bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling the student and the discipline in CAI drill and practice
Authors: Lorton Paul , Killam Rosemary N.
Published: November 2005

Models built into computer assisted instructional courses have several advantages. They make the underlying theoretical assumptions more explicit and, at the same time, give a clearer direction to the actual development of the CAI program. The purpose of this discussion is to present some of the areas in which models have had an implicit or explicit impact and to indicate how our current work is focused by these efforts.

The main purpose of the modeling discussed here is to provide better, more effective instruction (models of the learner) with substantially generated curriculum (models of the discipline). The drill and practice context is emphasized because that is one with a history of models in both areas and one which has demonstrated potential.
A tutoring and student modelling paradigm for gaming environments
Authors: Burton Richard R. , Brown John Seely
Published: November 2005

This paper describes a paradigm for tutorial systems capable of automatically providing feedback and hints in a game environment. The paradigm is illustrated by a tutoring system for the PLATO game “How the West Was Won”. The system uses a computer-based “Expert” player to evaluate a student's moves and construct a “differential model” of the student's behavior with respect to the Expert's. The essential aspects of the student's behavior are analyzed with respect to a set of “issues”, which are addressed to the basic conceptual constraints that might prevent the student's full utilization of the environment. Issues are viewed as procedural specialists that “wake-up” or become active when an instance of an issue manifests itself in a move. These issue specialists help the Tutor isolate what to comment on. The intent of the system is to transform a “fun” game into a productive learning environment without altering the student's enjoyment.
Software engineering education
Authors: Freeman Peter
Published: November 2005

A report will be made on the results of a one day invitational workshop held at the University of California at Irvine on 9 February 1976. The workshop will have brought together 50 leading educators and practitioners to discuss software engineering education and training: goals, constraints, and methods as seen from different perspectives.

Workshop Goals

Increased awareness by all of the specific needs for software engineering education and training; a better understanding of the present and future role of software engineers; feedback on current trends in software engineering education; a published record of the workshop including contributed position papers and an abbreviated report of the discussions in order to make the proceedings available to a wider audience.
A generalized system for university mathematics instruction
Authors: Smith Robert L. , Blaine Lee H.
Published: November 2005

EXCHECK is a system for developing mathematically-based CAI courses. It is currently being used at Stanford University to teach a college-credit course in axiomatic set theory

The design of this system had several goals. First, we wanted an instructional system that would provide a semantic base for our work on processing natural language and computer-generated audio. Axiomatic mathematics fits this description in that the underlying semantics is relatively well understood, but many of the interesting problems of natural language are also involved in the informal language of mathematics and the informal expression of mathematical proofs.

Second, we recognized that traditional proof checkers were inadequate for teaching mathematics, or for that matter, introductory logic. People understand mathematical concepts and arguments at a level much higher than the traditional formal systems of mathematical logic.

Finally, we designed the EXCHECK system to be an extensible system in which other curricula could be implemented with incrementally less work.
Computers and society courses and computer literacy (panel session)
Authors: Cotterman William , Engel Gerald , Horowitz Ellis , Austing Richard
Published: November 2005

This panel will report on the progress and results of an NSF funded project of ACM to prepare a bibliography of materials in the area of computer impact on society and to identify objectives for computers and society and computer literacy courses. The project committee has computerized about 3000 annotated entries in the bibliography and has provided the capability of obtaining sublists according to a hierarchy of categories. In addition, course objectives for several kinds of computers and society courses have been specified.
An instructional interpreter for basic
Authors: Barr Avron , Beard Marian
Published: November 2005

The BASIC Instructional Program (BIP) was developed to investigate tutorial modes of interaction in computer-assisted instruction (CAI). BIP is a problem-solving laboratory that helps students while they are solving introductory programming problems in the BASIC language. The problems are presented in an individualized sequence based on a representation of the structure of the curriculum and a model of the student's state of knowledge. This paper describes the BIP system, with emphasis on recently developed features. The goal of the tutorial laboratory is informative interaction with the student, which is provided by an instructional BASIC interpreter, information on BASIC syntax cross-referenced with the BIP student manual, and debugging aids. The system also has access through the curriculum representation to features that the student may use to help her solve her current problem. These features include hints, easier “subtasks,” a stored solution that can itself be executed, and an interactive flow chart representation of the solution. The nature of the student-BIP interaction is captured in an annotated student dialogue of a typical session.
Panel discussion
Authors: Bar Avron , Brown John Seely , Gentner Donald , Goldstein Ira , Miller Mark , Fletcher J. D.
Published: November 2005

An important area of computer-assisted instruction is the development of intelligent instructional systems. These systems can be distinguished from more conventional approaches by the automation of instructional interaction and choice of strategy. They promise both to reduce the costs of instructional materials preparation and to increase the adaptability and individualization of the instruction delivered. An appropriately intelligent instructional system should create a reactive environment in which a student can test his own hypotheses concerning the subject matter, probe for information at different levels of difficulty and abstraction, acquire wide experience in minimum time, obtain instructional material generated for his unique abilities and needs, receive instructional aids for partially completed solutions, and receive critiques for completed problem solutions.

