bluuebunny/crossref_metadata_2025 huggingface dataset:
QUICK
Authors: Fletcher Sharon , Luce Thomas
Published: November 2005

Traditionally, CAI has been characterized by (1) individualized instruction based on performance, and (2) real-time interaction. Efforts to provide CAI on general purpose equipment have not been successful, and as a result many have turned to dedicated equipment (TICCIT, PLATO). An alternate approach to CAI, on general purpose equipment, is proposed in this paper. A typical interaction between a student and a CAI system can be viewed as a stimulus from the system, followed by a response from the student, followed by feedback plus another stimulus from the system. In many applications, the student response interval can be relatively long. The approach used by QUICK is to purposely extend this student response time by means of the type of stimulus issued; then it is no longer necessary to have an interactive program waiting for the student to respond. Instead, the interaction can be accomplished via a batch job triggered by student input. In the QUICK system, the unit of courseware is a task, consisting of information, instructions, and a number of questions to be answered, which may take the student from a few minutes to several hours or days to complete. In a science course, for example, a task might contain instructions for performing an experiment. Such a system has a wide range of applications, from CMI type uses which primarily direct the student to existing materials for study, to CAI type uses which provide tutorials and drill excercises for the student. The QUICK system has been implemented and used in a first year Biology course and an introductory FORTRAN programming course at PURDUE. Student input can be accomplished via several devices - teletype terminal, punched card reader, or marked sense card reader. This paper presents some details of the currently implemented QUICK system, as well as some goals and future directions.
An interactive pseudo-assembler for introductory computer science
Authors: Sjoerdsma Ted
Published: November 2005

Since 1968 the University of Iowa Computer Science Department has used a locally developed
E
asy
A
ssembler
SY
stem (EASY) to accomplish a better comprehension of the concepts taught in the segment of the introductory computing course which dealt with internal structure and organization.

In the fall of 1973 my attention focused on EASY (with all of its problems) as a likely candidate for a computerized-interactive-tutorial segment of this course. Since the consistency of use and precision in presentation were important aspects of teaching the concepts related to EASY, such an approach seemed natural.
A diversified undergraduate computer science program
Authors: Cheng Richard
Published: November 2005

This paper introduces a set of unique undergraduate computer science programs, some of which have been operating for more than two years at Rochester Institute of Technology. These programs are intended to meet current computer science manpower demands where as a generalized computer science curriculum is not sufficient to cover the range of students required by such demands. As is shown in Figure 1, the set of programs extend from a general computer science curriculum to cover several quasi-specialized areas.
Computer science and minority colleges & universities
Authors: Lewis Jesse
Published: November 2005

Jackson State University is the lead institution in a Cooperative Regional Educational Computing Network. The network is funded by the National Science Foundation. When it began operating in January, 1974, it involved eleven (11) other participating institutions. Now there are seventeen (17).

The purpose of the network is to provide appropriate equipment, with an accompanying massive educational effort, so as to allow each of the participating institutions to become more aware of the academic implications of computers. The ultimate goal is to profoundly affect basic curricula.

The results have been positive. Some faculty at participating institutions have reconstructed course content so as to include the use of the computer at appropriate points in their courses. More positive is the fact that a large number of students from disadvantaged educational and cultural backgrounds now have access to interactive computing.
The head and the heart: using gender analysis to study the social construction of computer systems
Authors: Greenbaum Joan
Published: November 2005

In recent years there has been a good deal of healthy experimentation with system development methods and work organization, particularly within Scandinavia. This paper attempts to go further into the questions of the development and use of computer systems by using a gender analysis of the issues. Specifically, it examines the organization of labor and patterns of communication used in developing computer systems. It suggests that the use of gender-biased dichotomies strongly influences both the questions system developers ask and the way questions are asked.
The market for wired city services
Authors: Rittenhouse Robert G.
Published: November 2005

This paper attempts to develop estimates of the amount and pattern of home use that mught ensue if home information/computer systems were introduced into the contemporary social system. This discussion is not intended to have technological orientation. The services described are possibl, and exist, on a small scale. The prolems involved in duilding a large system which provides multiple services are intentionally omitted. Also the effects of different regulatory climates are not explored in any detall. The primary concern is with the market for home use of wored city services.
The role of computer systems in the nuclear power debate
Authors: Bowyer Kevin W.
Published: November 2005

One of the primary reasons for the current "decline" of nuclear power is that reactors have not operated reliably. This unreliability has raised questions of both safety and economics. Computer systems have been a part of this failure of technology. If nuclear power is to be revived as an energy option for our country, both the quantity and quality of computer applications must increase.
Technology
Authors: Parslow R. D.
Published: November 2005

"Short-term unemployment trends are likely . . . But far more critical are the long-term dangers of drastic population bipolarization. This would appear to generate a small minority of technologically oriented elitists against a vast majority of unskilled, nearly unemployable workers. This event, predicted by some and doubted by others, would probably represent the end of the road for contemporary Western civilization as now understood" (1)
Human communication via data networks
Authors: Turoff Murray
Published: November 2005

