bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obesity and Breast Cancer: Progress to Understanding the Relationship
Authors: Brown Kristy A. , Simpson Evan R. 
Published: December 2009

Abstract
Epidemiological evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase (AMPK) is recognized to be a master regulator of energy homeostasis. One of its actions is to phosphorylate and inhibit the actions of cAMP-responsive element binding protein (CREB)-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the CREB-dependent regulation of aromatase is a crucial determinant of breast tumor formation through local production of estrogens. We report here that the regulation of aromatase expression in the breast by AMPK and CRTC2, in response to the altered adipokine milieu associated with obesity, provides an important link between obesity and breast cancer risk. Cancer Res; 70(1); 4–7
The Nicotinamide Phosphoribosyltransferase: A Molecular Link between Metabolism, Inflammation, and Cancer
Authors: Gallí Mara , Van Gool Frédéric , Rongvaux Anthony , Andris Fabienne , Leo Oberdan 
Published: December 2009

Abstract
Beyond its well-described role in cellular metabolism, intracellular nicotinamide adenine dinucleotide (NAD) levels have been shown to affect the enzymatic activity of a series of NAD-dependent enzymes, influencing biological responses such as cell survival and inflammation. Nicotinamide phosphoribosyl transferase activity has been shown to be essential for maintaining adequate intracellular NAD levels, suggesting that this enzyme may in fact play a central role in modulating the activity of a wide range of NAD-dependent enzymes. Several recent observations concur with this hypothesis and suggest that by regulating NAD availability, Nampt is able to control both cell viability and the inflammatory response. Nampt may thus represent a novel pharmacological target with valuable anti-inflammatory and antitumor properties. Cancer Res; 70(1); 8–11
Diagnosing Cervical Cancer and High-Grade Precursors by HPV16 Transcription Patterns
Authors: Schmitt Markus , Dalstein Véronique , Waterboer Tim , Clavel Christine , Gissmann Lutz , Pawlita Michael 
Published: December 2009

Abstract
Infections with high-risk human papillomaviruses (HPV), mainly HPV type 16, can cause malignant transformation of the human cervical epithelium and the development of cervical cancer (CxCa). A rapid and precise diagnosis of the precancerous lesions by conventional cytology or HPV DNA tests remains difficult and often leads to overtreatment. We quantitatively analyzed the HPV16 transcriptome of 80 HPV16 DNA-positive cervical scrapes classified as mild cytologic grade, including no intraepithelial lesion or malignancy (NIL/M; normal, n = 25) and low-grade squamous intraepithelial lesion (LSIL; n = 24), and severe cytologic grade, including high-grade squamous intraepithelial lesion (HSIL; n = 24) and CxCa (n = 7), with novel nucleic acid sequence-based amplification–Luminex assays. In severe lesions, HPV16 E6*II and E1C encoding transcripts were strongly upregulated, whereas spliced E1^E4 and L1 encoding transcripts were markedly downregulated. Using a combination of the four marker transcripts, 100% of CxCa and 67% of HSIL cases were correctly identified as severe, and 74% of LSIL and 92% of NIL/M samples as mild cytologic grade. Compared with a commercially available HPV E6/E7 mRNA assay, the specificity of the marker combination for discriminating severe and mild cytologic lesions increased from 23% to 83%. In conclusion, we identified a novel HPV16 RNA pattern for grading of cervical lesions with a potentially high diagnostic value for the primary screening of CxCa precursors and the triage of cervical lesions. Cancer Res; 70(1); 249–56
Systems Biologists Seek Fuller Integration of Systems Biology Approaches in New Cancer Research Programs
Authors: Wolkenhauer Olaf , Auffray Charles , Baltrusch Simone , Blüthgen Nils , Byrne Helen , Cascante Marta , Ciliberto Andrea , Dale Trevor , Drasdo Dirk , Fell David , Ferrell James E. , Gallahan Daniel , Gatenby Robert , Günther Ulrich , Harms Brian D. , Herzel Hanspeter , Junghanss Christian , Kunz Manfred , van Leeuwen Ingeborg , Lenormand Philippe , Levi Francis , Linnebacher Michael , Lowengrub John , Maini Philip K. , Malik Arif , Rateitschak Katja , Sansom Owen , Schäfer Reinhold , Schürrle Karsten , Sers Christine , Schnell Santiago , Shibata Darryl , Tyson John , Vera Julio , White Michael , Zhivotovsky Boris , Jaster Robert 
Published: December 2009

