bluuebunny/crossref_metadata_2025_split huggingface dataset:
LBO-1.6 Efficacy of the quadrivalent HPV vaccine to prevent anal intraepithelial neoplasia among young men who have sex with men
Authors: Goldstone S 
Published: July 2011

IntroductionMost anal cancers are associated with HPV, particularly HPV 16. The incidence of anal cancer is increased among men who have sex with men (MSM) compared with the general population. Screening and treatment of anal intraepithelial neoplasia (AIN), the anal cancer precursor, are not yet standard of care, and prevention efforts are needed to reduce the incidence of anal cancer. We tested the quadrivalent HPV vaccine to determine its ability to reduce the incidence of AIN/anal cancer.Methods598 MSM aged 16–26 years with five or fewer lifetime sex partners were randomised to receive vaccine or placebo at enrolment, month 2 and month 6. Subjects underwent detailed anogenital exams and HPV sampling from the penis, scrotum, perineal/perianal and anal canal at enrolment, month 7 and at 6-month intervals afterwards. Efficacy analyses were performed in a per-protocol (PPE) population (sero-negative and DNA-negative from day 1 through month 7 to the relevant vaccine HPV type) and in all enrolees in an intent-to treat (ITT) analysis. Median follow-up of the PPE population was 2.5 years (post-dose 3).ResultsVaccine efficacy against HPV 6/11/16/18-related AIN and anal cancer in the PPE population was 77.5% (95% CI 39.6 to 93.3) (5 vaccine cases vs 24 placebo cases). Efficacy against high-grade AIN (AIN 2+) was 74.9% (95% CI 8.8 to 95.4). In the ITT population the efficacy was 50.3% (95% CI 25.7 to 67.2) and 54.2% (95% CI 18.0 to 75.3), respectively. No anal cancer was seen in either treatment group.ConclusionsThese results demonstrate that the quadrivalent HPV vaccine is efficacious in preventing AIN related to HPV 6/11/16/18 in MSM subjects naïve to vaccine HPV types at enrolment, as well as in an ITT population. The quadrivalent HPV vaccine may be a useful measure to reduce the incidence of anal disease in at-risk populations.
CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer
Authors: Righi Elda , Kashiwagi Satoshi , Yuan Jianping , Santosuosso Michael , Leblanc Pierre , Ingraham Rachel , Forbes Benjamin , Edelblute Beth , Collette Brian , Xing Deyin , Kowalski Magdalena , Mingari Maria Cristina , Vianello Fabrizio , Birrer Michael , Orsulic Sandra , Dranoff Glenn , Poznansky Mark C. 
Published: July 2011

Abstract
The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1–derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3+ regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell–mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease. Cancer Res; 71(16); 5522–34. ©2011 AACR.
p53-Dependent Regulation of Mitochondrial Energy Production by the RelA Subunit of NF-κB
Authors: Johnson Renée F. , Witzel Ini-Isabée , Perkins Neil D. 
Published: July 2011

Abstract
Aberrant activity of the nuclear factor kappaB (NF-κB) transcription factor family, which regulates cellular responses to stress and infection, is associated with many human cancers. In this study, we define a function of NF-κB in regulation of cellular respiration that is dependent upon the tumor suppressor p53. Translocation of the NF-κB family member RelA to mitochondria was inhibited by p53 by blocking an essential interaction with the HSP Mortalin. However, in the absence of p53, RelA was transported into the mitochondria and recruited to the mitochondrial genome where it repressed mitochondrial gene expression, oxygen consumption, and cellular ATP levels. We found mitochondrial RelA function to be dependent on its conserved C-terminal transactivation domain and independent of its sequence-specific DNA-binding ability, suggesting that its function in this setting was mediated by direct interaction with mitochondrial transcription factors. Taken together, our findings uncover a new mechanism through which RelA can regulate mitochondrial function, with important implications for how NF-κB activity and loss of p53 can contribute to changes in tumor cell metabolism and energy production. Cancer Res; 71(16); 5588–97. ©2011 AACR.
Comparing Signaling Networks between Normal and Transformed Hepatocytes Using Discrete Logical Models
Authors: Saez-Rodriguez Julio , Alexopoulos Leonidas G. , Zhang MingSheng , Morris Melody K. , Lauffenburger Douglas A. , Sorger Peter K. 
Published: July 2011