There are two major reasons why you should learn something about computer conferencing. Delphi techniques, and other data network communication modes.One is that the capacity for group interaction, and one's own efficiency in communicating with others, can be significantly enhanced with a well-conceived conferencing system. We have learned this through direct experience in communication regarding the wage and price 1.2 and in system design work.The second reason, to be developed later in some detail, regards cost. Economics already favors computerized conferencing, even for fairly small groups, within organizations that have computers and terminals. As mini-system and terminal costs decline, and digital data networks come into wide use, we should by the late seventies find this communications mode to be quite commonplace.
Self-optimizing computer-assisted tutoring
Authors: Kimball Ralph Brain
Published: November 2005

This thesis presents a theoretical model for a self-optimizing computer-assisted tutor. The construction of a tutor for the subject of methods of integration in calculus is described, followed by the results of two experiments with students using the calculus tutor. The relationships between the theoretical predictions and the experimental results are presented, and suggestions for future research are given.The definition of a tutor in computer-based education is extended and clarified. A tutor must transmit problem-solving heuristics, choose appropriate examples, deal with arbitrary student examples, handle diverse student backgrounds, and learn superior problem-solving herustics from the students. This research establishes a logical and quantitative methodology for transmitting problem-solving heuristics and demonstrates the use of problem archives as the basis of the tutor's own heuristic schemes.
The portable computer in the classroom
Authors: Haspel Charles
Published: November 2005

A portable computer and a higher level language allow comprehensive, dynamic and easily modifiable classroom demonstrations. The IBM 5100 computer with APL is such a combination. This paper describes the use of this combination of computer and language to demonstrate aspects of queueing and formal grammars. In each case the area is briefly described and the demonstration illustrated and explained with emphasis on the human factors that go into making it effective.The cheif advantage obtained is that students' questions which fall outside prepared material can be answered and illustrated by suitably modified demonstrations.
The Error of Futurism: Prediction and Computer Ethics
Authors: Horner D. S.
Published: November 2005

The aim of this paper is to challenge the assumption that we can
insure ourselves against natural and moral evils through
improvement in our powers of prediction. I argue that computer
ethicists need to take account of the epistemological and logical
limits to our knowledge of the future. The supposition that we can
accurately predict future events is 'the error of futurism'. At
least part of the job of Computer Ethics has been seen to be the
need to foresee and forestall the undesirable and unintended
consequences of computer technologies. The paper seeks to show that
our faith in the power of prediction is ill-founded and is often
based on a misconceived picture of the future. There are reasons
for supposing that the limits on prediction are not only
epistemological but also logical. The epistemological problems are
illustrated by reference to: 'information effects' (problems with
information gathering and processing); Oedipus effects (the effect
of making a predictive statement about the human situation to which
that statement refers); and 'revenge effects' (unintended,
undesirable, unpredictable consequences of innovation). The logical
problem with prediction is that when we refer to 'future events' we
don't refer to events at all. The phrase 'future event' is not a
descriptive phrase that characterises some special kind of event as
the phrases 'sudden event' or 'historic event' do. 'Future event'
refers to an unrealised possibility until it comes to pass. The Y2K
phenomenon is illustrative of some of these problems of accurate
prediction. We can use our knowledge of the past (and we surely can
talk about 'our knowledge of the past') as a guide to action. This
does not imply that the future will necessarily be like the past
only that it is reasonable to proceed on this basis and that
prediction must play a much more limited role in our thinking. It
can hardly be moral to claim to know what we cannot know.
High Technology War and 'Surgical Strikes'
Authors: Bissett A. K.
Published: November 2005

The involvement of computers in modern weaponry is considerable,
especially in efforts to improve accuracy. This question of
accuracy, and the discourse of 'surgical strikes' associated with
high technology weapons in modern war, are examined. Drawing upon
the writings of Carl von Clausewitz, the misleading and often
dangerous implications of this ideology are discussed. We question
whether the fundamental nature of war has changed.
CCAAT/Enhancer Binding Protein α Knock-in Mice Exhibit Early Liver Glycogen Storage and Reduced Susceptibility to Hepatocellular Carcinoma
Authors: Tan Ee Hong , Hooi Shing Chuan , Laban Mirtha , Wong Esther , Ponniah Sathivel , Wee Aileen , Wang Nai-dy
Published: November 2005

The CCAAT/enhancer binding protein α (C/EBPα) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPα. Recent work showed reductions of C/EBPα levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpα expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpα knock-in mouse in which a single-copy c/ebpα is regulated by one allele of the α-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpα expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPα content in WT nodules whereas knock-in nodules stained strongly for C/EBPα. The p21 protein was examined because it mediates a C/EBPα growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPα-positive nodules were positive for nuclear p21, suggesting that C/EBPα may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPα production can inhibit liver tumor growth in vivo.
A Comparative Study on the Protection Profile of Lidocaine, Amifostine, and Pilocarpin on the Parotid Gland during Radiotherapy
Authors: Hakim Samer G. , Kosmehl Hartwig , Lauer Isabel , Nadrowitz Roger , Wedel Thilo , Sieg Peter
Published: November 2005

