bluuebunny/crossref_metadata_2025 huggingface dataset:
The structure and use of a test generating system designed to facilitate individually paced instruction
Authors: Palay Roger M.
Published: November 2005

The structure and use of a test-generating system having the following parameters is described.

1. Each test is a ten item multiple choice instrument where each item has five (5) alternatives.

2. Each test is generated from a relatively small file (most often less than 150 card images).

3. Although the file contains only five (5) disjoint tests, over nine million different tests (each with its own set of correct answers) can be generated from it.

4. The correct answers to each test are stored directly on the test (in coded form).

5. Test responses are machine correctable and such correcting need not be done on the system that generated the test.

6. The reliability of different forms of tests generated from one file is theoretically high (no statistical evidence is available to support a claim of high reliability).

7. The grading program produces a total score as well as giving the correct answers for all items on that test.
Secondary school model automatic test generation
Authors: Muscat Eugene J.
Published: November 2005

A review of the literature dealing with automatic test generation yields a wide variety of subject matter applications. Most decriptives, however, deal with college level projects. This paper out lines secondary school requirements that may encourage the development of appropriate test generation models. Our discussion will center on a common need for remediation at the secondary level, namely, mathematics skill building (addition, subtraction, multiplication and division). The subject matter selection is only to assure that the suggestions made are as concrete as possible. The paper will concentrate on the structural and procedural aspects of school site test generation and will not deal with the computer programming requirements.

The basic model assumes remedial curriculum that will be directed as a student population of 500 students. This supposes that the entire student population is not utilizing a single test generation package. The recommendations allow for adding additional curriculum services and increasing student use. A test generating laboratory should emerge that would operate as a service bureau. This center will be detailed below.

The discussion will be organized under the following headings:

The discussion will be organized under the following headings:

Hardware Requirements

Turnaround

Personnel

Cost
Learning mathematics with recursive computer programs
Authors: Peelle Howard A.
Published: November 2005

Recursion is a powerful idea*—with correspondingly powerful implications for learning and teaching mathematics. Computer scientists have previously pointed out that the use of recursion often permits more lucid and concise descriptions of algorithms [1]; mathematicians know that recursion is a fundamental concept upon which entire systems of mathematics can be built [11]; and, the theory of recursive functions is now developing into an area of mathematics whose importance has been compared with that of geometry and algebra [3].

The purposes of this paper are to illuminate the fundamentals of recursion; to illustrate several recursive computer programs which provide perspicuous representations of certain mathematical procedures; and to invite students and teachers of mathematics to reach greater understandings by trying them.
Computer graphics as an aid to teaching geometric transformations
Authors: McAdams Joseph K. , DeKock Arlan R.
Published: November 2005

During the past several years, there has been much discussion and controversy over what should be taught in high school mathematics, in general, and in high school geometry, in particular. Numerous mathematicians have encouraged the teaching of transformations as part of the standard high school mathematics curriculum[l-4,6-9]. The results of a recent survey of high school teachers of mathematics indicate that 19% have taught geometric transformations, 26% feel adequately prepared to teach such a topic, and 50% would like to teach the topic if materials were available for the average college prep student[5].

The topic of transformations is important because transformations are a unifying factor in algebra and geometry. Algebra and geometry are essentially the same material taught from different approaches. In particular, the abstract algebraic concept of a group can be conveyed in purely geometric terms by groups of transformations.
A new approach to teaching a first course in compiler construction
Authors: Shapiro Henry D. , Mickunas M. Dennis
Published: November 2005

A new approach to teaching a first course in compiler construction is presented, in which the traditional term project is replaced by several smaller, independent, programming assignments. Each assignment is a compiler for a simple language using a different parsing technique. A means is described to augment the programming assignments, so that a greater variety of experiences is provided students. A short review of the literature is included.
ASSIST-V
Authors: Hughes Charles E. , Pfleeger Charles P.
Published: November 2005

This paper describes a program called ASSIST-V which is designed to provide students and other researchers with an environment in which they may write and analyze operating systems for the IBM 360/370 series of machines. ASSIST-V is an extended version of a student-oriented assembler/interpreter called ASSIST. A user of ASSIST-V is presented with a machine which simulates the full set of S/360 machine instructions (including privileged instructions): the standard 360/370 interrupt structure, I/0 channels, and I/0 devices. Since the machine environment is simulated, ASSIST-V can provide debugging and statistics-gathering features not available on an actual “bare” machine.
On-line large screen display system for computer instruction
Authors: Cheng Richard
Published: November 2005