The panel is composed of investigators who are actively engaged in the design, development, and evaluation of intelligent instructional systems. Each member of the panel will briefly outline an aspect of his current work that illustrates a problem or issue appropriate for general discussion. An attempt will be made to assess the state-of-the-art of intelligent instructional systems and to indicate reasonable next steps for their development. Attendees are encouraged to arrive bearing questions, comments, and information.
Microprocessor applications in the nuclear industry
Authors: Ethiridge C. Dwayne
Published: November 2005

Microprocessors in the nuclear industry, particularly at the los Al amos Scientific Laboratory, have been and are being utilized in a wide variety of applications ranging from data acquistion and control for basic physics research to monitoring special nuclear material in long-term storage. Microprocessor systems have been developed to support weapons diagnostics measurements during undergorund weapons testing at the Nevada Test Site. Multiple single-component microcomputers are now controlling the measurement and recording of nuclear reactor operating power levels. The CMOS microprocess data-acquisition instrumentation has operated on ballon flights to monitor power plant emissions. Target chamber mirror-positioning equipment for laser fusion facilities employs microprocessors.
Computers and social power
Authors: Kling Rob
Published: November 2005

The following essay is an early draft of a major now in progress. The author would appreciate comments and criticism. In addition, the editors of Computers and Society welcome your correspondence on this article and will publish such public commentary in forthcoming issues.
Community memory
Authors: Colstad Ken , Lipkin Efrem
Published: November 2005

This brief summary of an article by Colstad and Lipkin is exerpted from the full length article which appeared in an IEEE proceedings. It is included here as an introduction to the next paper, Implications of Community Memory. Both papers illustrate a paradox which may be seen in many "people's computing" groups. While attempting to bring the computer into useful daily interaction with a variety of citizens for a variety of applications, such groups often unwittingly reinforce myths about computers which, as Berk notes, are a primary obstacle to social acceptance of the technology as a tool for society. Although the experiment and its acceptance are interesting, the myths of the computer as brain and the computer as question answering machine have not been dispelled by operation of the public information network. Perhaps the myths have been strengthened by the enthusiasm of the proponent groups.
Privacy and computer data banks
Authors: Liedtke Norman
Published: November 2005

The right to privacy is becoming one of the key issues of our times. The single biggest threat to individual privacy is the "computer data bank". It has only been since the mid-sixties that personal privacy and the computer data bank have collided. Furthermore, it has only been since the early seventies that legislation has begun to react to the expanding infringement on privacy. Even today many people are not accurately informed on the issue.My main thesis is, "people are generally aware of infringement on their privacy but feel helpless to stop it". Secondly, I wanted to discover if, "people would be willing to take limited action to protect their privacy if they were presented with a method". This is my supporting hypothesis. I combined field work, through questionnaire, with library research.This paper is divided into three parts. First I will give a relatively brief background on the privacy issue. Then I will discuss the information and work surrounding my field study. Finally, I will give my conclusions and recommendations for the future.
Computer-based instruction in spelling
Authors: Lorton Paul
Published: November 2005

Two mathematical models of paired-associate learning (the One Element Model and the Single Operator Linear Model) were used to develop optimal strategies for presenting speeling words of 42 elementary school children. The study was conducted within a coputer-based drill and practice project using computer terminals with audio capability.For the study two computer programs were developed. One program presented and corrected a daily list of sixteen words for each student. The second program planned lessons for each student from the list of 48 words the student was studying. Words for a lesson were selected by the second program as a function of the mathematical model each word represented and the child's previous performance on each word.An analysis of the correct response made by each child through the study demonstrated that the strategy derived from the One Element Model produced significantly better final performance than the strategy developed from the Single Operator Linear Model.
Hacking into Hacking: Gender and the Hacker Phenomenon
Authors: Adam A. E.
Published: November 2005

Women hackers, and whether there are any, has proved to be an
endlessly fascinating topic. This paper explores the gender
dimensions of hacking in terms of the male domination of hacking,
the presence or absence of women hackers, the influence of the
frontier metaphor and especially frontier masculinity." Central
tenets of the 'hacker ethic' are examined including whether hacker
communities are more egalitarian than other communities, the equal
opportunities, freedom of information and work ethics of the hacker
ethic. Whilst these are all problematic in gender terms there are
hints that a female version of the hacker ethic is emerging amongst
women hackers which is more explicitly political in motivation.
Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule
Authors: Tayem Yasin , Johnson Tony R. , Mann Brian E. , Green Colin J. , Motterlini Roberto
Published: November 2005

