bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-221 Targets Bmf in Hepatocellular Carcinoma and Correlates with Tumor Multifocality
Authors: Gramantieri Laura , Fornari Francesca , Ferracin Manuela , Veronese Angelo , Sabbioni Silvia , Calin George Adrian , Grazi Gian Luca , Croce Carlo Maria , Bolondi Luigi , Negrini Massimo 
Published: August 2009

Abstract
Deregulated cell proliferation and apoptosis play a major role in hepatocellular carcinoma (HCC). MicroRNAs participate in the modulation of key molecules linked to hepatocarcinogenesis.
Purpose: This study aims to investigate the role of miR-221 in the modulation of Bmf, a proapoptotic BH3-only protein, and to characterize miR-221 contribution to hepatocarcinogenesis through modulation of apoptosis.
Experimental Design: Transfection of miR-221 and anti-miR-221 in HCC-derived cell lines and luciferase reporter assay were used to assess Bmf as a target of miR-221. Modulation of miR-221 and Bmf expression contributed to characterize their role in anoikis. Primary HCC tissues were analyzed to assess the clinical relevance of in vitro findings.
Results: Enforced miR-221 expression caused Bmf down-regulation, whereas anti-miR-221 induced its up-regulation. A luciferase reporter assay confirmed Bmf as a target of miR-221. Following matrix detachment, miR-221 silencing led to increased apoptotic cell death. The analysis of HCC tissues revealed an inverse correlation between miR-221 and Bmf expression and a direct correlation between Bmf and activated caspase-3, as a marker of apoptosis. High miR-221 levels were associated with tumor multifocality and reduced time to recurrence after surgery.
Conclusions: Our results indicate that miR-221, by targeting Bmf, inhibits apoptosis. Moreover, in HCC, miR-221 overexpression is associated with a more aggressive phenotype. These findings, together with the previously reported modulation of CDKN1B/p27 and CDKN1C/p57, show that miR-221 simultaneously affects multiple pro-oncogenic pathways and suggest miR-221 as a potential target for nonconventional treatment against HCC. (Clin Cancer Res 2009;15(16):5073–81)
Heat Shock Protein 90 Inhibitor BIIB021 (CNF2024) Depletes NF-κB and Sensitizes Hodgkin's Lymphoma Cells for Natural Killer Cell–Mediated Cytotoxicity
Authors: Böll Boris , Eltaib Farag , Reiners Katrin S. , von Tresckow Bastian , Tawadros Samir , Simhadri Venkateswara R. , Burrows Francis J. , Lundgren Karen , Hansen Hinrich P. , Engert Andreas , Pogge von Strandmann Elke 
Published: August 2009

Abstract
Purpose: In Hodgkin's lymphoma, constitutive activation of NF-κB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-κB in Hodgkin's lymphoma cells.
Experimental Design: We analyzed the effect of HSP90 inhibition on viability and NF-κB activity in Hodgkin's lymphoma cells and the consequences for their recognition and killing through natural killer (NK) cells.
Results: The novel orally administrable HSP90 inhibitor BIIB021 (CNF2024) inhibited Hodgkin's lymphoma cell viability at low nanomolar concentrations in synergy with doxorubicin and gemcitabine. Annexin V/7-aminoactinomycin D binding assay revealed that BIIB021 selectively induced cell death in Hodgkin's lymphoma cells but not in lymphocytes from healthy individuals. We observed that BIIB021 inhibited the constitutive activity of NF-κB and this was independent of IκB mutations. Furthermore, we analyzed the effect of HSP90 inhibition on NK cell–mediated cytotoxicity. BIIB021 induced the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell–mediated killing. In a xenograft model of Hodgkin's lymphoma, HSP90 inhibition significantly delayed tumor growth.
Conclusions: HSP90 inhibition has direct antitumor activity in Hodgkin's lymphoma in vitro and in vivo. Moreover, HSP90 inhibition may sensitize Hodgkin's lymphoma cells for NK cell–mediated killing via up-regulation of ligands engaging activating NK cell receptors. (Clin Cancer Res 2009;15(16):5108–16)
CD133+ Glioblastoma Stem-like Cells are Radiosensitive with a Defective DNA Damage Response Compared with Established Cell Lines
Authors: McCord Amy M. , Jamal Muhammad , Williams Eli S. , Camphausen Kevin , Tofilon Philip J. 
Published: August 2009

