bluuebunny/crossref_metadata_2025_split huggingface dataset:
Permuting streaming data using RAMs
Authors: Püschel Markus , Milder Peter A. , Hoe James C. 
Published: April 2009

This article presents a method for constructing hardware structures that perform a fixed permutation on streaming data. The method applies to permutations that can be represented as linear mappings on the bit-level representation of the data locations. This subclass includes many important permutations such as stride permutations (corner turn, perfect shuffle, etc.), the bit reversal, the Hadamard reordering, and the Gray code reordering.
The datapath for performing the streaming permutation consists of several independent banks of memory and two interconnection networks. These structures are built for a given streaming width (i.e., number of inputs and outputs per cycle) and operate at full throughput for this streaming width.
We provide an algorithm that completely specifies the datapath and control logic given the desired permutation and streaming width. Further, we provide lower bounds on the achievable cost of a solution and show that for an important subclass of permutations our solution is optimal.
We apply our algorithm to derive datapaths for several important permutations, including a detailed example that carefully illustrates each aspect of the design process. Lastly, we compare our permutation structures to those of Järvinen et al. [2004], which are specialized for stride permutations.
Adiponectin-Activated AMPK Stimulates Dephosphorylation of AKT through Protein Phosphatase 2A Activation
Authors: Kim Kun-yong , Baek Ahmi , Hwang Ji-Eun , Choi Yeon A. , Jeong Joon , Lee Myeong-Sok , Cho Dea Ho , Lim Jong-Seok , Kim Keun Il , Yang Young 
Published: April 2009

Abstract
Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56γ was directly phosphorylated by AMPK at Ser298 and Ser336, leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr307. We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A. [Cancer Res 2009;69(9):4018–26]
p53-Altered FBXW7 Expression Determines Poor Prognosis in Gastric Cancer Cases
Authors: Yokobori Takehiko , Mimori Koshi , Iwatsuki Masaaki , Ishii Hideshi , Onoyama Ichiro , Fukagawa Takeo , Kuwano Hiroyuki , Nakayama Keiichi I. , Mori Masaki 
Published: April 2009

Abstract
A molecular target associated with the progression of gastric cancer has not yet been uncovered. FBXW7 is a tumor suppressor gene transcriptionally controlled by p53 that plays a role in the regulation of cell cycle exit and reentry via c-Myc degradation. Few studies have addressed the clinical significance of FBXW7 expression in gastric cancer. Therefore, we examined FBXW7 mRNA expression to determine its clinicopathologic significance in 100 cases of gastric cancer. Low expression levels of FBXW7 in primary gastric cancer contributed to malignant potential, such as lymph node metastasis (P = 0.0012), tumor size (P = 0.0003), and poor prognosis (P = 0.018). In comparison with 52 cases of gastric cancer without the p53 mutation, 29 cases with the mutation exhibited lower expression levels of FBXW7 (P = 0.0034), revealing a significant relationship between p53 mutation and FBXW7 expression. Furthermore, we found that gastric cancer patients who had low FBXW7 expression levels and p53 mutation had a distinctively poor prognosis in comparison with other subgroups (P = 0.0033). In conclusion, we showed a role for p53 in the transcriptional regulation of FBXW7 expression in clinical gastric cancer cases and showed that disruption of both p53 and FBXW7 contributes to poor prognosis. [Cancer Res 2009;69(9):3788–94]
A Double Hit to Kill Tumor and Endothelial Cells by TRAIL and Antiangiogenic 3TSR
Authors: Ren Bin , Song Keli , Parangi Sareh , Jin Taiguang , Ye Min , Humphreys Robin , Duquette Mark , Zhang Xuefeng , Benhaga Nordine , Lawler Jack , Khosravi-Far Roya 
Published: April 2009

Abstract
As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH2-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels. [Cancer Res 2009;69(9):3856–65]
Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway
Authors: Kurosu Tetsuya , Ohki Manabu , Wu Nan , Kagechika Hiroyuki , Miura Osamu 
Published: April 2009

Abstract
Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL–driven cells. Sorafenib also inhibited BCR/ABL–induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL–expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors. [Cancer Res 2009;69(9):3927–36]
AZD1152 Rapidly and Negatively Affects the Growth and Survival of Human Acute Myeloid Leukemia Cells In vitro and In vivo
Authors: Oke Adedayo , Pearce Daniel , Wilkinson Robert W. , Crafter Claire , Odedra Rajesh , Cavenagh Jamie , Fitzgibbon Jude , Lister Andrew T. , Joel Simon , Bonnet Dominique 
Published: April 2009

