bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of Hypoxia-Induced CXCR4 Triggering during B-Cell Development and Lymphomagenesis
Authors: Piovan Erich , Tosello Valeria , Indraccolo Stefano , Masiero Massimo , Persano Luca , Esposito Giovanni , Zamarchi Rita , Ponzoni Maurilio , Chieco-Bianchi Luigi , Dalla-Favera Riccardo , Amadori Alberto 
Published: September 2007

AbstractThe chemokine receptor CXCR4 plays a central role in organ-specific homing and tumor spreading and is induced by hypoxia. B lymphocytes are exposed to low oxygen tensions during their development, but the influence of hypoxia on their physiology is poorly understood. Here, we show that hypoxia is associated with up-regulation of CXCR4 expression in human normal and malignant B cells, through both transcriptional and posttranslational mechanisms. However, a dichotomic functional response to CXCR4 triggering was observed: both peripheral B cells and lymphomas arising from mature B cells displayed increased responses to CXCR4 triggering under hypoxia, whereas germinal center (GC) B cells as well as GC-derived lymphomas showed CXCR4 receptor desensitization. This phenomenon was associated with differential modulation of key signal-transducing molecules, including mitogen-activated protein kinase phosphatase-1 and regulator of G protein signaling molecule-1. The unresponsiveness of GC-derived lymphomatous B cells to CXCR4 triggering under hypoxia may have implications for the development and pathogenesis of GC-derived lymphoid tumors. [Cancer Res 2007;67(18):8605–14]
Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts
Authors: Chen Dong , Reierstad Scott , Lin Zhihong , Lu Meiling , Brooks Chris , Li Newton , Innes Joy , Bulun Serdar E. 
Published: September 2007

AbstractAromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E2 (PGE2), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)– and protein kinase C (PKC)–dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE2-stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE2 or its surrogate hormonal mixture dibutyryl cAMP (Bt2cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH2-terminal kinase (JNK)-1, and extracellular signal–regulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA–mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE2- or Bt2cAMP + PDA–induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wild-type p38α or JNK1 enhanced PGE2-stimulated aromatase expression via PII. PGE2 or Bt2cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKA-activating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE2 activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer. [Cancer Res 2007;67(18):8914–22]
Reactive Oxygen Species, DNA Damage, and Error-Prone Repair: A Model for Genomic Instability with Progression in Myeloid Leukemia?
Authors: Rassool Feyruz V. , Gaymes Terry J. , Omidvar Nader , Brady Nicola , Beurlet Stephanie , Pla Marika , Reboul Murielle , Lea Nicholas , Chomienne Christine , Thomas Nicholas S.B. , Mufti Ghulam J. , Padua Rose Ann 
Published: September 2007

Abstract
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML. [Cancer Res 2007;67(18):8762–71]
The Role of Platelet/Endothelial Cell Adhesion Molecule–1 (CD31) and CD38 Antigens in Marrow Microenvironmental Retention of Acute Myelogenous Leukemia Cells
Authors: Gallay Nathalie , Anani Ludovic , Lopez Adriana , Colombat Philippe , Binet Christian , Domenech Jorge , Weksler Babette B. , Malavasi Fabio , Herault Olivier 
Published: September 2007

AbstractIn acute myelogenous leukemia (AML), leukemic cell-microenvironment interactions within various niches (stromal/osteoblastic or sinusoidal endothelial cell niches) have a role in leukemia cell survival and drug resistance. The AML leukemic cells express platelet/endothelial cell adhesion molecule–1 (CD31) and CD38, two adhesion molecules that could interact with microenvironmental elements, i.e., CD31 on the surface of marrow endothelial cells (CD31/CD31 and CD38/CD31 interactions) and hyaluronate (CD38/hyaluronate interactions). We report a physical association of these two antigens on the plasma membrane of myeloid leukemic cells. In this context, in vitro experiments done using interaction-blocking anti-CD31 and anti-CD38 monoclonal antibodies (CLB-HEC75 and OKT10, respectively) indicate that an excess of CD31 on the cell membrane of leukemic cells (CD31/CD38 MFI ratio &gt;1) promotes a homotypic interaction with marrow endothelial cells, resulting in higher transendothelial migration. Conversely, an excess of CD38 (CD31/CD38 MFI ratio &lt;1) allows leukemic cells to be entrapped within the bone marrow microenvironment through hyaluronate adhesion. The results obtained in vitro using fluorescence resonance energy transfer, co-capping, and co-immunoprecipitation experiments, and hyaluronate adhesion and transendothelial migration assays, are supported by immunophenotypic characterization of marrow leukemic cells from 78 AML patients on which CD38 expression levels were found to be positively correlated with those of CD31. Importantly, the excess of CD31 in those samples was associated with a higher peripheral WBC count. These findings indicate that bone marrow retention of AML cells depends on CD31 and CD38 coexpression levels. [Cancer Res 2007;67(18):8624–32]
Activation of the Signal Transducers and Activators of the Transcription 3 Pathway in Alveolar Epithelial Cells Induces Inflammation and Adenocarcinomas in Mouse Lung
Authors: Li Yuan , Du Hong , Qin Yulin , Roberts Jennifer , Cummings Oscar W. , Yan Cong 
Published: September 2007