Abstract
Purpose: CD133+ glioblastoma tumor stem-like cells (TSC) have been defined as radioresistant. However, although previously classified relative to CD133− cells, the radiosensitivity of CD133+ TSCs with respect to the standard glioblastoma model, established glioma cell lines, has not been determined. Therefore, to better understand the radioresponse of this cancer stem cell, we have used established cell lines as a framework for defining their in vitro radioresponse.
Experimental Design: The intrinsic radiosensitivity of CD133+ TSC cultures and established glioma cell lines was determined by clonogenic assay. The TSCs and established cell lines were also compared in terms of DNA double-strand break (DSB) repair capacity and cell cycle checkpoint activation.
Results: Based on clonogenic analysis, each of the six TSC cultures evaluated was more sensitive to radiation than the established glioma cell lines. Consistent with increased radiosensitivity, the DSB repair capacity as defined by neutral comet assay and γH2AX and Rad51 foci was significantly reduced in TSCs compared with the cell lines. Although G2 checkpoint activation was intact, in contrast to the cell lines, DNA synthesis was not inhibited in TSCs after irradiation, indicating the absence of the intra-S-phase checkpoint.
Conclusions: These data indicate that the mechanisms through which CD133+ TSCs respond to radiation are significantly different from those of the traditional glioblastoma in vitro model, established glioma cell lines. If TSCs play a critical role in glioblastoma treatment response, then such differences are likely to be of consequence in the development and testing of radiosensitizing agents. (Clin Cancer Res 2009;15(16):5145–53)
Profiling of Chemonaive Osteosarcoma and Paired-Normal Cells Identifies EBF2 as a Mediator of Osteoprotegerin Inhibition to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis
Authors: Patiño-García Ana , Zalacain Marta , Folio Cecilia , Zandueta Carolina , Sierrasesúmaga Luis , San Julián Mikel , Toledo Gemma , De Las Rivas Javier , Lecanda Fernando 
Published: August 2009

AbstractPurpose: Osteosarcoma is the most prevalent bone tumor in children and adolescents. At present, the mechanisms of initiation, maintenance, and metastasis are poorly understood. The purpose of this study was to identify relevant molecular targets in the pathogenesis of osteosarcoma.Experimental Design: Tumor chemonaive osteoblastic populations and paired control normal osteoblasts were isolated and characterized phenotypically from seven osteosarcoma patients. Global transcriptomic profiling was analyzed by robust microarray analysis. Candidate genes were confirmed by real-time PCR and organized in molecular pathways. EBF2 and osteoprotegerin (OPG) levels were determined by real-time PCR and OPG protein levels were assessed by ELISA. Immunohistochemical analysis was done in a panel of 46 osteosarcoma samples. Silencing of EBF2 was achieved by lentiviral transduction of short hairpin RNA. Apoptosis was determined by caspase-3/7 activity.Results: A robust clustered transcriptomic signature was obtained in osteosarcoma. Transcription factor EBF2, a known functional bone regulator, was among the most significantly overexpressed genes. Immunohistochemical analysis showed that osteosarcoma is expressed in ∼70% of tumors analyzed. Because EBF2 was shown previously to act as a transcriptional activator of OPG, elevated levels of EBF2 were associated with high OPG protein levels in osteosarcoma samples compared with normal osteoblastic cells. Knockdown of EBF2 led to stunted abrogation of OPG levels and increased sensitivity to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis.Conclusions: These findings suggest that EBF2 represents a novel marker of osteosarcoma. EBF2 up-regulation may be one of the mechanisms involved in the high levels of OPG in osteosarcoma, contributing to decrease TRAIL-induced apoptosis and leading to TRAIL resistance. (Clin Cancer Res 2009;15(16):5082–91)
Epidermal Growth Factor Receptor Inhibitors and Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer
Authors: Horn Leora , Sandler Alan 
Published: August 2009

Abstract
Non-small cell lung cancer (NSCLC) is a major global health problem and represents the leading cause of cancer-related deaths worldwide. The majority of patients with NSCLC are diagnosed with advanced-stage disease, and the prognosis for such patients is poor. The currently approved cytotoxic chemotherapy is associated with substantial limitations in both efficacy and safety. The availability of agents targeted against the epidermal growth factor receptor (EGFR), as well as the antiangiogenic agent bevacizumab, have provided some clinical benefit. Nonetheless, the efficacy of these agents is also inadequate, and resistance has emerged as a clinical problem. Numerous novel targeted therapies are now in clinical development and may have potential for overcoming the limitations associated with currently available agents. In this article we review clinical data for molecular-targeted therapies in NSCLC, with emphasis on EGFR inhibitors and antiangiogenic agents. (Clin Cancer Res 2009;15(16): 5040–8)
Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study
Authors: Cao Jie , Zhou Jing , Gao Yan , Gu Liankun , Meng Huanxin , Liu Hongwei , Deng Dajun 
Published: August 2009

