bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression
Authors: Banerjee Sanjib , Lin Chuen-Fu L. , Skinner Kristin A. , Schiffhauer Linda M. , Peacock James , Hicks David G. , Redmond Eileen M. , Morrow David , Huston Alissa , Shayne Michelle , Langstein Howard N. , Miller-Graziano Carol L. , Strickland Jennifer , O'Donoghue Lauren , De Asit K. 
Published: January 2011

Abstract
Tumor cells release several factors that can help the progression of the tumor by directly supporting tumor growth and/or suppressing host antitumor immunity. Here, we report that human primary breast tumor cells not only express elevated levels of heat shock protein 27 (Hsp27) at the intracellular level but also release extremely high levels of Hsp27 compared with the same patients' serum Hsp27 levels, predicting an acutely increased concentration of soluble Hsp27 in the human breast tumor microenvironment (HBTM). We demonstrate that Hsp27 levels in the HBTM can be extremely elevated as evidenced by high soluble Hsp27 levels in patients' tumor interstitial fluid. Because increasing numbers of tumor-associated macrophages (TAM) in the HBTM negatively correlate to patients' clinical outcomes and we have previously reported the immunoregulatory activity of soluble Hsp27, here, we tested for any specific effects of soluble Hsp27 on human monocyte to macrophage differentiation. We demonstrate that soluble Hsp27 causes the differentiation of monocytes to macrophages with immuno-tolerizing phenotypes (HLA-DRlow, CD86low, PD-L1high, ILT2high, and ILT4high). We detected the presence of TAMs with similar phenotypes in breast cancer patients. Hsp27-differentiated macrophages induce severe unresponsiveness/anergy in T cells. Moreover, these macrophages lose tumoricidal activity but become extremely proangiogenic, inducing significant neovascularization, a process that is critically important for tumor growth. Thus, our data demonstrate a novel immune escape and tumor growth–supporting mechanism mediated by soluble Hsp27 that may be operative in human breast cancer. Cancer Res; 71(2); 318–27. ©2011 AACR.
Phospholipase D Meets Wnt Signaling: A New Target for Cancer Therapy
Authors: Kang Dong Woo , Choi Kang-Yell , Min Do Sik 
Published: January 2011

Abstract
Phospholipase D (PLD) has been increasingly recognized as a critical regulator of cell proliferation and tumorigenesis. PLD regulates downstream effectors by generating phosphatidic acid (PA), and the expression and activity of PLD are elevated in many different types of human cancer. Aberrant activation of Wnt/β-catenin signaling, followed by hyper-activation of target genes, is linked to a wide range of cancers. New studies reveal a direct connection between the PLD and the Wnt signaling pathways; PLD is a transcriptional target of β-catenin/T-cell factor (TCF) and reinforces Wnt/β-catenin signaling related with cellular transformation. In this review, we discuss the emerging importance of PLD and PA in the Wnt/β-catenin signaling network, which is associated with tumorigenesis, and suggest that the PLD/PA signaling pathway is a potential therapeutic target for the treatment of cancer. Cancer Res; 71(2); 293–7. ©2011 AACR.
HMGA2 Overexpression-Induced Ovarian Surface Epithelial Transformation Is Mediated Through Regulation of EMT Genes
Authors: Wu Jingjing , Liu Zhaojian , Shao Changshun , Gong Yaoqin , Hernando Eva , Lee Peng , Narita Masashi , Muller William , Liu Jinsong , Wei Jian-Jun 
Published: January 2011

Abstract
The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes. Cancer Res; 71(2); 349–59. ©2011 AACR.
NCI Image-Guided Drug Delivery Summit
Authors: Tandon Pushpa , Farahani Keyvan 
Published: January 2011

Abstract
On April 17, 2010, scientists from academia, the National Cancer Institute (NCI), and the Food and Drug Administration (FDA) assembled at “The NCI Image Guided Drug Delivery Summit,” in Washington D.C., to discuss recent advances, barriers, opportunities, and regulatory issues related to the field. The meeting included a scientific session and an NCI/FDA session, followed by a panel discussion of speakers from both sessions. Image-guided drug delivery (IGDD) in cancer is a form of individualized therapy where imaging methods are used in guidance and monitoring of localized and targeted delivery of therapeutics to the tumor. So, a systematic approach to IGDD requires mechanisms for targeting, delivery, activation, and monitoring of the process. Although the goal in IGDD is to optimize the therapeutic ratio through personalized image-guided treatments, a major challenge is in overcoming the biological barriers to the delivery of therapeutics into tumors and cells. Speakers discussed potential challenges to clinical translation of nano-based drug delivery systems including in vivo characterization of nanocarriers, preclinical validation of targeting and delivery, studies of biodistribution, pharmacokinetics, pharmacodynamics, and toxicity as well as scale-up manufacturing of delivery systems. Physiologic and quantitative imaging techniques may serve as enabling tools that could potentially transform many existing challenges into opportunities for advancement of the field. Cancer Res; 71(2); 314–7. ©2011 AACR.
Physical Oncology: A Bench-to-Bedside Quantitative and Predictive Approach
Authors: Frieboes Hermann B. , Chaplain Mark A.J. , Thompson Alastair M. , Bearer Elaine L. , Lowengrub John S. , Cristini Vittorio 
Published: January 2011