Nephrotoxicity is one of the main side effects caused by cisplatin (CP), a widely used antineoplastic agent. Here, we examined the effect of a novel water-soluble carbon monoxide-releasing molecule (CORM-3) on CP-mediated cytotoxicity in renal epithelial cells and explored the potential therapeutic benefits of carbon monoxide in CP-induced nephrotoxicity in vivo. Exposure of LLC-PK1 cells to CP (50 μM) caused significant apoptosis as evidenced by caspase-3 activation and an increased number of floating cells. Treatment with CORM-3 (1–50 μM) resulted in a remarkable and concentration-dependent decrease in CP-induced caspase-3 activity and cell detachment. This effect involved activation of the cGMP pathway as 1H-oxadiazole [4, 3-a] quinoxaline-1-ore (ODQ), a guanylate cyclase inhibitor, completely abolished the protection elicited by CORM-3. Using a rat model of CP-induced renal failure, we found that treatment with CP (7.5 mg/kg) caused a significant elevation in plasma urea (6.6-fold) and creatinine (3.1-fold) levels, which was accompanied by severe morphological changes and marked apoptosis in tubules at the corticomedullary junction. A daily administration of CORM-3 (10 mg/kg ip), starting 1 day before CP treatment and continuing for 3 days thereafter, resulted in amelioration of renal function as shown by reduction of urea and creatinine levels to basal values, a decreased number of apoptotic tubular cells, and an improved histological profile. A negative control (iCORM-3) that is incapable of liberating CO failed to prevent renal dysfunction mediated by CP, indicating that CO is directly involved in renoprotection. Our data demonstrate that CORM-3 can be used as an effective therapeutic adjuvant in the treatment of CP-induced nephrotoxicity.
Identification of SFRP1 as a Candidate Mediator of Stromal-to-Epithelial Signaling in Prostate Cancer
Authors: Joesting Margaret S. , Perrin Steve , Elenbaas Brian , Fawell Stephen E. , Rubin Jeffrey S. , Franco Omar E. , Hayward Simon W. , Cunha Gerald R. , Marker Paul C.
Published: November 2005

Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/β-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.
Sensitization for γ-Irradiation–Induced Apoptosis by Second Mitochondria-Derived Activator of Caspase
Authors: Giagkousiklidis Stavros , Vogler Meike , Westhoff Mike-Andrew , Kasperczyk Hubert , Debatin Klaus-Michael , Fulda Simone
Published: November 2005

Resistance to current treatment regimens, such as radiation therapy, remains a major concern in oncology and may be caused by defects in apoptosis programs. Because inhibitor of apoptosis proteins (IAPs), which are expressed at high levels in many tumors, block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could target a key control point in resistance. Here, we report for the first time that full-length or mature second mitochondria-derived activator of caspase (Smac), an inhibitor of IAPs, significantly enhanced γ-irradiation–induced apoptosis and reduced clonogenic survival in neuroblastoma, glioblastoma, or pancreatic carcinoma cells. Notably, Smac had no effect on DNA damage/DNA repair, activation of nuclear factor-κB, up-regulation of p53 and p21 proteins, or cell cycle arrest following γ-irradiation, indicating that Smac did not alter the initial damage and/or cellular stress response. Smac enhanced activation of caspase-2, caspase-3, caspase-8, and caspase-9, loss of mitochondrial membrane potential, and cytochrome c release on γ-irradiation. Inhibition of caspases also blocked γ-irradiation–induced mitochondrial perturbations, indicating that Smac facilitated caspase activation, which in turn triggered a mitochondrial amplification loop. Interestingly, mitochondrial perturbations were completely blocked by the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone or the relatively selective caspase-2 inhibitor N-benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone, whereas caspase-8 or caspase-3 inhibitors only inhibited the increased drop of mitochondrial membrane potential provided by Smac, suggesting that caspase-2 was acting upstream of mitochondria after γ-irradiation. In conclusion, our findings provide evidence that targeting IAPs (e.g., by Smac agonists) is a promising strategy to enhance radiosensitivity in human cancers.
Methylation-Associated Silencing of theNuclear Receptor 1I2Gene in Advanced-Type Neuroblastomas, Identified by Bacterial Artificial Chromosome Array-Based Methylated CpG Island Amplification
Authors: Misawa Akiko , Inoue Jun , Sugino Yuriko , Hosoi Hajime , Sugimoto Tohru , Hosoda Fumie , Ohki Misao , Imoto Issei , Inazawa Johji
Published: November 2005