Abstract
Purpose: Inactivation of p16 gene by CpG methylation is a frequent event in oral epithelial dysplasia. To investigate the predictive value of p16 methylation on malignant potential in oral epithelial dysplasia, we carried out the prospective cohort study.
Experimental Design: One hundred one patients with histologically confirmed mild or moderate oral epithelial dysplasia were included in the present cohort study. p16 Methylation status of the oral epithelial dysplasia lesions from 93 cases was obtained by methylation-specific PCR. Progression of the oral epithelial dysplasia lesions was examined in 78 cases histologically during a 45.8 months follow-up period. The association between p16 methylation and progression of oral epithelial dysplasia was analyzed.
Results: Of the 93 enrolled cases, 15 cases were lost during the follow-up because of changes of contact information, with a compliance of 83.9%. p16 Methylation was detectable in oral epithelial dysplasia lesions from 32 (41.0%) of 78 enrolled patients. Oral epithelial dysplasia–related squamous cell carcinomas were observed in 22 patients (28.2%) during the follow-up. Rate of progression to oral cancer in patients with the p16-methylated oral epithelial dysplasia was significantly higher than that with the p16-unmethylated oral epithelial dysplasia (43.8% versus 17.4%; adjusted odds ratio, 3.7; P = 0.013), especially for patients at the baseline age of ≥60 years (adjusted odds ratio, 12.0; P = 0.003) and patients with moderate oral epithelial dysplasia (adjusted odds ratio, 15.6; P = 0.022). The overall sensitivity and specificity of prediction of malignant transformation of oral epithelial dysplasia by p16 methylation were 63.6% and 67.9%, respectively.
Conclusion: p16 Methylation was correlated with malignant transformation of oral epithelial dysplasia and is a potential biomarker for prediction of prognosis of mild or moderate oral epithelial dysplasia. (Clin Cancer Res 2009;15(16):5178–83)
Genomic and Mutational Profiling to Assess Clonal Relationships Between Multiple Non–Small Cell Lung Cancers
Authors: Girard Nicolas , Ostrovnaya Irina , Lau Christopher , Park Bernard , Ladanyi Marc , Finley David , Deshpande Charuhas , Rusch Valerie , Orlow Irene , Travis William D. , Pao William , Begg Colin B. 
Published: August 2009

Abstract
Purpose: In cases of multiple non–small cell lung cancer, clinicians must decide whether patients have independent tumors or metastases and tailor treatment accordingly. Decisions are currently made using the Martini and Melamed criteria, which are mostly based on tumor location and histologic type. New genomic tools could improve the ability to assess tumor clonality.
Experimental Design: We obtained fresh-frozen tumors specimens from patients who underwent surgery on at least two occasions for presumptively independent NSCLC. We did array comparative genomic hybridization (aCGH), mutational profiling of select genes, and detailed clinicopathologic review.
Results: We analyzed a total of 42 tumors from 20 patients (6 patients with synchronous tumors, 14 patients with metachronous tumors, 24 potential tumor pair comparisons); 22 tumor pairs were evaluable by aCGH. Surprisingly, classification based on genomic profiling contradicted the clinicopathologic diagnosis in four (18%) of the comparisons, identifying independent primaries in one case diagnosed as metastasis and metastases in three cases diagnosed as independent primaries. Matching somatic point mutations were observed in these latter three cases. Another four tumor pairings were assigned an “equivocal” result based on aCGH; however, matching somatic point mutations were also found in these tumor pairs. None of the tumor pairs deemed independent primaries by aCGH harbored matching mutations.
Conclusion: Genomic analysis can help distinguish clonal tumors from independent primaries. The development of rapid, inexpensive, and reliable molecular tools may allow for refinement of clinicopathologic criteria currently used in this setting. (Clin Cancer Res 2009;15(16):5184–90)
PIK3CA Mutation Associates with Improved Outcome in Breast Cancer
Authors: Kalinsky Kevin , Jacks Lindsay M. , Heguy Adriana , Patil Sujata , Drobnjak Marija , Bhanot Umeshkumar K. , Hedvat Cyrus V. , Traina Tiffany A. , Solit David , Gerald William , Moynahan Mary Ellen 
Published: August 2009

Abstract
Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer.
Experimental Design: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor &gt;1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer–specific survival were examined using Kaplan-Meier or competing risk methodology.
Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer–specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004).
Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase–targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized. (Clin Cancer Res 2009;15(16):5049–59)
Vitexins, Nature-Derived Lignan Compounds, Induce Apoptosis and Suppress Tumor Growth
Authors: Zhou YingJun , Liu Yiliang Ellie , Cao JianGuo , Zeng GuangYao , Shen Cui , Li YanLan , Zhou MeiChen , Chen Yiding , Pu Weiping , Potters Louis , Shi Y. Eric 
Published: August 2009