AbstractThe lung is an organ for host defense to clear up pathogens through innate and adaptive immunity. This process involves up-regulation of proinflammatory cytokines and chemokines that lead to activation of the signal transducers and activators of the transcription 3 (Stat3) signaling pathway. Overexpression of Stat3C in alveolar type II epithelial cells of CCSP-rtTA/(tetO)7-Stat3C bitransgenic mice leads to severe pulmonary inflammation, including immune cell infiltration and up-regulation of proinflammatory cytokines and chemokines in the lung. As a consequence, spontaneous lung bronchoalveolar adenocarcinoma was observed in bitransgenic mice. Aberrantly expressed genes in the bitransgenic model were identified and served as biomarkers for human bronchoalveolar adenocarcinoma. During tumorigenesis, genes that are critical to epithelial cell proliferation in lung development were reactivated. Therefore, Stat3 is a potent proinflammatory molecule that directly causes spontaneous lung cancer in vivo. [Cancer Res 2007;67(18):8494–503]
Lupeol Suppresses Cisplatin-Induced Nuclear Factor-κB Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model
Authors: Lee Terence K. , Poon Ronnie T.P. , Wo Jana Y. , Ma Stephanie , Guan Xin-Yuan , Myers Jeffrey N. , Altevogt Peter , Yuen Anthony P.W. 
Published: September 2007

Abstract
A poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients is commonly associated with the presence of regional metastasis. Cisplatin-based chemotherapy concurrent with radiation therapy is commonly used in the treatment of locally advanced HNSCC. However, the result is dismal due to common acquisition of chemoresistance and radioresistance. Epidemiologic studies have shown the importance of dietary substances in the prevention of HNSCC. Here, we found that lupeol, a triterpene found in fruits and vegetables, selectively induced substantial HNSCC cell death but exhibited only a minimal effect on a normal tongue fibroblast cell line in vitro. Down-regulation of NF-κB was identified as the major mechanism of the anticancer properties of lupeol against HNSCC. Lupeol alone was not only found to suppress tumor growth but also to impair HNSCC cell invasion by reversal of the NF-κB–dependent epithelial-to-mesenchymal transition. Lupeol exerted a synergistic effect with cisplatin, resulting in chemosensitization of HNSCC cell lines with high NF-κB activity in vitro. In in vivo studies, using an orthotopic metastatic nude mouse model of oral tongue squamous cell carcinoma, lupeol at a dose of 2 mg/animal dramatically decreased tumor volume and suppressed local metastasis, which was more effective than cisplatin alone. Lupeol exerted a significant synergistic cytotoxic effect when combined with low-dose cisplatin without side effects. Our results suggest that lupeol may be an effective agent either alone or in combination for treatment of advanced tumors. [Cancer Res 2007;67(18):8800–9]
RAV12 Accelerates the Desensitization of Akt/PKB Pathway of Insulin-like Growth Factor I Receptor Signaling in COLO205
Authors: Chi-Hang Li Jonathan , Li Ronghao 
Published: September 2007

Abstract
RAV12 is a high-affinity immunoglobulin G1 (IgG1) chimeric antibody recognizing an N-linked carbohydrate epitope expressed on a number of human carcinomas and adenocarcinomas. RAV12 is efficacious in treating colon, gastric, and pancreatic tumors in xenograft models in vivo. Insulin-like growth factor-I receptor (IGF-IR) is a protein widely overexpressed in tumor-derived cell lines that promotes cell survival and prevents apoptosis. We found the RAV12 epitope (RAAG12) decorated the IGF-IR proteins of RAV12-responsive cell lines such as COLO201, COLO205, and SNU-16. Here, we report findings of IGF-IR signaling manipulation by RAV12. We found that RAV12 caused a significantly accelerated IGF-I–mediated IGF-IR phosphorylation and desensitization in COLO205. We also observed significant changes in some of the major downstream signaling components of IGF-IR. Data suggested that RAV12 treatment accelerated the desensitization of Akt/PKB through IRS1, and such activation could be attenuated by Tyrphostin AG538 (IGF-IR inhibitor), LY294002, or Wortmannin (phosphoinositide-3-kinase inhibitor). Furthermore, RAV12-inhibited IGF-I stimulated COLO205 growth, and the inhibition could be significantly augmented by mitogen-activated protein kinase inhibitor. [Cancer Res 2007;67(18):8856–64]
Efficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX
Authors: Hu Baoli , Gilkes Daniele M. , Chen Jiandong 
Published: September 2007