To identify genes whose expression patterns are altered by methylation of DNA, we established a method for scanning human genomes for methylated DNA sequences, namely bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA). In the course of a program using BAMCA to screen neuroblastoma cell lines for aberrant DNA methylation compared with stage I primary neuroblastoma tumors, we identified CpG methylation-dependent silencing of the nuclear receptor 1I2 (NR1I2) gene. NR1I2 was methylated in a subset of neuroblastoma cell lines and also in advanced-stage primary tumors with amplification of MYCN. Its methylation status was inversely associated with gene expression. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored NR1I2 transcription in neuroblastoma cell lines lacking endogenous expression of this gene. A CpG island located around exon 3 of NR1I2 showed promoter activity, and its methylation status was clearly and inversely correlated with NR1I2 expression status. The gene product, NR1I2, has a known function in regulating response to xenobiotic agents but it also suppressed growth of neuroblastoma cells in our experiments. We identified some possible transcriptional targets of NR1I2 by expression array analysis. The high prevalence of NR1I2 silencing by methylation in aggressive neuroblastomas, together with the growth-suppressive activity of NR1I2, suggests that this molecule could serve as a diagnostic marker to predict prognosis for neuroblastomas.
Sensitization of Human Carcinoma Cells to Alkylating Agents by Small Interfering RNA Suppression of 3-Alkyladenine-DNA Glycosylase
Authors: Paik Johanna , Duncan Tod , Lindahl Tomas , Sedgwick Barbara
Published: November 2005

One of the major cytotoxic lesions generated by alkylating agents is DNA 3-alkyladenine, which can be excised by 3-alkyladenine DNA glycosylase (AAG). Inhibition of AAG may therefore result in increased cellular sensitivity to chemotherapeutic alkylating agents. To investigate this possibility, we have examined the role of AAG in protecting human tumor cells against such agents. Plasmids that express small interfering RNAs targeted to two different regions of AAG mRNA were transfected into HeLa cervical carcinoma cells and A2780-SCA ovarian carcinoma cells. Stable derivatives of both cell types with low AAG protein levels were sensitized to alkylating agents. Two HeLa cell lines with AAG protein levels reduced by at least 80% to 90% displayed a 5- to 10-fold increase in sensitivity to methyl methanesulfonate, N-methyl-N-nitrosourea, and the chemotherapeutic drugs temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea. These cells showed no increase in sensitivity to UV light or ionizing radiation. After treatment with methyl methanesulfonate, AAG knockdown HeLa cells were delayed in S phase but accumulated in G2-M. Our data support the hypothesis that ablation of AAG activity in human tumor cells may provide a useful strategy to enhance the efficacy of current chemotherapeutic regimens that include alkylating agents.
Heterogeneous Tumor Evolution Initiated by Loss of pRb Function in a Preclinical Prostate Cancer Model
Authors: Hill Reginald , Song Yurong , Cardiff Robert D. , Van Dyke Terry
Published: November 2005

Because each change in the evolution of a cancer is predicated on the effects of previous events, a full understanding of selective changes and their effect on tumor progression can only be understood in the context of appropriate initiating events. Here, we define the effect of pRb function inactivation in prostate epithelium on both the initiation of prostate cancer and the establishment of selective pressures that lead to diminished Pten function and tumor evolution. Using genetically engineered mice, we show that inactivation of the pRb family proteins (Rb/p107/p130) induces epithelial proliferation and apoptosis and is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions. Over time, adenocarcinomas develop in all mice with no evidence of neuroendocrine tumors. Apoptosis is dependent on Pten function and not p53, unlike other epithelial cell types tested previously. Consequently, Pten hemizygosity reduces apoptosis by 50%, accelerating progression to adenocarcinomas with heterogeneous composition. Heterogeneity is associated with concurrent Pten haploinsufficiency and focal selective progression to complete Pten loss, which yields distinct tumor properties. Given that this analysis models the apparent timing of highly penetrant events in human prostate cancer, observed effects may recapitulate the natural evolution of prostate cancer development.
Simultaneous Inhibition of EGFR, VEGFR, and Platelet-Derived Growth Factor Receptor Signaling Combined with Gemcitabine Produces Therapy of Human Pancreatic Carcinoma and Prolongs Survival in an Orthotopic Nude Mouse Model
Authors: Yokoi Kenji , Sasaki Takamitsu , Bucana Corazon D. , Fan Dominic , Baker Cheryl H. , Kitadai Yasuhiko , Kuwai Toshio , Abbruzzese James L. , Fidler Isaiah J.
Published: November 2005

Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.
Alternative Splicing of Fibroblast Growth Factor Receptor 3 Produces a Secreted Isoform That Inhibits Fibroblast Growth Factor–Induced Proliferation and Is Repressed in Urothelial Carcinoma Cell Lines
Authors: Tomlinson Darren C. , L'Hôte Corine G. , Kennedy Wendy , Pitt Eva , Knowles Margaret A.
Published: November 2005