The aim of this study was to evaluate the individual and the synergetic radioprotective effect of lidocaine, amifostine, and pilocarpin on the parotid gland. Forty-nine rabbits were randomized into seven groups (n = 7)—control, irradiated sham-treated, irradiated/lidocaine–pretreated, irradiated/amifostine–pretreated, irradiated/pilocarpin–pretreated, irradiated/lidocaine + pilocarpin–pretreated, and irradiated/amifostine + pilocarpin–pretreated groups. One week before irradiation (15 Gy) and 72 hours as well as 1 month afterward, the parotid gland was investigated morphologically, sialoscintigraphically, and immunohistochemically with the use of tenascin-C and α smooth muscle actin. Compared with control animals, there was a significant reduction of the salivary ejection fraction in the irradiated untreated group 72 hours following radiation. Only animals pretreated with lidocaine or amifostine (alone or combined with pilocarpin) showed a slight nonsignificant reduction of salivary ejection fraction. Immunohistochemically, we observed a significant loss of α smooth muscle actin and an up-regulation of tenascin-C expression in irradiated/untreated glands. These changes were less evident in animals pretreated with lidocaine or lidocaine + pilocarpin. Amifostine and pilocarpin did not show any influence on tenascin-C or α smooth muscle actin expression. Ultrastructural damage was observed in irradiated untreated and pilocarpin–pretreated glands. In contrast, lidocaine and amifostine could largely preserve the glandular ultrastructure. One month postradiation, all changes were regressive regardless of treatment protocol. Potential radioprotective agents show different effects on both morphology and function of the parotid gland. Associated immunohistochemical and ultrastructural findings could prove the prevailed protection profile of lidocaine. This may provide a prophylactic approach in the field of radioprotection of salivary glands.
Effective Treatment of Preexisting Melanoma with Whole Cell Vaccines Expressing α(1,3)-Galactosyl Epitopes
Authors: Rossi Gabriela R. , Mautino Mario R. , Unfer Robert C. , Seregina Tatiana M. , Vahanian Nicholas , Link Charles J.
Published: November 2005

The hyperacute immune response in humans is a potent mechanism of xenograft rejection mediated by complement-fixing natural antibodies recognizing α(1,3)-galactosyl epitopes (αGal) not present on human cells. We exploited this immune mechanism to create a whole cell cancer vaccine to treat melanoma tumors. B16 melanoma vaccines genetically engineered to express αGal epitopes (B16αGal) effectively treated preexisting s.c. and pulmonary αGal-negative melanoma (B16Null) tumors in the α(1,3)-galactosyltransferase knockout mouse model. T cells from mice vaccinated with B16αGal recognized B16Null melanoma cells measured by detection of intracellular tumor necrosis factor-α. We showed successful adoptive transfer of immunity to recipient mice bearing lung melanoma metastasis. Mice receiving lymphocytes from donors previously immunized with B16αGal had reduced pulmonary metastases. The transfer of lymphocytes from mice vaccinated with control vaccine had no effect in the pulmonary metastasis burden. This study unequivocally establishes for the first time efficacy in the treatment of preexisting melanoma tumors using whole cell vaccines expressing αGal epitopes. Vaccination with B16αgal induced strong long-lasting cell-mediated antitumor immunity extended to B16Null. These data formed the basis for the testing of this therapeutic strategy in human clinical trials currently under way.
The Inflammatory Cytokine Tumor Necrosis Factor-α Regulates Chemokine Receptor Expression on Ovarian Cancer Cells
Authors: Kulbe Hagen , Hagemann Thorsten , Szlosarek Piotr W. , Balkwill Frances R. , Wilson Julia L.
Published: November 2005

Epithelial ovarian cancer cells express the chemokine receptor, CXCR4, which may be associated with increased survival and metastatic potential, but the regulation of this receptor is not understood. The inflammatory cytokine tumor necrosis factor-α (TNF-α) is found in ovarian cancer biopsies and is associated with increased tumor grade. In this report, we show that CXCR4 expression on human epithelial ovarian cancer cells is associated with, and can be modulated by, TNF-α. Ovarian cancer cells with high endogenous expression of TNF-α expressed higher levels of CXCR4 mRNA and protein than cells with low TNF-α expression. Stimulation of ovarian cancer cell lines and primary epithelial cancer cells with TNF-α resulted in increased CXCR4 mRNA and protein. The TNF-α–stimulated increase in CXCR4 mRNA was due partly to de novo synthesis, and up-regulation of CXCR4 cell surface protein increased migration to the CXCR4 ligand CXCL12. CXCR4 mRNA and protein was down-regulated by anti-TNF-α antibody or by targeting TNF-α mRNA using RNAi. TNF-α stimulation activated components of the nuclear factor κB pathway, and overexpression of the inhibitor of κB also reduced CXCR4 expression. Coculture of macrophages with ovarian cancer cells also resulted in cancer cell up-regulation of CXCR4 mRNA in a TNF-α–dependent manner. Finally, there was a correlation between the levels of TNF-α and CXCR4 mRNA in clinical biopsies of ovarian cancer, and TNF-α protein was expressed in CXCR4-positive tumor cells. TNF-α is a critical mediator of tumor promotion in a number of experimental cancers. Our data suggest that one mechanism may be through nuclear factor κB–dependent induction of CXCR4.
Activated Tyrosine Kinase Ack1 Promotes Prostate Tumorigenesis: Role of Ack1 in Polyubiquitination of Tumor Suppressor Wwox
Authors: Mahajan Nupam P. , Whang Young E. , Mohler James L. , Earp H. Shelton
Published: November 2005