Abstract
The p53 tumor suppressor plays a key role in protection against malignant transformation. MDM2 and MDMX are important regulators of the transcriptional activity and stability of p53 by binding to its NH2 terminus. Recent studies suggest that inhibition of both MDM2 and MDMX is necessary for robust activation of p53 in certain tumor cells. However, small-molecule MDM2 inhibitors such as Nutlin fail to inhibit MDMX despite significant homology between the two proteins. The therapeutic efficacy of such compounds may be compromised by MDMX overexpression. To evaluate the feasibility and biological effects of simultaneously disrupting p53 binding to MDM2 and MDMX, we used phage display to identify a novel peptide that can inhibit p53 interactions with MDM2 (IC50 = 10 nmol/L) and MDMX (IC50 = 100 nmol/L). Expression of a scaffold protein (thioredoxin) displaying this peptide sequence by adenovirus disrupts both MDM2 and MDMX interaction with p53, resulting in efficient p53 activation, cell cycle arrest, and apoptosis of tumor cells overexpressing MDM2 and MDMX. Intratumoral injection of the adenovirus also induces growth suppression of tumor xenografts in mice in a p53-dependent fashion. These results show the therapeutic potential of targeting both MDM2 and MDMX in cancer, and provide a novel structural motif for the design of potent p53 activators. [Cancer Res 2007;67(18):8810–7]
Topoisomerase IIβ–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane
Authors: Lyu Yi Lisa , Kerrigan John E. , Lin Chao-Po , Azarova Anna M. , Tsai Yuan-Chin , Ban Yi , Liu Leroy F. 
Published: September 2007

Abstract
Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal γ-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2β−/− mouse embryonic fibroblasts (MEF) compared with TOP2β+/+ MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIβ (Top2β). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2β, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2β, which could implicate Top2β in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2β in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2β-DNA covalent complexes exposes the Top2β-concealed DNA double-strand breaks. [Cancer Res 2007;67(18):8839–46]
Aberrant Huntingtin Interacting Protein 1 in Lymphoid Malignancies
Authors: Bradley Sarah V. , Smith Mitchell R. , Hyun Teresa S. , Lucas Peter C. , Li Lina , Antonuk Danielle , Joshi Indira , Jin Fang , Ross Theodora S. 
Published: September 2007

Abstract
Huntingtin interacting protein 1 (HIP1) is an inositol lipid, clathrin, and actin binding protein that is overexpressed in a variety of epithelial malignancies. Here, we report for the first time that HIP1 is elevated in non–Hodgkin's and Hodgkin's lymphomas and that patients with lymphoid malignancies frequently had anti-HIP1 antibodies in their serum. Moreover, p53-deficient mice with B-cell lymphomas were 13 times more likely to have anti-HIP1 antibodies in their serum than control mice. Furthermore, transgenic overexpression of HIP1 was associated with the development of lymphoid neoplasms. The HIP1 protein was induced by activation of the nuclear factor-κB pathway, which is frequently activated in lymphoid malignancies. These data identify HIP1 as a new marker of lymphoid malignancies that contributes to the transformation of lymphoid cells in vivo. [Cancer Res 2007;67(18):8923–31]
Integrative Genomic Analysis of Phosphatidylinositol 3′-Kinase Family Identifies PIK3R3 as a Potential Therapeutic Target in Epithelial Ovarian Cancer
Authors: Zhang Lin , Huang Jia , Yang Nuo , Greshock Joel , Liang Shun , Hasegawa Kosei , Giannakakis Antonis , Poulos Nikolaos , O'Brien-Jenkins Ann , Katsaros Dionyssios , Butzow Ralf , Weber Barbara L. , Coukos George 
Published: September 2007