This paper is concerned with a new instructional method to teach computer programming techniques to students in Computer Science as well as other scientific and non-scientific disciplines. Several courses in the Computer Science curriculum could be substantially enhanced if the instructional gap between the classroom lecture and the computer programming excercises could be eliminated. Rochester Institute of Technology has experimented to achieve this objective by means of an on-line large screen display system which will permit the instructors to perform classroom demonstrations to emphasize the key point of concepts or example of applications to a class of students through a keyboard with a computer. This new instructional method will eliminate deficiencies in conventional chalkboard approaches which result in material being covered too fast to be digested by the students or the course content to be diluted to match the pace of the class.
Instructional uses of the olin experimental classroom
Authors: Kumar V. K. , Rogers James L.
Published: November 2005

The Olin Experimental Classroom at Case Western Reserve University provides a laboratory-like environment in which instructors can assess the results of trying out different teaching methods, techniques, etc. From a hasty look at three of the essential hardware components of this facility as shown in Figure 1 - keyset response units for each student, a process-control computer which scans the response units, and a display for the instructor - one could easily conclude that the Olin Experimental Classroom is simply another “student response system” or “wired classroom”. In fact, the differences between the traditional student response systems and the Olin Experimental Classroom begin with the very purposes for which these facilities are intended, and the differences extend to every aspect of t h e i r respective operation.
How much cai is hidden in commercial software?
Authors: Sobel Helen L.
Published: November 2005

It is somewhat astonishing to find that a well-developed software package designed for business uses provides an extremely interesting teaching instrument with an as yet unrealized potential

For many years report generating systems such as REPORTER have been extensively used as work horses in business and industry. Administrators in these areas require up-to-date information presented in an understandable, well-organized form. The business executive may need a daily, weekly, or monthly report of the sales records of the company's employees, listing for each sales representative the number of items sold in each category, the amount of income produced, the number of items returned in each category, etc.

The Burroughs
REPORT
writ
ER
is based upon an entirely different premise which not only permits but encourages user involvement and understanding. The programs which create each REPORT are accessible, small, modular in structure, and limited to the specific options requested by the user. While it can be easily used in a non-technical manner, and need not be explored in any depth, there are no formidable barriers to a more intelligent mastery of this tool.

The unique characteristic of the Burroughs REPORTER is its production of an independent COBOL program for each set of specifications entered. It
The bayesian computer-assisted data analysis (CADA) monitor
Authors: Isaacs Gerald L. , Novick Melvin R.
Published: November 2005

Many steps are involved in completing a Bayesian statistical analysis. Some are skilled tasks requiring the expertise of a professional, others are purely mechanical. The former include such tasks as choice of model, specification of the prior distribution and interpretation of the posterior distribution; the latter include such things as the arithmetic necessary to combine the prior distribution with the data to produce the posterior distribution and to produce probability statements from that distribution. Unfortunately, it is all too often the case that the arithmetic gets in the way of the professional's decision-making responsibilities by breaking concentration and line of thought; and at times the sheer bulk of computation precludes the use of advanced techniques by the unaided researcher. What is required is a monitoring system that does all of the arithmetic and, even further, sees to it that all of the steps in the analysis are performed correctly and in their proper sequence. Also, within an instructional process, it can be very useful to have a system that helps a student learn by guiding his steps through a valid statistical analysis even if he doesn't yet fully understand what he is doing. For these and other reasons, a system of Computer-Assisted Data Analysis (CADA) was developed at the University of Iowa (Novick, 1971, 1973). Further investigation into available computer technology coupled with expansion of the theoretical base on which the original system rested resulted in the refinement and expansion of the available programs and the construction of a monitor to facilitate their use.
The use of information theory and personal probabilities in computer based learning
Authors: Vawter Richard
Published: November 2005

If a student to machine response falls outside a predetermined range during computer based instruction, then some off line procedures (or an ignore command) must be invoked. This observation points out that student to machine response is generally that of a multiple choice format with a perhaps large, but still finite, list of possible responses. In this paper we will discuss the uses of information theory and the Bayesian philosophy of probability to evaluate student to machine responses when there is a well defined set of possible answers.
Multi-disciplinary programming exercises
Authors: Ragsdale Ronald G.
Published: November 2005

Courses in computer science, data processing or other areas that involve the learning of computer programming often require the student to complete programming exercises. These exercises give the students practice in translating some process into a set of computer commands that accomplish the same process. Very often the exercises are relatively “content free” (write a program to add a set of numbers...) and the objectives attained by the exercises are entirely in the data processing, computer science domain. This paper is based on the assumption that the content of typical programming exercises is an unutilized resource that can be used to facilitate learning in other subject matter areas without jeopardizing the attainment of the programming goals.
Computing science courses - training or education?
Authors: Willis Neil
Published: November 2005

The debate about the usefulness or otherwise of Computing Science degrees has raged for some time.