Aberrant activation of tyrosine kinases is linked causally to human cancers. Activated Cdc42-associated kinase (Ack1), an intracellular tyrosine kinase, has primarily been studied for its signaling properties but has not been linked to specific pathologic conditions. Herein, we report that expression of activated Ack1 in LNCaP cells, while minimally increasing growth in culture, enhanced anchorage-independent growth in vitro and dramatically accelerated tumorigenesis in nude mice. Molecular chaperone heat shock protein 90β (Hsp90β)–bound Ack1 and treatment of cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed tumorigenesis. Further, we identify the tumor suppressor WW domain containing oxidoreductase (Wwox) as an Ack1-interacting protein. Activated Ack1 tyrosine phosphorylated Wwox, leading to rapid dissociation of the Ack1-Wwox complex and concomitant Wwox polyubiquitination followed by degradation. Tyrosine phosphorylation of Wwox was critical for its degradation, as splice variant WwoxΔ5-8 that was not phosphorylated by Ack1 failed to undergo polyubiquitination and degradation. It has been reported that phosphorylation of Wwox at Tyr33 stimulated its proapoptotic activity. We observed that Y33F Wwox mutant was still tyrosine phosphorylated and polyubiquitinated by Ack1 action. Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr287, suggesting that phosphorylation of distinct tyrosine residues activate or degrade Wwox. Primary androgen-independent prostate tumors but not benign prostate showed increased tyrosine-phosphorylated Ack1 and decreased Wwox. Taken together, these data indicate that Ack1 stimulated prostate tumorigenesis in part by negatively regulating the proapoptotic tumor suppressor, Wwox. Further, these findings suggest that Ack1 could be a novel therapeutic target for prostate cancer.
Efficient Deletion of Normal Brca2-Deficient Intestinal Epithelium by Poly(ADP-Ribose) Polymerase Inhibition Models Potential Prophylactic Therapy
Authors: Hay Trevor , Jenkins Helen , Sansom Owen J. , Martin Niall M.B. , Smith Graeme C.M. , Clarke Alan R.
Published: November 2005

The genes encoding the BRCA1 and BRCA2 tumor suppressors are the most commonly mutated in human familial breast cancers. Both have separate roles in the maintenance of genomic stability through involvement in homologous recombination, an error-free process enabling cells to repair DNA double-strand breaks. We have previously shown that cre-mediated conditional deletion of Brca2 within the mouse small intestine sensitizes the tissue to DNA damage. Eventually, the tissue repopulates via stem cells in which recombination at the floxed Brca2 allele has not taken place. In this study, we have treated Brca2-deficient small intestine with a potent small-molecule inhibitor of poly(ADP-ribose) polymerase 1 (PARP1), an enzyme predominantly involved in the recognition of DNA single-strand breaks. Brca2 deficiency rendered otherwise normal cells exquisitely sensitive to PARP inhibition, resulting in very high levels of apoptosis as early as 6 hours after treatment, with evidence for repopulation of the tissue at 12 hours. Furthermore, the intestines of animals treated with serial injections of the inhibitor repopulated very rapidly in comparison with those from untreated mice. Our results represent the first in vivo demonstration that inhibition of PARP1 activity confers exquisite sensitivity to death in physiologically normal Brca2-deficient cells, suggesting that such a regimen may be extremely potent prophylactically in women heterozygous for the BRCA2 gene, as well as against established tumors lacking functional BRCA2.
The p53 Tumor Suppressor Network Is a Key Responder to Microenvironmental Components of Chronic Inflammatory Stress
Authors: Staib Frank , Robles Ana I. , Varticovski Lyuba , Wang Xin W. , Zeeberg Barry R. , Sirotin Michail , Zhurkin Victor B. , Hofseth Lorne J. , Hussain S. Perwez , Weinstein John N. , Galle Peter R. , Harris Curtis C.
Published: November 2005

Activation of the p53 network plays a central role in the inflammatory stress response associated with ulcerative colitis and may modulate cancer risk in patients afflicted with this chronic disease. Here, we describe the gene expression profiles associated with four microenvironmental components of the inflammatory response (NO•, H2O2, DNA replication arrest, and hypoxia) that result in p53 stabilization and activation. Isogenic HCT116 and HCT116 TP53−/− colon cancer cells were exposed to the NO• donor Sper/NO, H2O2, hypoxia, or hydroxyurea, and their mRNA was analyzed using oligonucleotide microarrays. Overall, 1,396 genes changed in a p53-dependent manner (P < 0.001), with the majority representing a “unique” profile for each condition. Only 14 genes were common to all four conditions. Included were eight known p53 target genes. Hierarchical sample clustering distinguished early (1 and 4 hours) from late responses (8, 12, and 24 hours), and each treatment was differentiated from the others. Overall, NO• and hypoxia stimulated similar transcriptional responses. Gene ontology analysis revealed cell cycle as a key feature of stress responses and confirmed the similarity between NO• and hypoxia. Cell cycle profiles analyzed by flow cytometry showed that NO• and hypoxia induced quiescent S-phase and G2-M arrest. Using a novel bioinformatic algorithm, we identified several putative p53-responsive elements among the genes induced in a p53-dependent manner, including four [KIAA0247, FLJ12484, p53CSV (HSPC132), and CNK (PLK3)] common to all exposures. In summary, the inflammatory stress response is a complex, integrated biological network in which p53 is a key molecular node regulating gene expression.
Kisspeptin-10-Induced Signaling of GPR54 Negatively Regulates Chemotactic Responses Mediated by CXCR4: a Potential Mechanism for the Metastasis Suppressor Activity of Kisspeptins
Authors: Navenot Jean-Marc , Wang Zixuan , Chopin Michael , Fujii Nobutaka , Peiper Stephen C.
Published: November 2005