Abstract
Purpose: The phosphatidylinositol 3′-kinase (PI3K) family plays a key regulatory role in various cancer-associated signal transduction pathways. Here, we investigated the genomic alterations and gene expression of most known PI3K family members in human epithelial ovarian cancer.
Experimental Design: The DNA copy number of PI3K family genes was screened by a high-resolution array comparative genomic hybridization in 89 human ovarian cancer specimens. The mRNA expression level of PI3K genes was analyzed by microarray retrieval approach, and further validated by real-time reverse transcription-PCR. The expression of p55γ protein in ovarian cancer was analyzed on tissue arrays. Small interfering RNA was used to study the function of PIK3R3 in ovarian cancer.
Results: In ovarian cancer, 6 of 12 PI3K genes exhibited significant DNA copy number gains (&gt;20%), including PIK3CA (23.6%), PIK3CB (27.0%), PIK3CG (25.8%), PIK3R2 (29.2%), PIK3R3 (21.3%), and PIK3C2B (40.4%). Among those, only PIK3R3 had significantly up-regulated mRNA expression level in ovarian cancer compared with normal ovary. Up-regulated PIK3R3 mRNA expression was also observed in liver, prostate, and breast cancers. The PIK3R3 mRNA expression level was significantly higher in ovarian cancer cell lines (n = 18) than in human ovarian surface epithelial cells (n = 6, P = 0.002). Overexpression of p55γ protein in ovarian cancer was confirmed by tissue array analysis. In addition, we found that knockdown of PIK3R3 expression by small interfering RNA significantly increased the apoptosis in cultured ovarian cancer cell lines.
Conclusion: We propose that PIK3R3 may serve as a potential therapeutic target in human ovarian cancer.
Prognostic Value of Preoperative Serum Cell-Free Circulating DNA in Men with Prostate Cancer Undergoing Radical Prostatectomy
Authors: Bastian Patrick J. , Palapattu Ganesh S. , Yegnasubramanian Srinivasan , Lin Xiaohui , Rogers Craig G. , Mangold Leslie A. , Trock Bruce , Eisenberger Mario , Partin Alan W. , Nelson William G. 
Published: September 2007

AbstractPurpose: We evaluated the association of preoperative serum cell-free circulating DNA concentration in men with clinically localized prostate cancer who underwent radical prostatectomy with prostate-specific antigen (PSA) recurrence.Experimental Design: One hundred and ninety-two men with clinically localized prostate cancer, who underwent radical prostatectomy at the Johns Hopkins Hospital and had preoperative serum available for analyses constituted our study population. All serum samples were collected before prostate biopsy or at least 4 months after prostate biopsy. The total amount of serum cell-free circulating DNA from each sample was calculated using a standard curve generated via quantitative real-time PCR. PSA recurrence was defined as a single postoperative PSA level of ≥0.2. The natural logarithm (ln) of the DNA concentration was used for statistical analyses.Results: Of the 192 men in our study, 56 (29%) experienced PSA recurrence within the study period (median time to PSA recurrence 2 years). The median follow-up time for men free of disease at last follow-up was 3 years. The median serum cell-free DNA concentration of all men in the study was 5.3 ng/mL (mean 18.05 ng/mL; range 0.2-320 ng/mL). The mean serum DNA concentration for men who recurred and for those who did not was 3.8 ± 34.1 and 13.7 ± 33.6 ng/mL, respectively (P = 0.001). In a univariate analysis, ln DNA concentration was significantly associated with PSA recurrence (hazard ratio, 1.49; 95% confidence interval, 1.3-1.8; P &lt; 0.001). In the multivariate model, ln DNA concentration was significantly associated with PSA recurrence (hazard ratio, 2.56; 95% confidence interval, 1.1-1.6; P = 0.003). Using bootstrap analyses, serum cell-free DNA concentrations ≥5.75 ng/mL were associated with an increased risk of PSA recurrence within 2 years of radical prostatectomy.Conclusion: Our study suggests that preoperative serum cell-free DNA concentration may be a useful prognostic biomarker for men with clinically localized prostate cancer treated with radical prostatectomy.
Comparison of Gene Sets for Expression Profiling: Prediction of Metastasis from Low-Malignant Breast Cancer
Authors: Thomassen Mads , Tan Qihua , Eiriksdottir Freyja , Bak Martin , Cold Søren , Kruse Torben A. 
Published: September 2007

Abstract
Purpose: In the low-risk group of breast cancer patients, a subgroup experiences metastatic recurrence of the disease. The aim of this study was to examine the performance of gene sets, developed mainly from high-risk tumors, in a group of low-malignant tumors.
Experimental Design: Twenty-six tumors from low-risk patients and 34 low-malignant T2 tumors from patients with slightly higher risk have been examined by genome-wide gene expression analysis. Nine prognostic gene sets were tested in this data set.
Results: A 32-gene profile (HUMAC32) that accurately predicts metastasis has previously been developed from this data set. In the present study, six of the eight other gene sets have prognostic power in the low-malignant patient group, whereas two have no prognostic value. Despite a relatively small overlap between gene sets, there is high concordance of classification of samples. This, together with analysis of functional gene groups, indicates that the same pathways may be represented by several of the gene sets. However, the results suggest that low-risk patients may be classified more accurately with gene signatures developed especially for this patient group.
Conclusion: Several gene sets, mainly developed in high-risk cancers, predict metastasis from low-malignant cancer.