bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis and Biological Evaluation of 17-[4-(2-Aminoethoxy)phenyl]-16,17-secoestra-1,3,5(10)-triene Derivatives
Authors: Sakač Marija N. , Penov Gaši Katarina M. , Djurendić Evgenija A. , Andrić Silvana , Miljković Dušan A. 
Published: April 2007

Starting from 3-(benzyloxy)-16-(hydroxyimino)estra-1,3,5(10)-trien-17-one (1), 3-(benzyloxy)- 17-{4-[2-(dimethylamino)ethoxy]phenyl}-17-oxo-16,17-secoestra-1,3,5(10)-triene-16-nitrile (3a) was synthesized. Reduction of 3a with sodium borohydride yielded secocyano alcohol 4a, as well as the secoamino alcohol 5a when reduction was performed with sodium borohydride in the presence of cobalt(II) salt. Deprotection of the C-3 hydroxy group in compounds 3a-5a by catalytic hydrogenolysis resulted in the corresponding 3-hydroxy derivatives 3b-5b. Compounds 3b-5b were tested on residual estrogenic and potential antiestrogenic activities.
Extending reliability (Extended Abstract>
Authors: Boyle James M. 
Published: April 2007

Over the past decade, mathematical software libraries have matured from small, usually locally-assembled, collections of subroutines to large, commercially-provided libraries which are approaching the status of standards [Aird; Du Croz; Fox]**. Despite the high quality of such libraries and the obvious economic advantages of using routines whose development cost has been shared with many other users, applications programmers, when asked: “Why don't you use routine XYZ from IMSL, or from NAC, or from PORT?” frequently reply that library routines are too general, that they need a routine which takes advantage of special features of their problem, and that since they could not use a library routine without modifying it, they might as well write their own routine from scratch.
In many, if not most, instances, the latter assertion could be easily refuted by a simple competition on selected test problems. However, the need for a routine adapted, or tailored, to a particular problem is more difficult to dismiss. It usually arises from considerations of efficiency, which may range from the perceived inefficiency of the presence of unused options in a routine to the practical impossibility of using a routine whose data representation is utterly incompatible with that needed in the rest of the applications program.
Using tools for verification, documentation and testing
Authors: Osterweil Loen J. 
Published: April 2007

There has been considerable interest lately in methodologies for the production of high quality computer software. Work in this area has been carried out by researchers in a wide variety of disciplines and covers an impressive spectrum of approaches. Some of the more active current lines of research include: software management techniques [1, 2]; creation of error resistant programming techniques [3, 4, 5]; and design of error resistant programming languages [6, 7].
There has also been considerable activity in the creation of program testing, verification and documentation tools. The work in this area has been directed primarily towards two different but related goals—the detection and examination of errors present in a program, and the determination that a given program has no errors of some particular type. Among the diverse activities in this area, this paper shall focus on four of the major approaches—namely dynamic testing, symbolic execution, formal verification and static analysis. In this paper, the different patterns of strengths, weaknesses and applications of these approaches will be shown. It will, moreover, be demonstrated that these patterns are in many ways complementary, offering the hope that they can be coordinated and unified into a single comprehensive program testing and verification system capable of performing a diverse and useful variety of error detection, verification and documentation functions.
New languages for numerical software
Authors: Coughran Bill , Grosse Eric 
Published: April 2007

Existing languages for numerical software are not altogether satisfactory. Fortran, even preprocessed, has troublesome limitations. Unfortunately, proposed replacements have been discouragingly large, or omit essential features like variably dimensioned arrays and Fortran compatibility.
A new language has been designed to include such crucial features, but otherwise be as small as possible. This language, called T, includes: indention to indicate block structure, novel loop syntax, and engineering format for real constants. By preprocessing into PL/I, implementation cost was kept low.
But this language can only be regarded as a stopgap. The next step is to deal with more fundamental issues, by more fully exploiting arrays, by making pointers available in a controlled way, and by arranging for better declaration and syntax for using subroutine libraries.
Transportability in practice - recent experience with the NAG Library
Authors: Du Croz J. J. 
Published: April 2007