The product of the KiSS-1 gene is absent or expressed at low level in metastatic melanoma and breast cancer compared with their nonmetastatic counterparts. A polypeptide derived from the KiSS-1 product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Gαq subunits (GPR54 or KiSS-1R). To study the mechanism by which Kp-10 antagonizes metastatic spread, the effect on CXCR4-mediated signaling, which has been shown to direct organ-specific migration of tumor cells, was determined. Kp-10 blocked chemotaxis of tumor cells expressing CXCR4 in response to low and high concentrations of SDF-1/CXCL12 and inhibited mobilization of calcium ions induced by this ligand. Pretreatment with Kp-10 did not induce down-modulation of cell surface CXCR4 expression, reduce affinity for SDF-1/CXCL12, or alter Gαi subunit activation stimulated by this ligand. Although Kp-10 stimulated prolonged phosphorylation of extracellular signal-regulated kinase 1/2, it inhibited the phosphorylation of Akt induced by SDF-1. The ability of Kp-10 to inhibit signaling and chemotaxis induced by SDF-1 indicates that activation of GPR54 signaling may negatively regulate the role of CXCR4 in programming tumor metastasis.
Noninvasive Visualization of Adenovirus Replication with a Fluorescent Reporter in the E3 Region
Authors: Ono Hidetaka A. , Le Long P. , Davydova Julia G. , Gavrikova Tatyana , Yamamoto Masato
Published: November 2005

To overcome the inefficacy and undesirable side effects of current cancer treatment strategies, conditionally replicative adenoviruses have been developed to exploit the unique mechanism of oncolysis afforded by tumor-specific viral replication. Despite rapid translation into clinical trials and the established safety of oncolytic adenoviruses, the in vivo function of these agents is not well understood due to lack of a noninvasive detection system for adenovirus replication. To address this issue, we propose the expression of a reporter from the adenovirus E3 region as a means to monitor replication. Adenovirus replication reporter vectors were constructed with the enhanced green fluorescent protein (EGFP) gene placed in the deleted E3 region under the control of the adenoviral major late promoter while retaining expression of the adenovirus death protein to conserve the native oncolytic capability of the virus. Strong EGFP fluorescence was detected from these vectors in a replication-dependent manner, which correlated with viral DNA replication. Fluorescence imaging in vivo confirmed the ability to noninvasively detect fluorescent signal during replication, which generally corresponded with the underlying level of viral DNA replication. EGFP representation of viral replication was further confirmed by Western blot comparison with the viral DNA content in the tumors. Imaging reporter expression controlled by the adenoviral major late promoter provides a viable approach to noninvasively monitor adenovirus replication in preclinical studies and has the potential for human application with clinically relevant imaging reporters.
Identification of an Inactivating Cysteine Switch in Protein Kinase Cε, a Rational Target for the Design of Protein Kinase Cε–Inhibitory Cancer Therapeutics
Authors: Chu Feng , Koomen John M. , Kobayashi Ryuji , O'Brian Catherine A.
Published: November 2005

Critical roles played by some protein kinases in neoplastic transformation and progression provide a rationale for developing selective, small-molecule kinase inhibitors as antineoplastic drugs. Protein kinase Cε (PKCε) is a rational target for cancer therapy, because it is oncogenic and prometastatic in transgenic mouse models. PKCε is activated by sn-1,2-diacylglycerol (DAG). Attempts to develop selective PKCε inhibitors that block activation by DAG or compete with ATP have not yet met with success, suggesting a need for new strategies. We previously reported that cystamine and a metabolic cystine precursor inactivate PKCε in cells in a thiol-reversible manner. In this report, we first determined that PKCε became resistant to inactivation by disulfides when Cys452 was replaced with alanine by site-specific mutagenesis of human PKCε or a constitutively active PKCε mutant. These results showed that the disulfides inactivated PKCε by thiol-disulfide exchange, either upon Cys452 S-thiolation or by rearrangement to an intra-protein disulfide. Mass spectrometric analysis of peptide digests of cystamine-inactivated, carbamidomethylated PKCε detected a peptide S-cysteaminylated at Cys452, indicating that Cys452 S-cysteaminylation is a stable modification. Furthermore, PKCε inactivation by N-ethylmaleimide was Cys452 dependent, providing corroborative evidence that PKCε inhibitors can be designed by targeting Cys452 with small molecules that stably modify the residue. Cys452 is an active site residue that is conserved in only 11 human protein kinase genes. Therefore, the PKCε-inactivating Cys452 switch is a rational target for the design of antineoplastic drugs that selectively inhibit PKCε.
Transcription Repressor Activity of Spleen Tyrosine Kinase Mediates Breast Tumor Suppression
Authors: Wang Lei , Devarajan Eswaran , He Jin , Reddy Sekhar P. , Dai Jia Le
Published: November 2005