Abstract
Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology. Cancer Res; 70(1); 12–3
Imaging the Unfolded Protein Response in Primary Tumors Reveals Microenvironments with Metabolic Variations that Predict Tumor Growth
Authors: Spiotto Michael T. , Banh Alice , Papandreou Ioanna , Cao Hongbin , Galvez Michael G. , Gurtner Geoffrey C. , Denko Nicholas C. , Le Quynh Thu , Koong Albert C. 
Published: December 2009

Abstract
Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth. Cancer Res; 70(1); 78–88
Central Role of IFNγ–Indoleamine 2,3-Dioxygenase Axis in Regulation of Interleukin-12–Mediated Antitumor Immunity
Authors: Gu Tao , Rowswell-Turner Rachael B. , Kilinc Mehmet O. , Egilmez Nejat K. 
Published: December 2009

Abstract
Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8+ T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8+ T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4+ CD25+ Foxp3+ T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFNγ and persisted for up to 7 days. Administration of the IDO inhibitor d-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8+ T-cell to CD4+ Foxp3+ T-cell ratio. The ratio of proliferating CD8+ T-effector to CD4+ Foxp3+ T-suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFNγ-dependent IDO induction and T-suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12–mediated antitumor immune responses. Cancer Res; 70(1); 129–38.
Expression of Interleukin-1 Receptor–Associated Kinase-1 in Non–Small Cell Lung Carcinoma and Preneoplastic Lesions
Authors: Behrens Carmen , Feng Lei , Kadara Humam , Kim Hyun-Jung , Lee J. Jack , Mehran Reza , Hong Waun Ki , Lotan Reuben , Wistuba Ignacio I. 
Published: December 2009

Abstract
Purpose: To identify the pattern of interleukin-1 receptor–associated kinase (IRAK-1) protein expression in non–small cell lung carcinoma (NSCLC) and corresponding preneoplastic lesions.
Experimental Design: Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 306) and adjacent bronchial epithelial specimens (n = 315) were analyzed for the immunohistochemical expression of IRAK-1, and the findings were correlated with patients' clinicopathologic features. Furthermore, we investigated the correlation between IRAK-1 expression and expression of NF-κB and IL-1α in tumor specimens.
Results: NSCLC tumors showed significantly higher cytoplasmic and lower nuclear IRAK-1 expression than normal epithelium. Squamous dysplasias had significantly higher cytoplasmic IRAK-1 expression than normal epithelium. In tumors, a significant positive correlation was detected between IRAK-1 expression (nuclear and cytoplasmic; P = 0.011) and IL-1α cytoplasmic expression (P &lt; 0.0001). The correlation between the expression of the markers and patients' clinicopathologic features varied according to tumor histologic type and sex. High IRAK-1 cytoplasmic expression correlated with worse recurrence-free survival in women with NSCLC [hazard ratio (HR), 2.204; P = 0.033], but not in men. In adenocarcinoma, combined low level of expression of nuclear IRAK-1 and NF-κB correlated significantly with worse overall (HR, 2.485; P = 0.007) and recurrence-free (HR, 3.058; P = 0.006) survivals in stage I/II patients.
Conclusions: IRAK-1 is frequently expressed in NSCLC tissue specimens, and this expression is an early phenomenon in the sequential development of lung cancer. IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies. Clin Cancer Res; 16(1); 34–44
Phase I Study of the Angiogenesis Inhibitor BIBF 1120 in Patients with Advanced Solid Tumors
Authors: Mross Klaus , Stefanic Martin , Gmehling Daniela , Frost Annette , Baas Franziska , Unger Clemens , Strecker Ralph , Henning Jürgen , Gaschler-Markefski Birgit , Stopfer Peter , de Rossi Lothar , Kaiser Rolf 
Published: December 2009

Abstract
Purpose: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120.
Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.
Results: Most frequent BIBF 1120–related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (tmax = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.
Conclusions: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies. Clin Cancer Res; 16(1); 311–9
A Group of Genome-Based Biomarkers That Add to a Kattan Nomogram for Predicting Progression in Men with High-Risk Prostate Cancer
Authors: Paris Pamela L. , Weinberg Vivian , Albo Giancarlo , Roy Ritu , Burke Catherine , Simko Jeffry , Carroll Peter , Collins Colin 
Published: December 2009