Abstract
Purpose: Lignans such as secoisolariciresinol diglucoside in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo.
Experimental Design: We purified several Vitexin lignan compounds. Cytotoxic and antitumor effects were analyzed in cancer cells and in tumor xenograft models. In vivo metabolism of Vitexins was determined in rat.
Results: Contrasts to the classic lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound 6-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in poly ADP ribose polymerase protein, up-regulation of Bax, and down-regulation of Bcl-2. This induction of apoptosis seems to be mediated by activation of caspases because inhibition of caspases activity significantly reduced induced apoptosis. We showed a broad antitumor activity of EVn-50 on seven tumor xenograft models including breast, prostate, liver, and cervical cancers. Consistent with in vitro data, EVn-50 treatment induced apoptosis, down-regulated of Bcl-2, and up-regulated Bax in tumor xenografts.
Conclusion: Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classic lignans. Vitexin-induced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases. (Clin Cancer Res 2009;15(16):5161–9)
Nitric Oxide Synthase Variants and Disease-Free Survival among Treated and Untreated Breast Cancer Patients in a Southwest Oncology Group Clinical Trial
Authors: Choi Ji-Yeob , Barlow William E. , Albain Kathy S. , Hong Chi-Chen , Blanco Javier G. , Livingston Robert B. , Davis Warren , Rae James M. , Yeh I-Tien , Hutchins Laura F. , Ravdin Peter M. , Martino Silvana , Lyss Alan P. , Osborne C. Kent , Abeloff Martin D. , Hayes Daniel F. , Ambrosone Christine B. 
Published: August 2009

AbstractPurpose: Numerous chemotherapeutic agents are cytotoxic through generation of reactive species, and variability in genes related to oxidative stress may influence disease-free survival (DFS). We examined relationships between DFS and variants in NOS3, as well as NQO1, NQO2, and CBR3, among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial (S8897).Experimental Design: In the parent trial, women were assigned according to prognostic features; the high-risk group was randomized to cyclophosphamide, i.v. methotrexate, and 5-fluorouracil or to cyclophosphamide, i.v. doxorubicin, and 5-fluorouracil ± tamoxifen, and the low-risk group did not receive adjuvant therapy. We extracted DNA from normal lymph node tissue and examined functional polymorphisms in NOS3, NQO1, NQO2, and CBR3, in relation to DFS, using Cox proportional hazard model.Results: There were significant interactions between DFS, adjuvant therapy, and NOS3 Glu298Asp and −786 polymorphisms, alone and in combination (P for interaction = 0.008). When NOS3 genotypes were combined, women with genotypes encoding for lower nitric oxide who received chemotherapy had a &gt;2-fold increase in hazard of progression (hazard ratio, 2.32; 95% confidence interval, 1.26-4.25), whereas there was reduced risk for those who did not receive adjuvant therapy (hazard ratio, 0.42; 95% confidence interval, 0.19-0.95). There were no associations between the other genotypes and DFS in either group.Conclusion: Variants encoding lower activity of NOS3 may affect outcomes in breast cancer patients, with the direction of risk differing depending on chemotherapy status. These results may mirror the known dual functions of nitric oxide and nitric oxide synthase, depending on oxidative environment. (Clin Cancer Res 2009;15(16):5258–66) (Clin Cancer Res 2009;15(16):5258–)
Small Integrin-Binding Proteins as Serum Markers for Prostate Cancer Detection
Authors: Jain Alka , McKnight Dianalee A. , Fisher Larry W. , Humphreys Elizabeth B. , Mangold Leslie A. , Partin Alan W. , Fedarko Neal S. 
Published: August 2009

Abstract
Purpose: The small integrin-binding ligand N-linked glycoprotein (SIBLING) gene family includes bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), matrix extracellular phosphoglycoprotein (MEPE), and osteopontin (OPN). Previous studies have separately reported elevated expression of BSP, OPN, or DSPP in prostate tumor paraffin sections. We hypothesized that SIBLINGs may be informative serum markers for subjects with prostate cancer.
Methods: Expression levels of SIBLINGs in biopsies of normal tissue and tumors from prostate were determined by cDNA array and by immunohistochemical staining with monoclonal antibodies. Competitive ELISAs for measuring total BSP, DSPP, MEPE, and OPN were applied to a test group of 102 subjects with prostate cancer and 110 normal subjects and a validation group of 90 subjects.
Results: BSP, DMP1, DSPP, and OPN exhibited elevated mRNA expression and protein levels in biopsies. BSP, DSPP, and OPN were elevated in serum from prostate cancer subjects, with serum DSPP exhibiting the greatest difference, yielding an area under the receiver operator characteristic curve value of 0.98. Serum BSP and OPN levels were significantly elevated only in late stages, whereas DSPP was significantly elevated at all stages. Optimal serum value cutoff points derived for BSP, OPN, and DSPP were applied as a validation test to a new group of 90 subjects and DSPP yielded a sensitivity of 90% and a specificity of 100%.
Conclusion: Of the SIBLING gene family members, DSPP appears to be a strong candidate for use in serum assays for prostate cancer detection. (Clin Cancer Res 2009;15(16):5199–207)