Two guiding principles for the development of the NAG Library are:

the algorithms must be
adaptable
to the characteristic of the computer on which they are being run;

the software must be
transportable

(These concepts have been discussed in detail elsewhere.)
The purpose of this talk is to discuss how these principles have stood the test of practice over the past two years and how NAG's approach to library development has been refined in the light of experience.
The adaptability of algorithms is achieved with the aid of machine-dependent parameters, available through calls of library functions. The initial set of parameters was concerned only with the arithmetic properties of the computer. A new parameter is now being introduced, concerned with storage organizations: it will enable algorithms for certain operations of linear algebra to adapt, when run on a paged machine, to the approximate amount of real store available, and hence to achieve a dramatic reduction in page-thrashing.
The transportability of the software is proven by the fact that the NAG Library has now been implemented on 25 different computer systems - including several minicomputers, which required no fundamental change of approach. The talk will discuss various interesting problems which have arisen in the course of implementation. Frequently it has been deficiencies in the compiler and associated software that have caused the problems, rather than defects in the NAG routines. NAG's test software (though not always ideally suited to the task) has proved remarkably effective at detecting these problems before the Library is released to sites. This justifies NAG's policy of always distributing a tested compiled library (in addition to the source-text).
Desirable floating-point arithmetic and elementary functions for numerical computation
Authors: Hull D. E. 
Published: April 2007

The purpose of this talk is to summarize proposed specifications for floating-point arithmetic and elementary functions. The topics considered are: the base of the number system, precision control, number representation, arithmetic operations, other basic operations, elementary functions, and exception handling. The possibility of doing with-out fixed-point arithmetic is also mentioned.
The specifications are intended to be entirely at the level of a programming language such as Fortran. The emphasis is on convenience and simplicity from the user's point of view. Conforming to such specifications would have obvious beneficial implications for the portability of numerical software, and for proving programs correct, as well as attempting to provide facilities which are most suitable for the user. The specifications are not complete in every detail, but it is intended that they be complete “in spirit” - some further details, especially syntactic details, would have to be provided, but the proposals are otherwise relatively complete.
Handling of floating point exceptions
Authors: Eggers Thomas W. , Leonard Judson S. , Payne Mary H. 
Published: April 2007

An IEEE subcommittee on the standardization of microprocessor floating point arithmetic has a proposal under discussion. Part of that proposal concerns overflow and underflow exceptions.
The proposal calls for a “gradual” underflow implemented with demoralized numbers. For a sequence of addition/subtraction operations, the gradual underflow works very well: it almost has the effect of a machine with infinite range numbers. But if an addition/subtraction sequence is interrupted by a multiply or divide, things don't work nearly as well, and a fallback to symbolic information is likely. The proposal helps overflow hardly at all.
Composition of mappings given by embedded dependencies
Authors: Nash Alan , Bernstein Philip A. , Melnik Sergey 
Published: April 2007

Composition of mappings between schemas is essential to support schema evolution, data exchange, data integration, and other data management tasks. In many applications, mappings are given by embedded dependencies. In this article, we study the issues involved in composing such mappings.

Our algorithms and results extend those of Fagin et al. [2004], who studied the composition of mappings given by several kinds of constraints. In particular, they proved that full source-to-target tuple-generating dependencies (tgds) are closed under composition, but embedded source-to-target tgds are not. They introduced a class of second-order constraints,
SO tgds
, that is closed under composition and has desirable properties for data exchange.

We study constraints that need not be source-to-target and we concentrate on obtaining (first-order) embedded dependencies. As part of this study, we also consider full dependencies and second-order constraints that arise from Skolemizing embedded dependencies. For each of the three classes of mappings that we study, we provide: (a) an algorithm that attempts to compute the composition; and (b) sufficient conditions on the input mappings which guarantee that the algorithm will succeed.
In addition, we give several negative results. In particular, we show that full and second-order dependencies that are not limited to be source-to-target are not closed under composition (for the latter, under the additional restriction that no new function symbols are introduced). Furthermore, we show that determining whether the composition can be given by these kinds of dependencies is undecidable.
A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression
Authors: Wang Xiu-Fang , Birringer Marc , Dong Lan-Feng , Veprek Pavel , Low Pauline , Swettenham Emma , Stantic Marina , Yuan Lin-Hong , Zobalova Renata , Wu Kun , Ledvina Miroslav , Ralph Stephen J. , Neuzil Jiri 
Published: April 2007