Spleen tyrosine kinase (SYK) is a candidate tumor suppressor gene in breast. Loss of SYK expression in breast tumors as a result of DNA hypermethylation promotes tumor cell proliferation and invasion and predicts shorter survival of breast cancer patients. We previously reported that, in addition to its well-known cytoplasmic localization, the full-length Syk is also present in the nucleus and that Syk nuclear translocation is a rate-limiting step to determine Syk tumor suppressor function. Here, we show that the full-length form of Syk acts as a transcription repressor in the cell nucleus. Ectopic expression of Syk down-regulates the transcription of FRA1 and cyclin D1 oncogenes. This transcription-repressing activity of Syk is associated with its binding to members of the histone deacetylase family. Syk interacts with transcription factor Sp1 at the Sp1 DNA-binding site in the FRA1 promoter to repress Sp1-activated FRA1 transcription. Thus, breast tumorigenesis and progression resulting from the loss of SYK are underscored by the derepression of Sp1-mediated oncogene transcription.
Enhanced DDB2 Expression Protects Mice from Carcinogenic Effects of Chronic UV-B Irradiation
Authors: Alekseev Sergey , Kool Hanneke , Rebel Heggert , Fousteri Maria , Moser Jill , Backendorf Claude , de Gruijl Frank R. , Vrieling Harry , Mullenders Leon H.F.
Published: November 2005

UV-damaged DNA-binding protein (UV-DDB) is essential for global genome repair (GGR) of UV-induced cyclobutane pyrimidine dimers (CPD). Unlike human cells, rodent epidermal cells are deficient in GGR of CPDs and express a subunit of UV-DDB, DDB2, at a low level. In this study, we generated mice (K14-DDB2) ectopically expressing mouse DDB2 at elevated levels. Enhanced expression of DDB2 both delayed the onset of squamous cell carcinoma and decreased the number of tumors per mouse in chronically UV-B light-exposed hairless mice. Enhanced expression of DDB2 improved repair of both CPDs and pyrimidine(6-4)pyrimidone photoproducts (6-4PP) in dermal fibroblasts. However, GGR of CPDs in K14-DDB2 mice did not reach the level of efficiency of human cells, suggesting that another repair protein may become rate limiting when DDB2 is abundantly present. To complement these studies, we generated mice in which the DDB2 gene was disrupted. DDB2−/− and DDB2+/− mice were found to be hypersensitive to UV-induced skin carcinogenesis. On the cellular level, we detected a delay in the repair of 6-4PPs in DDB2−/− dermal fibroblasts. Neither the absence nor the enhanced expression of DDB2 affected the levels of UV-induced apoptosis in epidermal keratinocytes or cultured dermal fibroblasts. Our results show an important role for DDB2 in the protection against UV-induced cancer and indicate that this protection is most likely mediated by accelerating the repair of photolesions.
Precocious Puberty: Growth and Genetics
Authors: Phillip Moshe , Lazar Liora
Published: November 2005

The precise neuroendocrine mechanisms underlying activation of hypothalamic-pituitary-gonadal (HPG) axis maturation are elusive. The wide age range of pubertal onset among normal individuals throughout the world may suggest that both genetic and environmental factors modulate the timing of puberty. Early activation of the HPG axis, termed central precocious puberty (CPP), causes psychosocial difficulties and may lead to compromised final height, especially if medical intervention is delayed. Although CPP is considered to be idiopathic in the majority of patients, we have recently reported a 27.5% prevalence of familial cases among 147 patients with idiopathic CPP. Segregation analysis of this cohort suggested an autosomal dominant transmission with incomplete sex-dependent penetrance. Allelic variants of candidate genes that regulate the timing of puberty may cause familial CPP. Detection of these genes will provide a tool for identification of children at risk of developing CPP, enabling early intervention with the aim of preventing its distressing outcomes.
Management of Bone Health in Postmenopausal Women
Authors: Eastell Richard
Published: November 2005

Osteoporosis is a major public health problem. We now have an approach to case finding that involves the measurement of bone mineral density in people at high risk of fractures. The management of the individual includes the identification of risk factors, the choice of optimal therapy and the encouragement of long-term adherence with the planned treatment. The drugs that are available for the prevention of fractures are classed as anticatabolic or anabolic. The efficacy of these agents can be evaluated in the individual by monitoring changes in bone mineral density or bone turnover markers.
Therapeutic Strategies for Normal-Tension Glaucoma
Authors: Orgül Selim , Zawinka Claudia , Gugleta Konstantin , Flammer Josef
Published: November 2005

Treatment of normal-tension glaucoma has been a subject of debate for several years. Glaucomatous damage cannot be influenced directly, and current treatment modalities in normal-tension glaucoma are aimed at the control of risk factors. Intraocular pressure is a widely accepted risk factor and its reduction can improve the prognosis in normal-tension glaucoma patients. The repeated demonstration of the importance of hemodynamic factors in normal-tension glaucoma has, however, not been paralleled by a comparable progress in the development of therapeutic modalities capable of influencing favorably ocular blood flow. Today, calcium channel blockers seem to be the most promising adjunctive treatment to be considered in patients with glaucomatous optic neuropathy without increased intraocular pressure.
Studies on Corneal Wound Healing
Authors: Isnard N. , Bourles-Dagonet F. , Robert L. , Renard G.
Published: November 2005