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that play key roles in proliferation, differentiation, and tumorigenesis. FGFR3 was identified as the major family member expressed in both normal human urothelium and cultured normal human urothelial (NHU) cells and was expressed as the IIIb isoform. We also identified a splice variant, FGFR3 Δ8-10, lacking exons encoding the COOH-terminal half of immunoglobulin-like domain III and the transmembrane domain. Previous reports have assumed that this is a cancer-specific splice variant. We showed that FGFR3 Δ8-10 is a normal transcript in NHU cells and is translated, N-glycosylated, and secreted. Primary urothelium expressed high levels of FGFR3 transcripts. In culture, levels were reduced in actively proliferating cells but increased at confluence and as cells approached senescence. Cells overexpressing FGFR3 IIIb showed FGF1-induced proliferation, which was inhibited by the addition of FGFR3 Δ8-10. In bladder tumor cell lines derived from aggressive carcinomas, there were significant alterations in the relative expression of isoforms including an overall decrease in the proportion of FGFR3 Δ8-10 and predominant expression of FGFR3 IIIc in some cases. In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered.
Noninvasive In vivo Detection of Glutathione Metabolism in Tumors
Authors: Thelwall Peter E. , Yemin Avner Y. , Gillian Theresa L. , Simpson Nicholas E. , Kasibhatla Mohit S. , Rabbani Zahid N. , Macdonald Jeffrey M. , Blackband Stephen J. , Gamcsik Michael P.
Published: November 2005

Magnetic resonance spectroscopic imaging has been used to follow glutathione metabolism and evaluate glutathione heterogeneity in intact tumor tissue. Stable isotope-labeled glutathione was detected in s.c. implanted fibrosarcoma tumors in anesthetized rats following infusion of [2-13C]glycine. Using 1H-decoupled 13C magnetic resonance spectroscopy, the appearance of [2-13C]glycine at 42.4 ppm and the subsequent incorporation of this isotope label into the glycyl residue of glutathione at 44.2 ppm can be detected. The identity and relative concentrations of labeled metabolites observed in the in vivo spectrum were confirmed in studies of tissue extracts. The high level of isotopic enrichment and the concentration of glutathione in tumor tissue allow for collection of spatially localized spectra using 13C chemical shift imaging methods. These data provide the first direct images of glutathione in intact tumor tissue and show metabolic heterogeneity. This method may lead to the ability to monitor changes in tumor tissue redox state that may ultimately affect diagnosis, monitoring, and treatment.
BRCA1 and c-Myc Associate to Transcriptionally Repress Psoriasin, a DNA Damage–Inducible Gene
Authors: Kennedy Richard D. , Gorski Julia J. , Quinn Jennifer E. , Stewart Gail E. , James Colin R. , Moore Stephen , Mulligan Karl , Emberley Ethan D. , Lioe Tong F. , Morrison Patrick J. , Mullan Paul B. , Reid George , Johnston Patrick G. , Watson Peter H. , Harkin D. Paul
Published: November 2005

Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease–associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIα poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
Expression Profiling of Serous Low Malignant Potential, Low-Grade, and High-Grade Tumors of the Ovary
Authors: Bonome Tomas , Lee Ji-Young , Park Dong-Choon , Radonovich Mike , Pise-Masison Cindy , Brady John , Gardner Ginger J. , Hao Ke , Wong Wing H. , Barrett J. Carl , Lu Karen H. , Sood Anil K. , Gershenson David M. , Mok Samuel C. , Birrer Michael J.
Published: November 2005

Papillary serous low malignant potential (LMP) tumors are characterized by malignant features and metastatic potential yet display a benign clinical course. The role of LMP tumors in the development of invasive epithelial cancer of the ovary is not clearly defined. The aim of this study is to determine the relationships among LMP tumors and invasive ovarian cancers and identify genes contributing to their phenotypes. Affymetrix U133 Plus 2.0 microarrays (Santa Clara, CA) were used to interrogate 80 microdissected serous LMP tumors and invasive ovarian malignancies along with 10 ovarian surface epithelium (OSE) brushings. Gene expression profiles for each tumor class were used to complete unsupervised hierarchical clustering analyses and identify differentially expressed genes contributing to these associations. Unsupervised hierarchical clustering analysis revealed a distinct separation between clusters containing borderline and high-grade lesions. The majority of low-grade tumors clustered with LMP tumors. Comparing OSE with high-grade and LMP expression profiles revealed enhanced expression of genes linked to cell proliferation, chromosomal instability, and epigenetic silencing in high-grade cancers, whereas LMP tumors displayed activated p53 signaling. The expression profiles of LMP, low-grade, and high-grade papillary serous ovarian carcinomas suggest that LMP tumors are distinct from high-grade cancers; however, they are remarkably similar to low-grade cancers. Prominent expression of p53 pathway members may play an important role in the LMP tumor phenotype.
Negative Regulation of Estrogen Receptor α Transactivation Functions by LIM Domain Only 4 Protein
Authors: Singh Rajesh R. , Barnes Christopher J. , Talukder Amjad H. , Fuqua Suzanne A.W. , Kumar Rakesh
Published: November 2005