Abstract
Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic α-tocopheryl succinate (α-TOS). Treating erbB2-low or erbB2-high cells with α-TOS induced similar levels of apoptosis, whereas α-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. α-TOS rapidly accumulated in erbB2-high cells exposed to α-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by α-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. α-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting α-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors. [Cancer Res 2007;67(7):3337–44]
Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin
Authors: Cui Hongyan , Darmanin Stephanie , Natsuisaka Mitsuteru , Kondo Takeshi , Asaka Masahiro , Shindoh Masanobu , Higashino Fumihiro , Hamuro Junji , Okada Futoshi , Kobayashi Masataka , Nakagawa Koji , Koide Hideyuki , Kobayashi Masanobu 
Published: April 2007

AbstractAlthough hypovasculature is an outstanding characteristic of pancreatic cancers, the tumor cells survive and proliferate under severe hypoxic, glucose-deprived conditions caused by low blood supply. It is well known that the hypoxia-inducible factor-1 pathway is essential for the survival of pancreatic cancer cells under hypoxic conditions. To discover how pancreatic cancer cells adapt to glucose deprivation as well as hypoxia, we sought glucose deprivation–inducible genes by means of a DNA microarray system. We identified 63 genes whose expression was enhanced under glucose-deprived conditions at &gt;2-fold higher levels than under normal glucose conditions. Among these genes, asparagine synthetase (ASNS) was studied in detail. Although it is known to be associated with drug resistance in leukemia and oncogenesis triggered by mutated p53, its function is yet to be determined. In this study, we found that glucose deprivation induced the overexpression of ASNS through an AMP-activated protein kinase–independent and activating transcription factor-4–dependent manner and that ASNS protects pancreatic cancer cells from apoptosis induced by glucose deprivation itself. ASNS overexpression also induced resistance to apoptosis triggered by cisplatin [cis-diammine-dichloroplatinum (CDDP)] and carboplatin, but not by 5-fluorouracil, paclitaxel, etoposide, or gemcitabine. We show that glucose deprivation induces the activation of c-jun NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK) in a mock transfectant but not in an ASNS transfectant. Consequently, an inhibitor of JNK/SAPK decreased the sensitivity of pancreatic cancer cells to apoptosis by glucose deprivation and CDDP. These results strongly suggest that ASNS is induced by glucose deprivation and may play a pivotal role in the survival of pancreatic cancer cells under glucose-deprived conditions. [Cancer Res 2007;67(7):3345–55]
Mitogen-Activated Protein Kinase Kinase Inhibition Enhances Nuclear Proapoptotic Function of p53 in Acute Myelogenous Leukemia Cells
Authors: Kojima Kensuke , Konopleva Marina , Samudio Ismael J. , Ruvolo Vivian , Andreeff Michael 
Published: April 2007

Abstract
Activation of the Raf/MEK/ERK pathway and inactivation of wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML). We investigated the interaction of Raf/MEK/ERK and p53 pathways after their simultaneous blockades using a selective small-molecule antagonist of Mdm2, Nutlin-3a, and a pharmacologic MEK-specific inhibitor, PD98059. We found that PD98059, which itself has minimal apoptogenic activity, acts synergistically with Nutlin-3a to induce apoptosis in wild-type p53 AML cell lines OCI-AML-3 and MOLM-13. Interestingly, PD98059 enhanced nuclear proapototic function of p53 in these cells. In accordance with the activation of transcription-dependent apoptosis, PD98059 treatment promoted the translocation of p53 from the cytoplasm to the nucleus in OCI-AML-3 cells, in which p53 primarily initiates transcription-independent apoptosis when cells are treated with Nutlin-3a alone. The critical role of p53 localization in cells with increased p53 levels was supported by enhanced apoptosis induction in cells cotreated with Nutlin-3a and the nuclear export inhibitor leptomycin B. PD98059 prevented p53-mediated induction of p21 at the transcriptional level. The repressed expression of antiapototic p21 also seemed to contribute to synergism between PD98059 and Nutlin-3a because (a) the synergistic apoptogenic effect was preserved in G1 cells, (b) p53-mediated induction of p21 was preferentially seen in G1 cells, (c) PD98059 strongly antagonized p21 induction by Nutlin-3a, and (d) cells with high p21 levels were resistant to apoptosis. This is the first report showing that the Raf/MEK/ERK pathway regulates the subcellular localization of p53 and the relative contribution of transcription-dependent and transcription-independent pathways in p53-mediated apoptosis. [Cancer Res 2007;67(7):3210–9]
Nuclear Factor-κB and Manganese Superoxide Dismutase Mediate Adaptive Radioresistance in Low-Dose Irradiated Mouse Skin Epithelial Cells
Authors: Fan Ming , Ahmed Kazi Mokim , Coleman Mitchell C. , Spitz Douglas R. , Li Jian Jian 
Published: April 2007

