bluuebunny/crossref_metadata_2025_split huggingface dataset:
MP1
Authors: Singhoff Frank 
Published: November 2007

This tutorial assumes basic knowledge or experience with the Ada programming language. Basic understanding of tasking and real-time constraints -- at the level of tutorial MA1 -- would be helpful. We assume that attendees have a minimal background on real time operating systems, Ada tasking and critical real time applications/systems; however, a (very) short presentation of such topics will be included in the tutorial.
This tutorial deals with real time scheduling theory and its use with Ada. Real time scheduling theory was firstly proposed in 1974, but stays mostly unused by many software designers.
Too many practitioners have no background on real time scheduling. This tutorial should help them to understand the basis of such a theory and to apply it with Ada technologies. This tutorial is expected to help Ada engineers to predict the performances of their critical Ada real time applications.
This tutorial will be organized in three parts: 1. First, we define what a real time system is and then, the theoretical results of the real time scheduling theory are presented. The basic task models and schedulers are explained (their behavior and their properties). The tutorial focusses on fixed priority scheduler and its feasibility tests (eg. Rate monotonic and worst case task response time) which is the most useful scheduler with current real-life applications. However, a dynamic priority scheduler is also presented (eg. EDF). At the end of this first part, attendees should understand what a feasibility test is and how it can help them to predict performances of their real time applications. This part is ended with a short introduction on shared resource support (eg. what a priority inversion is, how PIP/PCP work).
2. Second, we show how real time scheduling features are taken into account in Ada international standards such as ISO/IEC Ada 1995 and 2005, the POSIX 1003 Ada binding and ARINC 653 (which is an avionic operating system standard providing an Ada binding). In this part, we try to show the relationships between the real time scheduling theory and the implementation of real time schedulers into practical systems.
3. Finally, some Ada program examples are presented and explained.
Towards a demonstrably-correct ada compiler
Authors: Nettleton Chris , Ifill Wilson , Marsh Colin 
Published: November 2007

We report on a significant new compiler technology for applications requiring the highest level of reliability. This work is partly funded by AWE plc and takes into account previous AWE work on a demonstrably correct compiler for a Pascal-like language. This work will be of interest to anyone developing safety-critical software.
Today's Ada compilers are based on 1980s' technology, when 4M Bytes of memory was considered sufficient for a project of 10 users. Using today's computers, when even a laptop computer has 512 M Bytes of memory; we can offer a much better compiler for a fraction of the cost. Initial estimates suggest a new technology compiler will be 1/50th the number of source lines, yet meet all our requirements for features and run-time performance.
We have already confirmed the feasibility of our approach in a prototype compiler. This handles a well-defined subset of Ada95 and employs algebraic simplifications in place of optimizations. By prohibiting recursion, we avoid costly run-time organization. Our prototype run-time system is just three instructions.
Our compiler is written in a notation much like ordinary mathematics, and is therefore amenable to mathematical techniques such as theorem proving. Later we intend to offer a proof of correctness. In the meantime, we will demonstrate correctness, both in the sense that a given program has been correctly compiled, and that all programs will be correctly compiled.
The prototype compiler performs well. It compiles at several thousand lines per second and generates code that compares well with that from our optimizing compiler.
Endostatin Binding to Ovarian Cancer Cells Inhibits Peritoneal Attachment and Dissemination
Authors: Yokoyama Yumi , Sedgewick Gerald , Ramakrishnan S. 
Published: November 2007

Abstract
Ovarian cancer cells use integrins to attach to the peritoneal wall. Integrin α5β1 is also the target for the angiogenesis inhibitor, endostatin. Therefore, the ability of endostatin to competitively inhibit tumor cell seeding of the peritoneum was investigated. An imaging method was developed to determine early phases of peritoneal dissemination of ovarian cancer cells. Using this method, endostatin was found to bind ovarian cancer cells through integrin α5β1 and inhibit vessel cooption efficiently. Although both angiostatin and endostatin are potent inhibitors of tumor angiogenesis, peritoneal attachment and vessel cooption was blocked only by the endostatin. Knocking down the expression of integrins α5 and β1 in ovarian cancer cells interfered with endostatin-mediated inhibition of peritoneal seeding. Furthermore, adenovirus-mediated in situ expression of endostatin either inside the peritoneum or by the ovarian tumor cells inhibited peritoneal seeding and dissemination in vivo. Endostatin treatment also prevented primary ovarian cancer cells from attaching to mouse peritoneal wall. These studies show a paraendothelial mechanism by which endostatin can inhibit peritoneal dissemination of ovarian cancer cells and raises the possibility of intraperitoneal expression of endostatin to reduce recurrence. [Cancer Res 2007;67(22):10813–22]
Examination of IGF2 and H19 Loss of Imprinting in Bladder Cancer
Authors: Byun Hyang-Min , Wong Hui-Lee , Birnstein Elliott Aaron , Wolff Erika M. , Liang Gangning , Yang Allen S. 
Published: November 2007