Corneal wound healing often leads to the development of scar tissue with loss of transparency. Reconstitution of transparent corneal stroma depends on the regulation of the biosynthetic activities of postlesional keratocytes and also to a large extent on the limitation of matrix degradation, attributed essentially to the upregulation of matrix metalloproteases and especially MMP-9. Using a standardized method for the production of reproducible corneal lesions by burning with iodine vapors, we could show that the local application of 0.5 mg/ml L-fucose reduced significantly MMP-9 upregulation and accelerated the recovery of the epithelial layer of the cornea. The iodine vapor used in the experiments produces a rapid loss of epithelium with no or slight effect below the basement membrane. A relatively rapid regrowth of epithelium was observed. The speed of this reepithelialization was stimulated by the local application of fucose. At 48 h after burn, there was a difference between fucose-treated and control corneas (epithelial thickness was about 50 µm for fucose-treated corneas and 37 µm for control corneas). Culture media of in vivo fucose-treated corneas showed an important decrease of MMP-9 activity (–51%, n = 6, p < 0.01). It appears that the in vivo fucose treatment reduced the MMP-9 activity released in the media. This effect is significant 24 h after iodine vapor burn. In order to study the effect of fucose on normal corneas, it was added to rabbit as well as human cornea explant cultures, and the production and release of MMP-9 was determined by zymography. Fucose at a concentration of 0.5 mg/ml produced a 70% decrease of MMP-9 activity released in the medium by corneal explant cultures. Other mono- and oligosaccharides were also tested. Besides lactose, fucose-rich oligosaccharides also produced significant inhibition. Galactose, melibiose, mannose and glucose were inactive. These results justify the use of fucose for the local treatment of corneal wounds.
Episcleral Venous Pressure in Untreated Primary Open-Angle and Normal-Tension Glaucoma
Authors: Selbach J. Michael , Posielek Kathrin , Steuhl Klaus-Peter , Kremmer Stephan
Published: November 2005

The aim of this prospective study was to investigate episcleral venous pressure (EVP) in different forms of glaucoma in comparison with age-matched controls. EVP was measured by means of a venomanometer in 32 eyes with untreated primary open-angle glaucoma (POAG), 36 eyes with untreated normal-tension glaucoma (NTG) as well as 56 control eyes without ophthalmological disease other than cataract. In addition to ophthalmological standard examination, cardiovascular parameters such as systolic and diastolic blood pressure and heart rate were recorded. In the POAG group, EVP was 12.1 ±0.5 mm Hg and in the NTG group 11.6 ± 0.4 mm Hg. This was significantly different from EVP of the controls (9.5 ± 0.2 mm Hg). The EVP/intraocular pressure (IOP) ratio was significantly different in NTG patients (80.0% ± 3.2) in comparison with both POAG patients (67.1% ± 2.8) and controls (69.2% ± 2.4). The difference between IOP and EVP (IOP – EVP) was 6.2 ± 0.6 in the POAG, 3.1 ± 0.45 in the NTG and 4.5 ± 0.4 in the control group. All these values were significantly different from each other. Regression analysis revealed a significant linear correlation between EVP and IOP in both the NTG and the POAG group. In the control group, however, the correlation was weak. This study is the first to demonstrate differences in EVP between untreated NTG and POAG and an age-matched healthy control group.
A Retrospective Analysis of Five Intra-Ocular Lenses and the Predictive Value of Six Different Intra-Ocular Lens Power Calculation Formulas
Authors: Zuidervaart Wieke , Luyten Gregorius P.M.
Published: November 2005

Purpose: To evaluate the refractive and visual outcome after implantation of five different lenses and to evaluate the accuracy of six different intra-ocular lens (IOL) power formulas. Setting: Department of Ophthalmology, University Medical Centre Rotterdam, The Netherlands. Methods: In total, 288 eyes had cataract surgery with implantation of a polymethylmethacrylate lens (Centra55B) or a foldable silicone lens (AMO SI40, Staar AA, Silens 5, Pliolens). The pre- and postoperative refraction and visual outcome were analysed for all lenses under study. Six different IOL power formulas have been used to compare the accuracy of the predictive refractive outcome. Results: The Staar Plate Haptic lens was found to have the best uncorrected visual acuity (UCVA) compared to the Centra55B, AMO SI40 and the Pliolens. Based on the A constant given by the company, the Pliolens revealed a significant overcorrection and the Staar Plate Haptic lens an undercorrection. The achieved postoperative refraction minus the intended postoperative refraction caused significant myopia with the Pliolens and hyperopia with the Staar Plate Haptic lens. The SRK-T and the Holladay formulas give the best predictive lens calculations in relation to the axial length. Conclusion: The A constant of all lenses has to be adjusted for our institute. Especially the AMO SI40, the Staar AA lens and the Silens 5 showed a remarkable difference compared to the A constant given by the company. All foldable lenses were comparable in their visual outcome. The significantly better UCVA of the Staar Plate Haptic lens can be explained by the emmetropic outcome of the postoperative refraction.
Topical Calcineurin Inhibitors Decrease the Production of UVB-Induced Thymine Dimers from Hairless Mouse Epidermis
Authors: Tran Christian , Lübbe Jann , Sorg Olivier , Doelker Laurence , Carraux Pierre , Antille Christophe , Grand Denise , Leemans Evelyne , Kaya Gürkan , Saurat Jean-Hilaire
Published: November 2005