Abstract
Substantial effort in recent years has been devoted to constructing and analyzing large-scale gene and protein networks on the basis of “omic” data and literature mining. These interaction graphs provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or drugs. Conversely, traditional approaches to analyzing cell signaling are narrow in scope and cannot easily make use of network-level data. Here, we combine network analysis and functional experimentation by using a hybrid approach in which graphs are converted into simple mathematical models that can be trained against biochemical data. Specifically, we created Boolean logic models of immediate-early signaling in liver cells by training a literature-based prior knowledge network against biochemical data obtained from primary human hepatocytes and 4 hepatocellular carcinoma cell lines exposed to combinations of cytokines and small-molecule kinase inhibitors. Distinct families of models were recovered for each cell type, and these families clustered topologically into normal and diseased sets. Cancer Res; 71(16); 5400–11. ©2011 AACR.
STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells
Authors: Babij Carol , Zhang Yihong , Kurzeja Robert J. , Munzli Anke , Shehabeldin Amro , Fernando Manory , Quon Kim , Kassner Paul D. , Ruefli-Brasse Astrid A. , Watson Vivienne J. , Fajardo Flordeliza , Jackson Angela , Zondlo James , Sun Yu , Ellison Aaron R. , Plewa Cherylene A. , San Miguel Tisha , Robinson John , McCarter John , Schwandner Ralf , Judd Ted , Carnahan Josette , Dussault Isabelle 
Published: July 2011

Abstract
Despite the prevalence of KRAS mutations in human cancers, there remain no targeted therapies for treatment. The serine–threonine kinase STK33 has been proposed to be required for the survival of mutant KRAS-dependent cell lines, suggesting that small molecule kinase inhibitors of STK33 may be useful to treat KRAS-dependent tumors. In this study, we investigated the role of STK33 in mutant KRAS human cancer cells using RNA interference, dominant mutant overexpression, and small molecule inhibitors. As expected, KRAS downregulation decreased the survival of KRAS-dependent cells. In contrast, STK33 downregulation or dominant mutant overexpression had no effect on KRAS signaling or survival of these cells. Similarly, a synthetic lethal siRNA screen conducted in a broad panel of KRAS wild-type or mutant cells identified KRAS but not STK33 as essential for survival. We also obtained similar negative results using small molecule inhibitors of the STK33 kinase identified by high-throughput screening. Taken together, our findings refute earlier proposals that STK33 inhibition may be a useful therapeutic approach to target human KRAS mutant tumors. Cancer Res; 71(17); 5818–26. ©2011 AACR.
Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer
Authors: Kayani Irfan , Avril Norbert , Bomanji Jamshed , Chowdhury Simon , Rockall Andrea , Sahdev Anju , Nathan Paul , Wilson Peter , Shamash Jonathan , Sharpe Kevin , Lim Louise , Dickson John , Ell Peter , Reynolds Andrew , Powles Thomas 
Published: July 2011

Abstract
Purpose: To test the hypothesis that sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant.
Experimental Design: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. 18F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUVmax) at 4 and 16 weeks with overall survival (OS).
Results: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUVmax = 6.8, range: &lt;2.5–18.4). In multivariate analysis, a high SUVmax and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36–8.45) and 3.67 (95% CI: 1.43–9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40–1.99) or OS (HR for responders = 0.80; 95% CI: 0.34–1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43–19.02) and HR = 12.13 (95% CI: 3.72–46.45), respectively].
Conclusions: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant. Clin Cancer Res; 17(18); 6021–8. ©2011 AACR.
Robust Gene Expression Signature from Formalin-Fixed Paraffin-Embedded Samples Predicts Prognosis of Non–Small-Cell Lung Cancer Patients
Authors: Xie Yang , Xiao Guanghua , Coombes Kevin R. , Behrens Carmen , Solis Luisa M. , Raso Gabriela , Girard Luc , Erickson Heidi S. , Roth Jack , Heymach John V. , Moran Cesar , Danenberg Kathy , Minna John D. , Wistuba Ignacio I. 
Published: July 2011