Abstract
Loss of imprinting (LOI) is a common epigenetic event in cancer and may serve as an early biomarker in some cancers. To obtain a better understanding of LOI, we studied 41 bladder tumors and their adjacent normal bladder mucosa. We found 2/9 (22.2%) cases that displayed LOI of IGF2 and 2/16 (12.5%) that had LOI of H19, as determined by the evaluation of mRNA for biallelic expression. In addition, we examined allele-specific methylation of the differentially methylated regions (DMR) of IGF2 and H19 using a new allele-specific pyrosequencing assay. We found that DNA methylation changes were a common finding (21/30, 70%) in the DMR regions, but could not clearly link DNA methylation changes with LOI as measured by biallelic expression. LOI and allele-specific DNA methylation changes are present in bladder cancer; however, a better understanding of the biology of LOI and its relationship to DNA methylation changes is needed before its use as an epigenetic biomarker. [Cancer Res 2007;67(22):10753–8]
Silencing of Prion Protein Sensitizes Breast Adriamycin-Resistant Carcinoma Cells to TRAIL-Mediated Cell Death
Authors: Meslin Franck , Hamaï Ahmed , Gao Ping , Jalil Abdelali , Cahuzac Nathalie , Chouaib Salem , Mehrpour Maryam 
Published: November 2007

Abstract
We investigated the relationship between the resistance to the proapoptotic action of tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and cellular prion protein (PrPc) function, using the TRAIL-sensitive MCF-7 human breast adenocarcinoma cell line and two TRAIL-resistant sublines: 2101 and MCF-7/ADR. All of the cell lines tested expressed TRAIL-R1 and TRAIL-R2. TRAIL decoy receptors were not detected, suggesting that the resistance of 2101 and MCF-7/ADR cells, strongly expressing PrPc, to TRAIL-mediated cell death was independent from the expression of TRAIL receptors and death-inducing signaling complex formation. Down-regulation of PrPc by small interfering RNA increased the sensitivity of Adriamycin- and TRAIL-resistant cells to TRAIL, but not to epirubicin/Adriamycin. TRAIL-mediated apoptosis in PrPc knocked-down cells was associated with caspase processing, Bid cleavage, and Mcl-1 degradation. In addition, an increased sensitivity of apoptosis-resistant cells to TRAIL after PrPc silencing was not associated with the increased recruitment of receptors and intracellular signaling molecule to the death-inducing signaling complex. Bcl-2 expression was substantially decreased after PrPc knock-down but the levels of Bcl-XL and Mcl-1 were not affected. The down-regulation of Bcl-2 was concomitant with Bax delocalization. Our findings support the notion that silencing of PrPc facilitates the activation of proapoptotic Bax by down-regulation of Bcl-2 expression, thereby abolishing the resistance of breast cancer cells to TRAIL-induced apoptosis. [Cancer Res 2007;67(22):10910–9]
Reactive Oxygen Species Regulate Angiogenesis and Tumor Growth through Vascular Endothelial Growth Factor
Authors: Xia Chang , Meng Qiao , Liu Ling-Zhi , Rojanasakul Yongyut , Wang Xin-Ru , Jiang Bing-Hua 
Published: November 2007