Abstract
Aurora kinases play a critical role in regulating mitosis and cell division, and their overexpression has been implicated in the survival and proliferation of human cancer. In this study, we report the in vitro and in vivo activities of AZD1152, a compound that has selectivity for aurora B kinase, in acute myeloid leukemia (AML) cell lines, primary AML samples, and cord blood cells. AZD1152 exerted antiproliferative or cytotoxic effects in all cell lines studied, inhibited the phosphorylation of histone H3 (pHis H3) on Ser10 in a dose-dependent manner, and resulted in cells with &gt;4N DNA content. THP-1 cells treated with AZD1152 accumulated in a state of polyploidy and showed a senescent response to the drug, in contrast to the apoptotic response seen in other cell lines. Accordingly, AZD1152 profoundly affected the growth of AML cell lines and primary AML in an in vivo xenotransplantation model. However, concentration-dependent effects on cell growth, apoptosis, and cell cycle progression were also observed when human cord blood and primary lineage–negative stem and progenitor cells were analyzed in vitro and in vivo. These data suggest that the inhibition of aurora B kinase may be a useful therapeutic strategy in the treatment of AML and that further exploration of dosing and treatment schedules is warranted in clinical trials. [Cancer Res 2009;69(10):4150–8]
Pharmacologic Abrogation of the Mitotic Spindle Checkpoint by an Indolocarbazole Discovered by Cellular Screening Efficiently Kills Cancer Cells
Authors: Stolz Ailine , Vogel Celia , Schneider Verena , Ertych Norman , Kienitz Anne , Yu Hongtao , Bastians Holger 
Published: April 2009

Abstract
The mitotic spindle checkpoint represents a signal transduction pathway that prevents the onset of anaphase until all chromosomes are properly aligned on a metaphase plate. Partial inactivation of this checkpoint allows premature separation of sister chromatids and results in aneuploidy, which might contribute to tumorigenesis. Unlike other cell cycle checkpoints, the spindle checkpoint is essential for cell viability, giving rise to the idea that the spindle checkpoint itself might represent a valuable target for anticancer therapy. We used a cell-based screen and identified the indolocarbazole compound Gö6976 as a pharmacologic inhibitor of the spindle checkpoint. Gö6976 potently overrides a spindle checkpoint–mediated mitotic arrest by abrogating the phosphorylation and kinetochore localization of several spindle checkpoint proteins. We identified the Aurora-A and Aurora-B kinases, which have been previously implicated in proper mitotic progression and spindle checkpoint function, as targets for Gö6976. Accordingly, Gö6976 treatment causes severe mitotic abnormalities and chromosome alignment defects, which are not properly detected by the drug-inactivated spindle checkpoint. This results in an aberrant progression of mitosis, leading to apoptosis in various human cancer cell lines, including spindle checkpoint–compromised cancer cells. Thus, our work describes a novel and promising strategy for anticancer treatment that targets the mitotic spindle checkpoint. [Cancer Res 2009;69(9):3874–83]
SCUBE2 Suppresses Breast Tumor Cell Proliferation and Confers a Favorable Prognosis in Invasive Breast Cancer
Authors: Cheng Chien-Jui , Lin Yuh-Charn , Tsai Ming-Tzu , Chen Ching-Shyang , Hsieh Mao-Chih , Chen Chi-Long , Yang Ruey-Bing 
Published: April 2009

Abstract
Signal peptide-CUB-epidermal growth factor–like domain-containing protein 2 (SCUBE2), originally identified from the endothelium and several nonendothelial primary cell types, was recently shown to be expressed in invasive breast carcinomas. However, the protein localization and biological significance of SCUBE2 in breast cancer are unknown. In this report, we show by anti-SCUBE2 immunostaining that SCUBE2 is mainly expressed in vascular endothelial and mammary ductal epithelial cells in normal breast tissue. In addition, we observed positive staining for SCUBE2 in 55% (86 of 156) of primary breast tumors. Patients with positive SCUBE2 protein–expressing tumors had better prognosis than those with negative SCUBE2 protein–expressing tumors in terms of disease-free survival. Multivariate analysis confirmed SCUBE2 protein expression as an independent prognostic factor for disease-free survival. Furthermore, overexpression of ectopic SCUBE2 protein resulted in suppression of MCF-7 breast cancer cell proliferation and reduced MCF-7 xenograft tumor growth in nude mice. Molecular and biochemical analyses revealed that the COOH terminal region of SCUBE2 directly bound to and antagonized bone morphogenetic protein activity. Together, our results show for the first time that altered SCUBE2 expression is important in breast cancer progression and SCUBE2 may serve as a useful prognostic marker. [Cancer Res 2009;69(8):3634–41]
Multiparameter Computational Modeling of Tumor Invasion
Authors: Bearer Elaine L. , Lowengrub John S. , Frieboes Hermann B. , Chuang Yao-Li , Jin Fang , Wise Steven M. , Ferrari Mauro , Agus David B. , Cristini Vittorio 
Published: April 2009