Abstract
Purpose: The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes.
Experimental Design: We randomly selected 100 Non–Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model.
Results: This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature.
Conclusions: We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings. Clin Cancer Res; 17(17); 5705–14. ©2011 AACR.
Tumor Engraftment in Nude Mice and Enrichment in Stroma- Related Gene Pathways Predict Poor Survival and Resistance to Gemcitabine in Patients with Pancreatic Cancer
Authors: Garrido-Laguna Ignacio , Uson Maria , Rajeshkumar N.V. , Tan Aik Choon , de Oliveira Elizabeth , Karikari Collins , Villaroel Maria C. , Salomon Ana , Taylor Gretchen , Sharma Rajni , Hruban Ralph H. , Maitra Anirban , Laheru Daniel , Rubio-Viqueira Belén , Jimeno Antonio , Hidalgo Manuel 
Published: July 2011

Abstract
Purpose: The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.
Experimental Design: Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival.
Results: A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine.
Conclusion: A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways. Clin Cancer Res; 17(17); 5793–800. ©2011 AACR.
Gene Set Enrichment Analysis Unveils the Mechanism for the Phosphodiesterase 4B Control of Glucocorticoid Response in B-cell Lymphoma
Authors: Kim Sang-Woo , Rai Deepak , Aguiar Ricardo C.T. 
Published: July 2011

Abstract
Purpose: Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes.
Experimental Design: We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, in vitro and in vivo, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/mTOR activities, and GC responses.
Results: Starting from the GSEA, we found that overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B.
Conclusions: Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies. Clin Cancer Res; 17(21); 6723–32. ©2011 AACR.
Admission, Discharge, or Change in B-Type Natriuretic Peptide and Long-Term Outcomes
Authors: Kociol Robb D. , Horton John R. , Fonarow Gregg C. , Reyes Eric M. , Shaw Linda K. , O'Connor Christopher M. , Felker G. Michael , Hernandez Adrian F. 
Published: July 2011

Background—
B-type natriuretic peptide (BNP) has been associated with short- and long-term postdischarge prognosis among hospitalized patients with heart failure. It is unknown if admission, discharge, or change from admission to discharge BNP measure is the most important predictor of long-term outcomes.

Methods and Results—

We linked patients ≥65 years of age from hospitals in Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) to Medicare claims. Among patients with recorded admission and discharge BNP, we compared Cox models predicting 1-year mortality and/or rehospitalization, including clinical variables and clinical variables plus BNP. We calculated the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) for the best-fit model for each outcome versus the model with clinical variables alone. Among 7039 patients in 220 hospitals, median (25th, 75th) admission and discharge BNP were 832 pg/mL (451, 1660) and 534 pg/mL (281, 1111). Observed 1-year mortality and 1-year mortality or rehospitalization rates were 35.2% and 79.4%. The discharge BNP model had the best performance and was the most important characteristic for predicting 1-year mortality (hazard ratio for log transformation, 1.34; 95% confidence interval, 1.28 to 1.40) and 1-year death or rehospitalization (hazard ratio, 1.15; 95% confidence interval, 1.12 to 1.18). Compared with a clinical variables only model, the discharge BNP model improved risk reclassification and discrimination in predicting each outcome (1-year mortality: NRI, 5.5%,
P
<0.0001; IDI, 0.023,
P
<0.0001; 1-year mortality or rehospitalization: NRI, 4.2%,
P
<0.0001; IDI, 0.010,
P
<0.0001).