Abstract
Reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. However, the direct roles of endogenous ROS production still remain to be elucidated. In this study, we found that high levels of ROS were spontaneously produced by ovarian and prostate cancer cells. This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in the cells. To further analyze the source of ROS production, we found that ovarian cancer cells have much higher expression of NOX4 NADPH oxidase, and that specific inhibition of NADPH oxidase subunit p47phox diminished ROS production. To analyze the functional relevance of ROS production, we showed that ROS regulated hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. Elevated levels of endogenous ROS were required for inducing angiogenesis and tumor growth. NOX4 knockdown in ovarian cancer cells decreased the levels of VEGF and HIF-1α and tumor angiogenesis. This study suggests a new mechanism of higher ROS production in ovarian cancer cells and provides strong evidence that endogenous ROS play an important role for cancer cells to induce angiogenesis and tumor growth. This information may be useful to understand the new mechanism of cancer cells in inducing tumorigenesis and to develop new therapeutic strategy by targeting ROS signaling in human cancer in the future. [Cancer Res 2007;67(22):10823–30]
Activation of Hepatic Stem Cell Marker EpCAM by Wnt–β-Catenin Signaling in Hepatocellular Carcinoma
Authors: Yamashita Taro , Budhu Anuradha , Forgues Marshonna , Wang Xin Wei 
Published: November 2007

Abstract
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Using a gene expression profiling approach, we recently identified a novel prognostic HCC subtype that resembles hepatic progenitor cells with the activation of stem cell markers and Wnt–β-catenin signaling, based on EpCAM (epithelial cell adhesion molecule, a hepatic stem cell marker) expression. In this study, we investigated whether the activation of the Wnt–β-catenin pathway regulates EpCAM expression. We found that nuclear accumulation of β-catenin induced, whereas the degradation of β-catenin or inhibition of Tcf/β-catenin complex formation reduced EpCAM gene expression in cultured normal human hepatocytes and HCC cell lines. We identified two Tcf binding elements in the EpCAM promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. EpCAM promoter luciferase activity was down-regulated by the degradation of β-catenin or inhibition of Tcf/β-catenin complex formation. Furthermore, we found that EpCAM-positive HCC is much more sensitive to Tcf/β-catenin binding inhibitors than EpCAM-negative HCC in vitro. Taken together, our data indicate that EpCAM is a Wnt–β-catenin signaling target gene and may be used to facilitate HCC prognosis by enabling effective stratification of patients with predicted pharmacologic responses to Wnt–β-catenin signaling antagonists. [Cancer Res 2007;67(22):10831–9]
Probabilistic Modeling of DNA Mismatch Repair Effects on Cell Cycle Dynamics and Iododeoxyuridine-DNA Incorporation
Authors: Gurkan Evren , Schupp Jane E. , Aziz Mohammad A. , Kinsella Timothy J. , Loparo Kenneth A. 
Published: November 2007

AbstractPrevious studies in our laboratory have described increased and preferential radiosensitization of mismatch repair-deficient (MMR−) HCT116 colon cancer cells with 5-iododeoxyuridine (IUdR). Indeed, our studies showed that MMR is involved in the repair (removal) of IUdR-DNA, principally the G:IU mispair. Consequently, we have shown that MMR− cells incorporate 25% to 42% more IUdR than MMR+ cells, and that IUdR and ionizing radiation (IR) interact to produce up to 3-fold greater cytotoxicity in MMR− cells. The present study uses the integration of probabilistic mathematical models and experimental data on MMR− versus MMR+ cells to describe the effects of IUdR incorporation upon the cell cycle for the purpose of increasing IUdR-mediated radiosensitivity in MMR− cells. Two computational models have been developed. The first is a stochastic model of the progression of cell cycle states, which is applied to experimental data for two synchronized isogenic MMR+ and MMR− colon cancer cell lines treated with and without IUdR. The second model defines the relation between the percentage of cells in the different cell cycle states and the corresponding IUdR-DNA incorporation at a particular time point. These models can be combined to predict IUdR-DNA incorporation at any time in the cell cycle. These mathematical models will be modified and used to maximize therapeutic gain in MMR− tumors versus MMR+ normal tissues by predicting the optimal dose of IUdR and optimal timing for IR treatment to increase the synergistic action using xenograft models and, later, in clinical trials. [Cancer Res 2007;67(22):10993–11000]
16-kDa Prolactin Inhibits Endothelial Cell Migration by Down-Regulating the Ras-Tiam1-Rac1-Pak1 Signaling Pathway
Authors: Lee Sok-Hyong , Kunz Jeannette , Lin Sue-Hwa , Yu-Lee Li-yuan 
Published: November 2007