Background: An increased incidence of ultraviolet-light-related skin tumours is a well-known problem in patients undergoing posttransplantation immunosuppression with systemic calcineurin inhibitors such as cyclosporine A or tacrolimus. UV-related carcinogenesis as a consequence of long-term treatment of sun-exposed sites with topical calcineurin inhibitors is therefore of theoretical concern. Results: In this study, we show that tacrolimus acts as a UVB filter when incorporated into liposome membranes. In hairless mice pretreated with 1% pimecrolimus cream, 0.1% tacrolimus ointment or vehicle, the amount of epidermal thymine dimers, measured 1 h after 1 J/cm2 of UVB irradiation, was decreased by 89, 84 and 47%, respectively, as compared to untreated mice. Forty-eight hours after UVB irradiation, 97, 89 and 93% of epidermal thymine dimer levels were removed in pimecrolimus-, tacrolimus- or vehicle-treated mice, respectively. In contrast, 69% of thymine dimers, originally present in much higher amounts than in treated mice, were removed from untreated controls. UVB-induced apoptosis was less pronounced in treated mice. Conclusion: Taken together, these results suggest that topical calcineurin inhibitors prevent DNA photodamage due to a filter effect of both vehicle and active components, whereas they do not affect the clearance of DNA photoproducts.
Successful Treatment of Acrodermatitis Continua of Hallopeau with Sequential Combination of Calcipotriol and Tacrolimus Ointments
Authors: Brill Thomas J. , Elshorst-Schmidt Thomas , Valesky Eva M. , Kaufmann Roland , Thaçi Diamant
Published: November 2005

Acrodermatitis continua of Hallopeau (ACH) is a rare type of pustular psoriasis affecting the digits. We report on a 43-year-old female patient who had been suffering from ACH for more than 20 years. Despite the fact that the disease was localized on one finger during the whole period, several topical and systemic treatments resulted in only temporary or partial improvement of the lesion. Although the monotherapies with calcipotriol and tacrolimus ointments gave no satisfying results in the long-term management of the disease, the combination of both agents led to a continuous improvement of the patient’s skin condition.
Severe Pustular Eruption Associated with Imatinib and Voriconazole in a Patient with Chronic Myeloid Leukemia
Authors: Gambillara E. , Laffitte E. , Widmer N. , Decosterd L.A. , Duchosal M.A. , Kovacsovics T. , Panizzon R.G.
Published: November 2005

Imatinib is a specific and potent inhibitor of the BCR-ABL tyrosine kinase. Several clinical trials have demonstrated the efficacy of imatinib in chronic myeloid leukemia. Adverse cutaneous reactions induced by imatinib are frequent and may be dose related. We report a case of an unusual pustular eruption in a patient with chronic myeloid leukemia, who received high doses imatinib for blast crisis and later voriconazole for invasive pulmonary aspergillosis. At the time of his skin eruption, elevated plasma levels of imatinib were recorded. Imatinib is primarily metabolized by the cytochrome CYP3A4. Voriconazole is a cytochrome CYP3A4 inhibitor and can lead to high plasma levels of imatinib. This case suggests that severe drug reactions to imatinib may be related not only to imatinib doses, but also to elevated plasma drug levels resulting from pharmacokinetic interactions. The monitoring of imatinib plasma levels may be of help for identifying patients at risk for severe toxicity.
Effect of Nitric Oxide on Ammoniagenesis in Rats
Authors: Cirrik Selma , Öner Gülsen
Published: November 2005

Aim: This in vitro study using rat cortical slices, isolated proximal tubules and mitochondria was conducted to investigate the effect of exogenous and endogenous nitric oxide on ammoniagenesis. Methods and Results: The cortical slices were incubated with phosphate-buffered saline containing 1 mML-glutamine at 37°C andglutamine-stimulated ammoniagenesis which was further elevated with 10–7M ANGII showed a time-dependent decrease during 2 h. 10–4M L-NAME or 10–5ML-canavanin caused a similar ammonia elevation to that of ANGII, whereas the addition of 10–5M SNAP attenuated the ammonia-increasing effects of ANGII and L-NAME. Basal or exogenous NO without significantly affecting glutamine uptake of the slices seemed to convert the glutamine deamidation pathway to transamination, since L-NAME increased the ammonia to glutamine ratio from 0.87 ± 0.08 mol/mol to 1.03 ± 0.04 (p < 0.01). L-NAME increased both ammoniagenesis and mitochondrial oxygen consumption but SNAP depressed them. Endogenous NO reduced ammoniagenesis without changing the mitochondrial permeability transition pore (PTP), whereas exogenous NO-induced attenuation in ammoniagenesis was associated with elevated PTP in a CsA-sensitive manner. Conclusion: These results demonstrated that in rat kidney, basal NO depresses mitochondrial oxygen consumption and attenuates ammoniagenesis without affecting PTP; however, exogenous NO inhibits ammonia production by disturbing PTP in isolated mitochondria.