum BAFF level in those who carried the low-risk alleles was 2 ng/mL compared with 4.3 ng/mL in those with the high-risk alleles (P = 0.02). Taken together, our data suggest that genetic variation in the TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels. [Cancer Res 2009;69(10):4217–24]