Abstract
Angiogenesis plays a key role in promoting tumorigenesis and metastasis. The 16-kDa fragment of prolactin (16k PRL) is an NH2-terminal natural breakdown fragment of the intact 23-kDa prolactin and has been shown to have potent antiangiogenic and antitumor activities. The mechanism(s) involved in the action of 16k PRL in endothelial cells remains unclear. In this study, we showed that 16k PRL reduced rat aortic endothelial cell (RAEC) migration in a wound-healing assay and in a Matrigel tube formation assay, suggesting that 16k PRL inhibits endothelial cell migration, an important activity involved in angiogenesis and tumorigenesis. We further investigated how 16k PRL attenuates endothelial cell migration. We first showed that RAEC migration is mediated through the Rho GTPase Rac1, as Rac1 inhibition by the Rac1-specific inhibitor NSC27366 or Rac1 knockdown by small interfering RNA both blocked RAEC migration. We next showed that 16k PRL reduced the activation of Rac1 in a concentration-dependent manner. Furthermore, 16k PRL inhibition of Rac1 is mediated through the suppression of T lymphoma invasion and metastasis 1 (Tiam1) and its upstream activator Ras in a phosphoinositide-3-kinase–independent manner. 16k PRL also down-regulated the phosphorylation of the downstream effector of Rac1, p21-activating kinase 1 (Pak1), and inhibited its translocation to the leading edge of migrating cells. Thus, 16k PRL inhibits cell migration by blocking the Ras-Tiam1-Rac1-Pak1 signaling pathway in endothelial cells. [Cancer Res 2007;67(22):11045–53]
Placental Growth Factor-1 Attenuates Vascular Endothelial Growth Factor-A–Dependent Tumor Angiogenesis during β Cell Carcinogenesis
Authors: Schomber Tibor , Kopfstein Lucie , Djonov Valentin , Albrecht Imke , Baeriswyl Vanessa , Strittmatter Karin , Christofori Gerhard 
Published: November 2007

Abstract
Members of the vascular endothelial growth factor (VEGF) family are critical players in angiogenesis and lymphangiogenesis. Although VEGF-A has been shown to exert fundamental functions in physiologic and pathologic angiogenesis, the exact role of the VEGF family member placental growth factor (PlGF) in tumor angiogenesis has remained controversial. To gain insight into PlGF function during tumor angiogenesis, we have generated transgenic mouse lines expressing human PlGF-1 in the β cells of the pancreatic islets of Langerhans (Rip1PlGF-1). In single-transgenic Rip1PlGF-1 mice, intra-insular blood vessels are found highly dilated, whereas islet physiology is unaffected. Upon crossing of these mice with the Rip1Tag2 transgenic mouse model of pancreatic β cell carcinogenesis, tumors of double-transgenic Rip1Tag2;Rip1PlGF-1 mice display reduced growth due to attenuated tumor angiogenesis. The coexpression of transgenic PlGF-1 and endogenous VEGF-A in the β tumor cells of double-transgenic animals causes the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers at the expense of highly angiogenic mVEGF-A homodimers resulting in diminished tumor angiogenesis and reduced tumor infiltration by neutrophils, known to contribute to the angiogenic switch in Rip1Tag2 mice. The results indicate that the ratio between the expression levels of two members of the VEGF family of angiogenic factors, PlGF-1 and VEGF-A, determines the overall angiogenic activity and, thus, the extent of tumor angiogenesis and tumor growth. [Cancer Res 2007;67(22):10840–8]
Overexpression of N-Myc Rapidly Causes Acute Myeloid Leukemia in Mice
Authors: Kawagoe Hiroyuki , Kandilci Ayten , Kranenburg Tanya A. , Grosveld Gerard C. 
Published: November 2007

Abstract
N-MYC encodes a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that is frequently overexpressed in human neuroblastoma. N-MYC overexpression has also been reported in human acute myeloid leukemias (AML), which we show here is a frequent event. Myeloid cells in N-Myc–overexpressing mouse bone marrow hyperproliferate but those in c-MYC–overexpressing bone marrow do not. The NH2-terminal transactivation domain, nuclear localization signal, and bHLH/LZ domain of N-Myc are essential for this effect. Microarray analysis revealed 969 differentially expressed genes between N-Myc– and c-MYC–overexpressing myeloid cells. N-Myc–overexpressing cells showed decreased transforming growth factor β signaling and increased c-Jun-NH2-kinase signaling, both of which are associated with proliferation and leukemic transformation of myeloid cells. Mice transplanted with bone marrow expressing wild-type N-Myc developed clonal and transplantable AML after ∼1 month; those transplanted with bone marrow expressing mutant N-Myc did not. Twist, a known suppressor of the p19Arf/p53 pathway, was up-regulated in all tumors. These results show that N-Myc overexpression is highly oncogenic in mouse myeloid cells and suggest that N-MYC up-regulation contributes to human myeloid leukemogenesis. [Cancer Res 2007;67(22):10677–85]
Transient Receptor Potential Melastatin 7–like Current in Human Head and Neck Carcinoma Cells: Role in Cell Proliferation
Authors: Jiang Jie , Li Ming-Hua , Inoue Koichi , Chu Xiang-Ping , Seeds Joshua , Xiong Zhi-Gang 
Published: November 2007