Abstract
Purpose: The three main treatment options for primary prostate cancer are surgery, radiation, and active surveillance. Surgical and radiation intervention for prostate cancer can be associated with significant morbidity. Therefore, accurate stratification predictive of outcome for prostate cancer patients is essential for appropriate treatment decisions. Nomograms that use clinical and pathologic variables are often used for risk prediction. Favorable outcomes exist even among men classified by nomograms as being at high risk of recurrence.
Experimental Design: Previously, we identified a set of DNA-based biomarkers termed Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) and have shown that they can predict risk of recurrence with 80% accuracy. Here, we examined the risk prediction ability of GEMCaP in a high-risk cohort and compared it to a Kattan nomogram.
Results: We determined that the GEMCaP genotype alone is comparable with the nomogram, and that for a subset of cases with negative lymph nodes improves upon it.
Conclusion: Thus, GEMCaP shows promise for predicting unfavorable outcomes for negative lymph node high-risk cases, where the nomogram falls short, and suggests that addition of GEMCaP to nomograms may be warranted. Clin Cancer Res; 16(1); 195–202
Targeting of Bone-Derived Insulin-Like Growth Factor-II by a Human Neutralizing Antibody Suppresses the Growth of Prostate Cancer Cells in a Human Bone Environment
Authors: Kimura Taichi , Kuwata Takeshi , Ashimine Satoshi , Yamazaki Manabu , Yamauchi Chisako , Nagai Kanji , Ikehara Akashi , Feng Yang , Dimitrov Dimiter S. , Saito Seiichi , Ochiai Atsushi 
Published: December 2009

Abstract
Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer.
Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells.
Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II–induced proliferation of MDA PCa 2b cells.
Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121–29
Rap1 Stabilizes β-Catenin and Enhances β-Catenin–Dependent Transcription and Invasion in Squamous Cell Carcinoma of the Head and Neck
Authors: Goto Mitsuo , Mitra Raj S. , Liu Min , Lee Julia , Henson Bradley S. , Carey Thomas , Bradford Carol , Prince Mark , Wang Cun-Yu , Fearon Eric R. , D'Silva Nisha J. 
Published: December 2009

Abstract
Purpose: In head and neck squamous cell carcinoma (HNSCC) cells, Rap1 shuttles between the nucleus and cytoplasm. Prior findings suggested that Rap1 may modulate the β-catenin–independent Wnt pathway in some settings, but the role of Rap1 in β-catenin–dependent Wnt signaling remains undefined.
Experimental Design and Results: We observed that β-catenin bound to active Rap1 in vitro and Rap1 activated β-catenin/T-cell factor (TCF)–dependent transcription. Immunofluorescence studies showed that ectopic expression of Rap1 increased nuclear translocation of β-catenin. Overexpression of active Rap1 facilitated an increase in β-catenin–mediated transcription that was abrogated by dominant-negative TCF4. Conversely, small interfering RNA–mediated inhibition of endogenous Rap1 expression inhibited β-catenin/TCF–mediated transcription as well as invasion of HNSCC. Furthermore, inhibition of Rap1 expression downregulated the expression of matrix metalloproteinase 7, a transcriptional target of β-catenin/TCF. In HNSCC cells stably transfected with β-catenin or treated with lithium chloride or Wnt3A to stabilize endogenous β-catenin, inhibition of Rap1 expression led to decreases in the free pool of β-catenin. Immunohistochemical studies of tissue from HNSCC patients revealed that increased β-catenin intensity correlated with higher tumor stage. Furthermore, the prognostic effect of active Rap1 on tumor N stage was found to depend on cytosolic β-catenin expression (P &lt; 0.013). When β-catenin is high, higher Rap1GTP intensity is associated with more advanced N stage.
Conclusions: The findings suggest that Rap1 enhances β-catenin stability and nuclear localization. In addition to indicating that Rap1 has a significant role in regulating β-catenin and β-catenin–dependent progression to more advanced N-stage lesions, these data highlight Rap1 as a potential therapeutic target in HNSCC. Clin Cancer Res; 16(1); 65–76
Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment
Authors: Klinghammer Konrad , Knödler Maren , Schmittel Alexander , Budach Volker , Keilholz Ulrich , Tinhofer Ingeborg 
Published: December 2009

Abstract
Purpose: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity.
Experimental Design: Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G→A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test.
Results: Overall, 21 patients (41%) developed skin rash with grade &gt;1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected.
Conclusions: Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment. Clin Cancer Res; 16(1); 304–10
Bevacizumab Safety in Patients with Central Nervous System Metastases
Authors: Besse Benjamin , Lasserre Susan F. , Compton Peter , Huang Jane , Augustus Stella , Rohr Ulrich-Peter 
Published: December 2009

Abstract
Purpose: Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified.
Experimental Design: A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified.
Results: In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage.
Conclusions: In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non–small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials. Clin Cancer Res; 16(1); 269–78