Conclusions—
Discharge BNP best predicts 1-year mortality and/or rehospitalization among older patients hospitalized with heart failure. Discharge BNP plus clinical variables modestly improves risk classification and model discrimination for long-term outcomes.
Summit on cell therapy for cancer: The importance of the interaction of multiple disciplines to advance clinical therapy
Authors: Melief Cornelis JM , O'Shea John J , Stroncek David F 
Published: July 2011

Abstract
The field of cellular therapy of cancer is moving quickly and the issues involved with its advancement are complex and wide ranging. The growing clinical applications and success of adoptive cellular therapy of cancer has been due to the rapid evolution of immunology, cancer biology, gene therapy and stem cell biology and the translation of advances in these fields from the research laboratory to the clinic. The continued development of this field is dependent on the exchange of ideas across these diverse disciplines, the testing of new ideas in the research laboratory and in animal models, the development of new cellular therapies and GMP methods to produce these therapies, and the testing of new adoptive cell therapies in clinical trials. The Summit on Cell Therapy for Cancer to held on November 1 and 2, 2011 at the National Institutes of Health (NIH) campus will include a mix of perspectives, concepts and ideas related to adoptive cellular therapy that are not normally presented together at any single meeting. This novel assembly will generate new ideas and new collaborations and possibly increase the rate of advancement of this field.
Optimal modulation and coding scheme allocation of scalable video multicast over IEEE 802.16e networks
Authors: Tsai Chia-Tai , Jan Rong-Hong , Chen Chien 
Published: July 2011

Abstract
With the rapid development of wireless communication technology and the rapid increase in demand for network bandwidth, IEEE 802.16e is an emerging network technique that has been deployed in many metropolises. In addition to the features of high data rate and large coverage, it also enables scalable video multicasting, which is a potentially promising application, over an IEEE 802.16e network. How to optimally assign the modulation and coding scheme (MCS) of the scalable video stream for the mobile subscriber stations to improve spectral efficiency and maximize utility is a crucial task. We formulate this MCS assignment problem as an optimization problem, called the total utility maximization problem (TUMP). This article transforms the TUMP into a precedence constraint knapsack problem, which is a NP-complete problem. Then, a branch and bound method, which is based on two dominance rules and a lower bound, is presented to solve the TUMP. The simulation results show that the proposed branch and bound method can find the optimal solution efficiently.
Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-κB pathways in monocytes/macrophages
Authors: Shim Young-Jun , Kang Byeong-Ho , Jeon Hye-Sook , Park In-Sun , Lee Ki-Up , Lee In-Kyu , Park Gil-Hong , Lee Kyung-Mi , Schedin Pepper , Min Bon-Hong 
Published: July 2011

ABSTRACTMost solid tumor tissues possess a significant population of macrophages, which are known to be closely linked with tumor progression and metastasis. Clusterin has been reported to be overexpressed in various tumors and to have a tumor-promoting role. As clusterin induction and macrophage infiltration occur concurrently at the tumor site, it raises a possibility that clusterin may regulate the function of macrophages via facilitating ECM remodeling. Here, we demonstrate for the first time the expression of MMP-9 by clusterin in human primary monocytes as well as human and murine macrophage cell lines, THP-1, and Raw264.7. MMP-9 expression was accompanied by increased enzymatic activity, as revealed by gelatin zymography. The MMP-9 activity promoted by clusterin was found to be dependent on the activation of ERK1/2 and PI3K/Akt but not p38 or JNK pathways. Inhibition of PI3K activity did not affect the activation of ERK1/2 and vice versa, indicating that the two pathways were independently operated to stimulate MMP-9 activity. Moreover, clusterin facilitated nuclear translocation of NF-κB p65 along with IκB-α degradation and phosphorylation, which was critical for MMP-9 expression. As NF-κB is a central regulator of inflammation, clusterin may provide a molecular link between inflammation and cancer via up-regulating NF-κB and MMP-9. Collectively, these data highlight a novel role of clusterin as a stimulator for MMP-9 expression in macrophages, which may contribute to the tissue reorganization by serving as a modulator for ECM degradation.