LIM domain only 4 (LMO4), a member of the LIM-only family of transcriptional coregulatory proteins, consists of two LIM protein-protein interaction domains that enable it to function as a linker protein in multiprotein complexes. Here, we have identified estrogen receptor α (ERα) and its corepressor, metastasis tumor antigen 1 (MTA1), as two novel binding partners of LMO4. Interestingly, LMO4 exhibited binding with both ERα and MTA1 and existed as a complex with ERα, MTA1, and histone deacetylases (HDAC), implying that LMO4 was a component of the MTA1 corepressor complex. Consistent with this notion, LMO4 overexpression repressed ERα transactivation functions in an HDAC-dependent manner. Accordingly, silencing of endogenous LMO4 expression resulted in a significant increased recruitment of ERα to target gene chromatin, stimulation of ERα transactivation activity, and enhanced expression of ERα-regulated genes. These findings suggested that LMO4 was an integral part of the molecular machinery involved in the negative regulation of ERα transactivation function in breast cells. Because LMO4 is up-regulated in human breast cancers, repression of ERα transactivation functions by LMO4 might contribute to the process of breast cancer progression by allowing the development of ERα-negative phenotypes, leading to increased aggressiveness of breast cancer cells.
MUC1 Oncoprotein Blocks Glycogen Synthase Kinase 3β–Mediated Phosphorylation and Degradation of β-Catenin
Authors: Huang Lei , Chen Dongshu , Liu Derek , Yin Li , Kharbanda Surender , Kufe Donald
Published: November 2005

Dysregulation of β-catenin is of importance to the development of diverse human malignancies. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and associates with β-catenin. However, the functional significance of the MUC1-β-catenin interaction is not known. Here, we show that MUC1 increases β-catenin levels in the cytoplasm and nucleus of carcinoma cells. Previous studies have shown that glycogen synthase kinase 3β (GSK3β) phosphorylates β-catenin and thereby targets it for proteosomal degradation. Consistent with the up-regulation of β-catenin levels, our results show that MUC1 blocks GSK3β-mediated phosphorylation and degradation of β-catenin. To further define the interaction between MUC1 and β-catenin, we identified a serine-rich motif (SRM) in the MUC1 cytoplasmic domain that binds directly to β-catenin Armadillo repeats. Mutation of the SRM attenuated binding of MUC1 to β-catenin and MUC1-mediated inhibition of β-catenin degradation. Importantly, disruption of the MUC1-β-catenin interaction with the SRM mutant also attenuated MUC1-induced anchorage-dependent and -independent growth and delayed MUC1-mediated tumorigenicity. These findings indicate that MUC1 promotes transformation, at least in part, by blocking GSK3β-mediated phosphorylation and thereby degradation of β-catenin.
Type I Insulin-like Growth Factor Receptor as a Therapeutic Target in Cancer
Authors: Miller Bradley S. , Yee Douglas
Published: November 2005

Data from experimental model systems and population studies have implicated type I insulin-like growth factor receptor (IGF1R) signaling in many different human cancers. Drugs to disrupt IGF1R function have been developed and are now entering clinical trial. This brief review will identify key areas to consider as these clinical trials move forward.
Evaluation of Arterial Stiffness in Patients with Branch Retinal Vein Occlusion
Authors: Nakazato Keiko , Watanabe Hideki , Kawana Keisuke , Hiraoka Takahiro , Kiuchi Takahiro , Oshika Tetsuro
Published: November 2005

Purpose: To assess the arterial stiffness in patients with branch retinal vein occlusion (BRVO). Methods: Brachial-ankle pulse wave velocity (PWV) and ankle-brachial index were measured in 10 patients with BRVO (mean age 67.9 ± 7.5 years) and in 18 age-matched controls (mean age 66.9 ± 6.8 years). The controls were subjects with systemic essential hypertension having no retinal lesions. Results: The PWV in the BRVO group was 1,946 ± 254 cm/s which was significantly higher than that in the control group (1,688 ± 274 cm/s; p = 0.014, Wilcoxon rank sum test). The ankle-brachial indexes were 1.16 and 1.15 in BRVO and control groups, respectively. There was no significant difference between the groups (p = 0.944). In the control group, there was a significant positive correlation between PWV and systolic blood pressure (Spearman correlation coefficient rs = 0.385, p = 0.043), while no significant correlation was found in the BRVO group (Spearman correlation coefficient rs = –0.188, p = 0.603). Conclusion: The arterial stiffness is increased in patients with BRVO which was thought to be due to the structural changes of the artery and not dependent on the blood pressure.
Trypan-Blue- and Endoillumination-Assisted Phacoemulsification in Eyes with Vitreous Hemorrhage during Combined Cataract and Vitreous Surgery
Authors: Yamamoto Narumichi , Ozaki Noriko , Murakami Kimio
Published: November 2005