Abstract
Mechanisms governing inducible resistance to ionizing radiation in untransformed epithelial cells pre-exposed to low-dose ionizing radiation (LDIR; ≤10 cGy) are not well understood. The present study provides evidence that pre-exposure to 10 cGy X-rays increases clonogenic survival of mouse skin JB6P+ epithelial cells subsequently exposed to 2 Gy doses of γ-rays. To elucidate the molecular pathways of LDIR-induced adaptive radioresistance, the transcription factor nuclear factor-κB (NF-κB) and a group of NF-κB–related proteins [i.e., p65, manganese superoxide dismutase (MnSOD), phosphorylated extracellular signal-regulated kinase, cyclin B1, and 14-3-3ζ] were identified to be activated as early as 15 min after LDIR. Further analysis revealed that a substantial amount of both 14-3-3ζ and cyclin B1 accumulated in the cytoplasm at 4 to 8 h when cell survival was enhanced. The nuclear 14-3-3ζ and cyclin B1 were reduced and increased at 4 and 24 h, respectively, after LDIR. Using YFP-fusion gene expression vectors, interaction between 14-3-3ζ and cyclin B1 was visualized in living cells, and LDIR enhanced the nuclear translocation of the 14-3-3ζ/cyclin B1 complex. Treatment of JB6P+ cells with the NF-κB inhibitor IMD-0354 suppressed LDIR-induced expression of MnSOD, 14-3-3ζ, and cyclin B1 and diminished the adaptive radioresistance. In addition, treatment with small interfering RNA against mouse MnSOD was shown to inhibit the development of LDIR-induced radioresistance. Together, these results show that NF-κB, MnSOD, 14-3-3ζ, and cyclin B1 contribute to LDIR-induced adaptive radioresistance in mouse skin epithelial cells. [Cancer Res 2007;67(7):3220–8]
Evidence that in Xeroderma Pigmentosum Variant Cells, which Lack DNA Polymerase η, DNA Polymerase ι Causes the Very High Frequency and Unique Spectrum of UV-Induced Mutations
Authors: Wang Yun , Woodgate Roger , McManus Terrence P. , Mead Samantha , McCormick J. Justin , Maher Veronica M. 
Published: April 2007

Abstract
Xeroderma pigmentosum variant (XPV) patients have normal DNA excision repair, yet are predisposed to develop sunlight-induced cancer. They exhibit a 25-fold higher than normal frequency of UV-induced mutations and very unusual kinds (spectrum), mainly transversions. The primary defect in XPV cells is the lack of functional DNA polymerase (Pol) η, the translesion synthesis DNA polymerase that readily inserts adenine nucleotides opposite photoproducts involving thymine. The high frequency and striking difference in kinds of UV-induced mutations in XPV cells strongly suggest that, in the absence of Pol η, an abnormally error-prone polymerase substitutes. In vitro replication studies of Pol ι show that it replicates past 5′T-T3′ and 5′T-U3′ cyclobutane pyrimidine dimers, incorporating G or T nucleotides opposite the 3′ nucleotide. To test the hypothesis that Pol ι causes the high frequency and abnormal spectrum of UV-induced mutations in XPV cells, we identified an unlimited lifespan XPV cell line expressing two forms of Pol ι, whose frequency of UV-induced mutations is twice that of XPV cells expressing one form. We eliminated expression of one form and compared the parental cells and derivatives for the frequency and kinds of UV-induced mutations. All exhibited similar sensitivity to the cytotoxicity of UV(254 nm), and the kinds of mutations induced were identical, but the frequency of mutations induced in the derivatives was reduced to ≤50% that of the parent. These data strongly support the hypothesis that in cells lacking Pol η, Pol ι is responsible for the high frequency and abnormal spectrum of UV-induced mutations, and ultimately their malignant transformation. [Cancer Res 2007;67(7):3018–26]
E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase
Authors: Kang Hyung-Gyoo , Jenabi Jasmine M. , Zhang Jingsong , Keshelava Nino , Shimada Hiroyuki , May William A. , Ng Tony , Reynolds C. Patrick , Triche Timothy J. , Sorensen Poul H.B. 
Published: April 2007

Abstract
Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or β1-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal–regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by α-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin–dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents. [Cancer Res 2007;67(7):3094–105]