Abstract
Clinical outcome prognostication in oncology is a guiding principle in therapeutic choice. A wealth of qualitative empirical evidence links disease progression with tumor morphology, histopathology, invasion, and associated molecular phenomena. However, the quantitative contribution of each of the known parameters in this progression remains elusive. Mathematical modeling can provide the capability to quantify the connection between variables governing growth, prognosis, and treatment outcome. By quantifying the link between the tumor boundary morphology and the invasive phenotype, this work provides a quantitative tool for the study of tumor progression and diagnostic/prognostic applications. This establishes a framework for monitoring system perturbation towards development of therapeutic strategies and correlation to clinical outcome for prognosis.[Cancer Res 2009;69(10):4493–501]
Major Findings We apply a biologically founded, multiscale, mathematical model to identify and quantify tumor biologic and molecular properties relating to clinical and morphological phenotype and to demonstrate that tumor growth and invasion are predictable processes governed by biophysical laws, and regulated by heterogeneity in phenotypic, genotypic, and microenvironmental parameters. This heterogeneity drives migration and proliferation of more aggressive clones up cell substrate gradients within and beyond the central tumor mass, while often also inducing loss of cell adhesion. The model predicts that this process triggers a gross morphologic instability that leads to tumor invasion via individual cells, cell chains, strands, or detached clusters infiltrating into adjacent tissue producing the typical morphologic patterns seen, e.g., in the histopathology of glioblastoma multiforme. The model further predicts that these different morphologies of infiltration correspond to different stages of tumor progression regulated by heterogeneity.
Quantitative Metrics of Net Proliferation and Invasion Link Biological Aggressiveness Assessed by MRI with Hypoxia Assessed by FMISO-PET in Newly Diagnosed Glioblastomas
Authors: Szeto Mindy D. , Chakraborty Gargi , Hadley Jennifer , Rockne Russ , Muzi Mark , Alvord Ellsworth C. , Krohn Kenneth A. , Spence Alexander M. , Swanson Kristin R. 
Published: April 2009

Abstract
Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal-appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics [assessed via mathematical models and routine magnetic resonance imaging (MRI)] and the hypoxic burden of the tumor [assessed via positron emission tomography (PET) imaging]. Our biomathematical model for glioma kinetics describes the spatial and temporal evolution of a glioma in terms of concentration of malignant tumor cells. This model has already been proven useful as a novel tool to dynamically quantify the net rates of proliferation (ρ) and invasion (D) of the glioma cells in individual patients. Estimates of these kinetic rates can be calculated from routinely available pretreatment MRI in vivo. Eleven adults with GBM were imaged preoperatively with 18F-fluoromisonidazole (FMISO)–PET and serial gadolinium-enhanced T1- and T2-weighted MRIs to allow the estimation of patient-specific net rates of proliferation (ρ) and invasion (D). Hypoxic volumes were quantified from each FMISO-PET scan following standard techniques. To control for tumor size variability, two measures of hypoxic burden were considered: relative hypoxia (RH), defined as the ratio of the hypoxic volume to the T2-defined tumor volume, and the mean intensity on FMISO-PET scaled to the blood activity of the tracer (mean T/B). Pearson correlations between RH and the net rate of cell proliferation (ρ) reached significance (P &lt; 0.04). Moreover, highly significant positive correlations were found between biological aggressiveness ratio (ρ/D) and both RH (P &lt; 0.00003) and the mean T/B (P &lt; 0.0007). [Cancer Res 2009;69(10):4502–9]
Major Findings Overall, biological aggressiveness assessed by serial MRI is linked with hypoxic burden assessed on FMISO-PET using a novel biomathematical model for glioma growth and invasion. This study suggests that patient-specific modeling of growth kinetics can provide novel and valuable insight into the quantitative connections between disparate information provided by multimodality imaging.
Global Histone Modifications in Breast Cancer Correlate with Tumor Phenotypes, Prognostic Factors, and Patient Outcome
Authors: Elsheikh Somaia E. , Green Andrew R. , Rakha Emad A. , Powe Des G. , Ahmed Rabab A. , Collins Hilary M. , Soria Daniele , Garibaldi Jonathan M. , Paish Claire E. , Ammar Amr A. , Grainge Matthew J. , Ball Graham R. , Abdelghany Magdy K. , Martinez-Pomares Luisa , Heery David M. , Ellis Ian O. 
Published: April 2009