Purpose: To study the safety and usefulness of trypan blue application and conventional endoillumination for enhancing visualization during phacoemulsification and foldable intraocular lens implantation in cases of cataract with vitreous hemorrhage. Methods: Ten eyes of 10 patients with cataract and coexisting vitreous hemorrhage underwent combined trypan-blue- and endoillumination-assisted phacoemulsification and foldable intraocular lens implantation with vitrectomy. In a two-step surgery, after staining the anterior capsule with trypan blue, continuous circular capsulorhexis was performed; then, phacoemulsification was performed using conventional endoillumination. Specular microscopy was performed before and 3 months after surgery on eyes that underwent trypan-blue- and endoillumination-assisted phacoemulsification and on control eyes that underwent standard phacoemulsification to evaluate the toxic effect of trypan blue on corneal endothelial cells. Results: Trypan blue application improved visualization of the anterior capsule, and a complete capsulorhexis could be performed in all eyes. In all 10 eyes, endoillumination was required to visualize the lens structure, and phacoemulsification could be accomplished. Specular microscopy revealed that there was no significant difference in the level of corneal endothelial cell loss between the trypan-blue- and endoillumination-assisted phacoemulsification group and the control group. Conclusion: The described double visualization technique may assist phacoemulsification in selected cases of cataract with vitreous hemorrhage.
Is Homelessness a Risk Factor for Eye Disease?
Authors: Pitz Susanne , Kramann Christina , Krummenauer Frank , Pitz Andreas , Trabert Gerhard , Pfeiffer Norbert
Published: November 2005

Background: There is general agreement on the presence of a correlation between poverty and impaired health. However, only scarce data are available on whether this also applies to the incidence of eye disease. The present study was carried out to evaluate the prevalence of ocular disease in homeless people in Germany. Methods: 107 homeless people (97 male, 10 female; mean age 49 years, range 18–81 years) treated in specialised social service institutions were investigated prospectively according to a standardised ophthalmological screening protocol. This comprised visual acuity, assessment of pupillary light reaction, intra-ocular pressure, slit lamp examination as well as funduscopy. Results: The median best-corrected visual acuity of all 213 eyes examined was 0.8 (range: no light perception to 1.25). 74 eyes of a subgroup of 50 patients showed one or more of the following disorders: 32% of the patients suffered from external eye disease, 8% exhibited a cataract associated with a visual acuity of 0.63 or below. 6% of the patients had optic nerve atrophy, and 4% suffered from amblyopia. Diabetic retinopathy as well as age-related macular degeneration were detected in 2%, while anophthalmos, lid malposition and traumatic choroidal rupture were noted in 1% of patients. The median visual acuity measured in these 74 eyes was 0.5 (range: no light perception to 1.25), which differs significantly from the acuity of 0.8 in the entire study population (p < 0.001). The prevalence of legal blindness according to WHO criteria was 2%. Conclusions: The present study revealed an unexpectedly high prevalence of optic nerve atrophy in homeless people. The prevalence for cataract and legal blindness was slightly higher than in representative epidemiological investigations. Thus, homelessness seems to be correlated with an increased ocular morbidity. As best-corrected visual acuity differed significantly between eyes with and those without eye disease, the assessment of this parameter may serve as a cost-effective first-stage screening method.
Comparison of Diagnostic Ability between a Fast Strategy, Tendency-Oriented Perimetry, and the Standard Bracketing Strategy
Authors: Gonzalez-Hernandez M. , Morales J. , Azuara-Blanco A. , Garcia Sanchez J. , Gonzalez de la Rosa M.
Published: November 2005

Purpose: To compare the diagnostic abilities of the standard bracketing strategy (BR) and a fast strategy, the tendency-oriented perimetry (TOP). Methods: Seventy-seven controls and 91 eyes from patients with glaucoma were analyzed with the strategies TOP and BR. Sensitivity (Se), specificity (Sp), the area under the receiver operating characteristic (ROC) curve (AC) and the optimum cutoff value (CO) were calculated for the visual field indices mean defect (MD), the square root of the loss variance (sLV) and the number of pathological points (NPP). Results: In the glaucoma group, the mean MD value using TOP and BR was 7.5 and 8.3 dB, respectively. The mean sLV value using TOP and BR was 5.0 and 5.3 dB, respectively. Indices provided by TOP had higher ROC values than the ones provided by BR. Using TOP, the index with the best diagnostic ability was sLV (Sp = 94.8, Se = 90.1, AC = 0.966, CO = 2.5 dB), followed by NPP and MD. Using BR, the best results were obtained for MD (Sp = 92.2, Se = 81.3, AC = 0.900, CO = 2.5 dB) followed by sLV and NPP. Conclusions: A fast strategy, TOP, had superior diagnostic ability than the standard BR. Although TOP provided lower LV values than BR, the diagnostic ability of this index was higher than that of the conventional strategy.
Multifocal Electroretinography Changes in the Macula at High Altitude: A Report of Three Cases
Authors: Pavlidis Mitrofanis , Stupp Tobias , Georgalas Ilias , Georgiadou Evi , Moschos Michail , Thanos Solon
Published: November 2005