Abstract
Cancer models relating basic science to clinical care in oncology may fail to address the nuances of tumor behavior and therapy, as in the case, discussed herein, of the complex multiscale dynamics leading to the often-observed enhanced invasiveness, paradoxically induced by the very antiangiogenic therapy designed to destroy the tumor. Studies would benefit from approaches that quantitatively link the multiple physical and temporal scales from molecule to tissue in order to offer outcome predictions for individual patients. Physical oncology is an approach that applies fundamental principles from the physical and biological sciences to explain certain cancer behaviors as observable characteristics arising from the underlying physical and biochemical events. For example, the transport of oxygen molecules through tissue affects phenotypic characteristics such as cell proliferation, apoptosis, and adhesion, which in turn underlie the patient-scale tumor growth and invasiveness. Our review of physical oncology illustrates how tumor behavior and treatment response may be a quantifiable function of marginally stable molecular and/or cellular conditions modulated by inhomogeneity. By incorporating patient-specific genomic, proteomic, metabolomic, and cellular data into multiscale physical models, physical oncology could complement current clinical practice through enhanced understanding of cancer behavior, thus potentially improving patient survival. Cancer Res; 71(2); 298–302. ©2011 AACR.
Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1
Authors: Aoki Koji , Kakizaki Fumihiko , Sakashita Hiromi , Manabe Toshiaki , Aoki Masahiro , Taketo Makoto M. 
Published: January 2011

Abstract
Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in ApcΔ716 mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27Kip1 by a nontranscriptional but homeodomain-dependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells. p27Kip1 stabilization was mediated by an inhibition of ubiquitylation-dependent proteolysis associated with decreased phosphorylation of Thr187 in p27Kip1. siRNA-mediated knockdown of p27Kip1 relieved the decrease in cyclin E-CDK2 activity and S-phase cell fraction elicited by CDX2 expression. Together, these results implicate a nontranscriptional function of CDX2 in tumor suppression mediated by p27Kip1 stabilization. Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27Kip1, whereas approximately 68% of high-CDX2 lesions retain expression of p27Kip1. These results show that low levels of CDX2 accelerate colon tumorigenesis by reducing p27Kip1 levels. Cancer Res; 71(2); 593–602. ©2011 AACR.
SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma
Authors: Kunst Henricus P.M. , Rutten Martijn H. , de Mönnink Jan-Pieter , Hoefsloot Lies H. , Timmers Henri J.L.M. , Marres Henri A.M. , Jansen Jeroen C. , Kremer Hannie , Bayley Jean-Pierre , Cremers Cor W.R.J. 
Published: January 2011

AbstractPurpose: Hereditary head and neck paraganglioma (HNPGL) syndromes are associated with mutations in the SDHD(PGL1), SDHC(PGL3), and SDHB(PGL4) genes encoding succinate dehydrogenase subunits. We recently described mutations in a previously uncharacterized human gene, now called SDHAF2, and showed that this was the long-sought “imprinted” PGL2 gene. Here, we present a new branch of the Dutch SDHAF2 (PLG2-SDH5) family.Experimental Design: The SDHAF2 family has been collected over a 30-year period. The family described here was linked to PGL2 and at-risk family members were invited to participate in this study. Patients were investigated and treated dependent on tumor size and localization. All family members have now been analyzed for the SDHAF2 mutation status.Results: Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies.Conclusions: We established the SDHAF2 mutation status of PGL2 family members. Phenotypic characterization of this family confirms the currently exclusive association of SDHAF2 mutations with HNPGL. This SDHAF2 family branch shows a young age at onset and very high levels of multifocality. A high percentage of patients were asymptomatic at time of detection. Clin Cancer Res; 17(2); 247–54. ©2011 AACR.
Primary CNS Lymphoma in Children and Adolescents: A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)
Authors: Abla Oussama , Weitzman Sheila , Blay Jean-Yves , O'Neill Brian Patrick , Abrey Lauren E. , Neuwelt Edward , Doolittle Nancy D. , Baehring Joachim , Pradhan Kamnesh , Martin S. Eric , Guerrera Michael , Shah Shafqat , Ghesquieres Hervé , Silver Michael , Betensky Rebecca A. , Batchelor Tracy 
Published: January 2011

Abstract
Purpose: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL).
Experimental Design: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries.
Results: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤14 vs. &gt;14 years), PS (0 or 1 vs. &gt;1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively.
Conclusion: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival. Clin Cancer Res; 17(2); 346–52. ©2011 AACR.
Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin
Authors: Tolcher Anthony W. , Sweeney Christopher J. , Papadopoulos Kyri , Patnaik Amita , Chiorean Elena G. , Mita Alain C. , Sankhala Kamalesh , Furfine Eric , Gokemeijer Jochem , Iacono Lisa , Eaton Cheryl , Silver Bruce A. , Mita Monica 
Published: January 2011