Abstract
Post-translational histone modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Immunohistochemistry was used to detect a series of histone lysine acetylation (H3K9ac, H3K18ac, H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) marks in a well-characterized series of human breast carcinomas (n = 880). Tissue staining intensities were assessed using blinded semiquantitative scoring. Validation studies were done using immunofluorescence staining and Western blotting. Our analyses revealed low or absent H4K16ac in the majority of breast cancer cases (78.9%), suggesting that this alteration may represent an early sign of breast cancer. There was a highly significant correlation between histone modifications status, tumor biomarker phenotype, and clinical outcome, where high relative levels of global histone acetylation and methylation were associated with a favorable prognosis and detected almost exclusively in luminal-like breast tumors (93%). Moderate to low levels of lysine acetylation (H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3), and arginine methylation (H4R3me2) were observed in carcinomas of poorer prognostic subtypes, including basal carcinomas and HER-2-positive tumors. Clustering analysis identified three groups of histone displaying distinct pattern in breast cancer, which have distinct relationships to known prognostic factors and clinical outcome. This study identifies the presence of variations in global levels of histone marks in different grades, morphologic types, and phenotype classes of invasive breast cancer and shows that these differences have clinical significance. [Cancer Res 2009;69(9):3802–9]
DNA Cross-Links in Human Tumor Cells Exposed to the Prodrug PR-104A: Relationships to Hypoxia, Bioreductive Metabolism, and Cytotoxicity
Authors: Singleton Rachelle S. , Guise Christopher P. , Ferry Dianne M. , Pullen Susan M. , Dorie Mary J. , Brown J. Martin , Patterson Adam V. , Wilson William R. 
Published: April 2009

Abstract
PR-104, currently in clinical trial, is converted systemically to the dinitrobenzamide nitrogen mustard prodrug PR-104A, which is reduced selectively in hypoxic cells to cytotoxic hydroxylamine (PR-104H) and amine (PR-104M) metabolites. Here, we evaluate the roles of this reductive metabolism, and DNA interstrand cross-links (ICL), in the hypoxic and aerobic cytotoxicity of PR-104. Using a panel of 9 human tumor cell lines, cytotoxicity was determined by clonogenic assay after a 2-hour aerobic or hypoxic exposure to PR-104A. PR-104H and PR-104M were determined by high performance liquid chromatography/mass spectrometry, and ICL with the alkaline comet assay. Under hypoxia, the relationship between ICL and cell killing was similar between cell lines. Under aerobic conditions, there was a similar relationship between ICL and cytotoxicity, except in lines with very low rates of aerobic reduction of PR-104A (A2780, C33A, H1299), which showed an ICL-independent mechanism of PR-104A cytotoxicity. Despite this, in xenografts from the same lines, the frequency of PR-104–induced ICL correlated with clonogenic cell killing (r2 = 0.747) with greatest activity in the fast aerobic metabolizers. In addition, changing levels of hypoxia in SiHa tumors modified both ICL frequency and tumor growth delay in parallel. We conclude that both aerobic and hypoxic nitroreduction of PR-104A contribute to the monotherapy antitumor activity of PR-104 in human tumor xenografts, and that ICL are responsible for its antitumor activity and represent a broadly applicable biomarker for tumor cell killing by this novel prodrug. [Cancer Res 2009;69(9):3884–91]
Computationally Guided Photothermal Tumor Therapy Using Long-Circulating Gold Nanorod Antennas
Authors: von Maltzahn Geoffrey , Park Ji-Ho , Agrawal Amit , Bandaru Nanda Kishor , Das Sarit K. , Sailor Michael J. , Bhatia Sangeeta N. 
Published: April 2009

AbstractPlasmonic nanomaterials have the opportunity to considerably improve the specificity of cancer ablation by i.v. homing to tumors and acting as antennas for accepting externally applied energy. Here, we describe an integrated approach to improved plasmonic therapy composed of multimodal nanomaterial optimization and computational irradiation protocol development. We synthesized polyethylene glycol (PEG)–protected gold nanorods (NR) that exhibit superior spectral bandwidth, photothermal heat generation per gram of gold, and circulation half-life in vivo (t1/2, ∼17 hours) compared with the prototypical tunable plasmonic particles, gold nanoshells, as well as ∼2-fold higher X-ray absorption than a clinical iodine contrast agent. After intratumoral or i.v. administration, we fuse PEG-NR biodistribution data derived via noninvasive X-ray computed tomography or ex vivo spectrometry, respectively, with four-dimensional computational heat transport modeling to predict photothermal heating during irradiation. In computationally driven pilot therapeutic studies, we show that a single i.v. injection of PEG-NRs enabled destruction of all irradiated human xenograft tumors in mice. These studies highlight the potential of integrating computational therapy design with nanotherapeutic development for ultraselective tumor ablation. [Cancer Res 2009;69(9):3892–900]