Abstract
Ion channels are involved in normal physiologic processes and in the pathology of various diseases. In this study, we investigated the presence and potential function of transient receptor potential melastatin 7 (TRPM7) channels in the growth and proliferation of FaDu and SCC25 cells, two common human head and neck squamous carcinoma cell lines, using a combination of patch-clamp recording, Western blotting, immunocytochemistry, small interfering RNA (siRNA), fluorescent Ca2+ imaging, and cell counting techniques. Although voltage-gated K+ currents were recorded in all cells, none of FaDu cells express voltage-gated Na+ or Ca2+ currents. Perfusion of cells with NMDA or acidic solution did not activate inward currents, indicating a lack of NMDA receptor and acid-sensing channels. Lowering extracellular Ca2+, however, induced a large nondesensitizing current reminiscent of Ca2+-sensing cation current or TRPM7 current previously described in other cells. This Ca2+-sensing current can be inhibited by Gd3+, 2-aminoethoxydiphenyl borate (2-APB), or intracellular Mg2+, consistent with the TRPM7 current being activated. Immunocytochemistry, Western blot, and reverse transcription-PCR detected the expression of TRPM7 protein and mRNA in these cells. Transfection of FaDu cells with TRPM7 siRNA significantly reduced the expression of TRPM7 mRNA and protein as well as the amplitude of the Ca2+-sensing current. Furthermore, we found that Ca2+ is critical for the growth and proliferation of FaDu cells. Blockade of TRPM7 channels by Gd3+ and 2-APB or suppression of TRPM7 expression by siRNA inhibited the growth and proliferation of these cells. Similar to FaDu cells, SCC25 cells also express TRPM7-like channels. Suppressing the function of these channels inhibited the proliferation of SCC25 cells. [Cancer Res 2007;67(22):10929–38]
Lymphoma Chemovirotherapy: CD20-Targeted and Convertase-Armed Measles Virus Can Synergize with Fludarabine
Authors: Ungerechts Guy , Springfeld Christoph , Frenzke Marie E. , Lampe Johanna , Johnston Patrick B. , Parker William B. , Sorscher Eric J. , Cattaneo Roberto 
Published: November 2007

Abstract
Combination chemotherapy regimen incorporating CD20 antibodies are commonly used in the treatment of CD20-positive non–Hodgkin's lymphoma (NHL). Fludarabine phosphate (F-araAMP), cyclophosphamide, and CD20 antibodies (Rituximab) constitute the FCR regimen for treating selected NHL, including aggressive mantle cell lymphoma (MCL). As an alternative to the CD20 antibody, we generated a CD20-targeted measles virus (MV)–based vector. This vector was also armed with the prodrug convertase purine nucleoside phosphorylase (PNP) that locally converts the active metabolite of F-araAMP to a highly diffusible substance capable of efficiently killing bystander cells. We showed in infected cells that early prodrug administration controls vector spread, whereas late administration enhances cell killing. Control of spread by early prodrug administration was also shown in an animal model: F-araAMP protected genetically modified mice susceptible to MV infection from a potentially lethal intracerebral challenge. Enhanced oncolytic potency after extensive infection was shown in a Burkitt's lymphoma xenograft model (Raji cells): After systemic vector inoculation, prodrug administration enhanced the therapeutic effect synergistically. In a MCL xenograft model (Granta 519 cells), intratumoral (i.t.) vector administration alone had high oncolytic efficacy: All mice experienced complete but temporary tumor regression, and survival was two to four times longer than that of untreated mice. Cells from MCL patients were shown to be sensitive to infection. Thus, synergy of F-araAMP with a PNP-armed and CD20-targeted MV was shown in one lymphoma therapy model after systemic vector inoculation. [Cancer Res 2007;67(22):10939–47]