Abstract
Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain–based targeted biologic (Adnectin) to enter clinical studies.
Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.
Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti–CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.
Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics. Cancer Res; 17(2); 363–71. ©2011 AACR. Clin Cancer Res; 17(2); 363–71. ©2011 AACR.
Exosomes and Cancer: A Newly Described Pathway of Immune Suppression
Authors: Zhang Huang-Ge , Grizzle William E. 
Published: January 2011

AbstractExosomes are small (30 to 100 nm) membrane-bound particles that are released from normal, diseased, and neoplastic cells and are present in blood and other bodily fluids. Exosomes contain a variety of molecules including signal peptides, mRNA, microRNA, and lipids. Exosomes can function to export from cells unneeded endogenous molecules and therapeutic drugs. When exosomes are taken up by specific cells, they may act locally to provide autocrine or paracrine signals or, at a distance, as a newly described nanoparticle-based endocrine system. Specifically, mRNA transferred to cells by exosomes can result in the production of new proteins. In cancer, signals via exosomes affect the immune system by inhibiting the functions of T cells and normal killer (NK) cells and by inhibiting the differentiation of precursors to mature antigen-presenting cells. Also, exosomes increase the number and/or activity of immune suppressor cells, including myeloid-derived suppressor cells, T-regulatory cells, and CD14+, HLA-DR−/low cells. The effects of exosomes on the development and progression of cancers, with an emphasis on suppression of immune surveillance, is described. Also discussed are potential uses of exosomes clinically, in the development of vaccines, in targeting tumors, and in diagnosis and/or early detection. Clin Cancer Res; 17(5); 959–64. ©2011 AACR.
Therapeutic Drug Monitoring for the Individualization of Docetaxel Dosing: A Randomized Pharmacokinetic Study
Authors: Engels Frederike K. , Loos Walter J. , van der Bol Jessica M. , de Bruijn Peter , Mathijssen Ron H.J. , Verweij Jaap , Mathot Ron A.A. 
Published: January 2011

Abstract
Purpose: Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PK-guided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure.
Experimental Design: A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area–based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing.
Results: Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%.
Conclusions: Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity. Clin Cancer Res; 17(2); 353–62. ©2011 AACR.
Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors
Authors: Khan Mohid S. , Tsigani Theodora , Rashid Mohammed , Rabouhans Jeremy S. , Yu Dominic , Luong Tu Vinh , Caplin Martyn , Meyer Tim 
Published: January 2011

Abstract
Purpose: Neuroendocrine tumors (NET) are heterogeneous tumors with widely variable survival. It is unknown whether they express EpCAM (epithelial cell adhesion molecule) and thus whether NET circulating tumor cells (CTC) are detectable. We systematically investigated EpCAM expression and CTC detection in patients with metastatic NETs and evaluated the potential of CTCs to predict radiological progression.
Experimental Design: EpCAM protein expression was evaluated in 74 samples of formalin-fixed, paraffin-embedded NET tissue by immunohistochemistry. Seventy-nine patients with metastatic NETs (42 midgut, 5 unknown primary, 19 pancreatic, 13 bronchopulmonary) had blood samples drawn for CTC isolation and enumeration utilizing the CellSearch platform. Patients were classified as having progressive or nonprogressive disease on the basis of serial imaging.
Results: Strong homogeneous, membranous EpCAM expression was observed in all ileal (n = 26) and pancreatic NETs (n = 16), whereas variable EpCAM expression was observed in bronchopulmonary NETs (n = 13). Forty-three percent of midgut and 21% of pancreatic NETs had CTCs detected with a range of 0–62 and 0–11, respectively. The absence of CTCs was strongly associated with stable disease (P &lt; 0.001). There was a moderate correlation between CTC levels and urinary 5-hydroxyindole acetic acid (r = 0.5, P = 0.007) and between CTC levels and burden of liver metastases (B = 8.91, P &lt; 0.001). There was no or low correlation between CTC levels and Ki-67 (r = 0.08, P = 0.59) and serum chromogranin A (r = 0.246, P = 0.03).
Conclusions: This is the first systematic analysis showing EpCAM expression and CTC detection in NETs. CTCs seem to be associated with progressive disease and may provide useful prognostic information given the variable survival rates in these tumors. Clin Cancer Res; 17(2); 337–45. ©2011 AACR.
Impact of Exploratory Biomarkers on the Treatment Effect of Bevacizumab in Metastatic Breast Cancer
Authors: Jubb Adrian M. , Miller Kathy D. , Rugo Hope S. , Harris Adrian L. , Chen Dafeng , Reimann James D. , Cobleigh Melody A. , Schmidt Maike , Langmuir Virginia K. , Hillan Kenneth J. , Chen Daniel S. , Koeppen Hartmut 
Published: January 2011

AbstractPurpose: The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial.Experimental Design: In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses.Results: Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing.Conclusion: These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing. Clin Cancer Res; 17(2); 372–81. ©2011 AACR.