Background: To evaluate the short- and long-term effects of high-altitude hypobaric hypoxia on macula morphology and function during ascents, acclimatizations, and descents between 500 m and 5,650 m, macula function was evaluated in three healthy climbers of a trekking expedition. Methods:Macula physiology was tested with multifocal electroretinography (MF ERG), near and farvisual acuity, and Amsler grid tests. Macula morphology was tested with optical coherence tomography (OCT) and with stereoscopic fundoscopy obtained 1 week before ascent, as well as 1 week and 2 weeks after high-altitude exposure. The following physiological parameters indicative of acclimatization were compared daily during the expedition at altitudes between 500 m and 5,050 m: hemoglobin, oxygen saturation, resting heart rate, retinal findings, and the Lake Louise score of acclimatization. Results: The central macula MF ERG responses were significantly reduced 1 week after high-altitude exposure, and had recovered by the follow-up examination performed during the following week. Near visual acuity and Amsler grid tests remained unaffected at both follow-up examinations. No significant changes were found in the follow-up OCT and daily fundoscopy examinations in all three well-acclimatized climbers. Conclusions: High-altitude hypobaric hypoxia affects the function of the highly sensitive macula region. This suggests that the exposure of persons with macula diseases such as age-related macula degeneration, tapetoretinal degeneration, or diabetic retinopathy to high altitudes may influence the disease progression. For this reason, this population should avoid prolonged and unnecessary high-altitude exposure without proper acclimatization.
Fas Ligand Reduces Viability in Primary Melanoma Short-Term Cell Cultures More than in Metastatic Melanoma Short-Term Cell Cultures
Authors: Hofbauer Günther F.L. , Hatta Naohito , Daigle Isabelle , Hemmi Silvio , Spanaus Schlapbach Katharina , Willers Jörg , Burg Günter , Simon Hans-Uwe , Dummer Reinhard
Published: November 2005

Background: Apoptotic pathway aberrations are reported as important tumor progression factors in melanoma. Objective: Effect of soluble Fas ligand (sFasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on short-term cultured melanoma cell viability from different stages of melanoma. Results: Recombinant human FasL reduced viability after 18 h in a dose-dependent manner in 4 of 5 cell cultures from primary tumors and 1 of 9 cell cultures from metastatic melanoma (67.5 vs. 96.4%, p = 0.007). DNA fragmentation on flow cytometry confirmed apoptosis. Incubation with TRAIL had no effect on melanoma cell viability. Immunohistochemistry showed Fas in 3 of 4 primary and in 6 of 7 metastatic lesions, no FasL in primary lesions, and FasL in 5 of 7 metastatic lesions. Conclusion: Melanoma short-term cell cultures from primary tumors show decreased viability under FasL, but not TRAIL stimulation rather than short-term cell cultures derived from metastases.
Survival of Mycosis Fungoides in Patients in the Southeast of England
Authors: Morales Maria M. , Putcha Venkata , Evans Helen S. , Olsen Jorn , Llopis Agustin , Møller Henrik
Published: November 2005

Background: Mycosis fungoides (MF) is the most common skin lymphoma. The aetiology of MF remains unknown, and no therapy has to date significantly altered patient survival. Objective: The present study examines trends in survival of MF patients in a well-defined population-based disease group, namely patients registered over a 40-year period at the Thames Cancer Registry, Southeast England. Methods: The Thames Cancer Registry is a population-based registry, covering a population of approximately 14 million people. Data were taken from the Surveillance, Epidemiology and End Results cancer registry programme and the National Centre for Health Statistics. The database was used to identify cases of MF diagnosed between 1961 and 2000. A total of 985 records were identified, 821 (83%) of which had complete information on age, sex, year of diagnosis and area of residence. The observed and relative survivals of patients diagnosed during the periods 1971–1975, 1981–1985 and 1991–1995 were examined over a 5-year period of follow-up, using the relsurv Stata program to perform Cox proportional hazard analysis. Results: A total of 821 MF eligible patients were available with a median follow-up of 4.3 years and a maximum follow-up of 30 years. The overall 5-year relative survival rate was 80%, and there was marked improvement between 1971 and 1981. The prognostic factors leading to a significantly poorer survival were high age, male sex, the presence of the Sézary syndrome, the use of hormone treatment and radiotherapy. Conclusions: A statistically significantly better survival over the last 20 years was found. The prognosis is generally good for most patients but not all. The best survival was seen for the female patients under 45 years of age without the presence of the Sézary syndrome. This difference in survival may be partly due to a difference in the disease stage or different treatment, or to both.