Critics of these degree courses have stated that the courses do not satisfy the needs of commercial and industrial users; that they do not train the graduate to be of immediate use or that the subject is developing too rapidly for degrees to impart any lasting knowledge and so on.

It may be (and is) argued by some, that an Institute of Higher Education (be it College, Polytechnic* or University) should not aim to train students to be of immediate use to industry. However there is obviously a demand for trained personnel in the computing field, as demonstrated by the proliferation of courses run by manufacturers, various professional bodies and commercial organizations, and it is to satisfy this demand that a number of Polytechnics in England, and Sheffield Polytechnic in particular, have designed courses aimed at
educating
students in the field of computing.
A survey on computer science curricula
Authors: Ruby Douglas A.
Published: November 2005

As in many businesses, the data processing industry largely depends on colleges and universities for the basic education of its technical and scientific personnel. Increasingly, the key to entry into this industry for the college graduate is becoming a degree in a discipline loosely defined as “computer science”. Since the computing industry is as broadly defined and as diverse as the various computer science majors, there has been a tendency for the industry on the whole to be only vaguely aware of what students are learning on campus. In addition, there has been a lack of communication by the industry concerning the qualities and skills it seeks in the “computer science” graduate.

This paper, then, discusses some of the attitudes of the McDonnell Douglas Automation Company (MCAUTO
tm
) concerning those qualities and skills it seeks in college graduates in the computing field.
A computer-aided flow diagram teaching system
Authors: Koffman Elliot B. , Friedman Frank L.
Published: November 2005

This paper describes a system intended to aid beginning computer science students develop a systematic approach towards problem solution using structured flow diagrams. The student is carefully monitored during the specification of an initial flow diagram and through successive stages of refinement. As each new flow diagram symbol is entered, the system checks to see that the student is being consistent with earlier work and has not introduced potential errors.

The flow diagram is an intermediate level representation of an algorithm which is independent of the particular programming language chosen for implementation. When the structured flow diagram has been completely refined, the final translation to a programming language is relatively automatic. To test the program logic, the resultant source code should be executed. The student can modify the flow diagram, generate new code, and re-execute until the program runs correctly.
A unique graduate program in computer science at Jackson State University
Authors: Iynengar S. Sitharama , Lewis Jesse C.
Published: November 2005

The two key elements of decision-making in today's environment are (i)efficient information processing and management and (ii) a degree of maturity in effective use of a broad range of analytical tools and techniques which pass under the general label of Mathematical Sciences.

The Department of Computer Science at Jackson State University started a Graduate Program during the 1974 academic year which offers a unique interdisciplinary program leading to a Master's Degree in Computer Science. This program emphasizes in programming languages, systems programming, operating systems, information systems analysis and design, the role of the computer as an integral part of the decision-making process, and the computer applications in the areas of statistics and management science. Advanced placement may be given via examination or acceptable certificate presentation from traditional or non-traditional institutions such as IBM Corporation. The students are presently using both the interactive and the batch capability of our IBM 360/40 for their course and project works. The university is upgrading to an IBM 370/145 during the spring semester (1976).
The master of science program in computer and information science at San Jose State University
Authors: NEIDLEMAN L. D.
Published: November 2005

Recently, in the fall of 1974, San Jose State University (SJSU) launched a new master's program in Computer and Information Science (CIS). The main function of this paper is to describe the program—detailing its origins, content, administration, present status and potential future. A secondary purpose is to present material about one of the program's options—Management Information Systems.(MIS). In order to accomplish the above goals, the paper is divided into five sections as follows: Background, Program Description, Current Results, MIS Option, and Summary.
The stepwise approach to introductory programming projects with examples
Authors: Sebaugh Jeanne L.
Published: November 2005

This paper primarily discusses the problem of the initial projects to be used in introducing students to a programming language. Examples are given of projects used for time-shared BASIC. Because of the expense, CAI was not considered practical for use in the introductory courses, even though the TUTOR series of courses (to learn BASIC) was available.
A video disc oriented educational system
Authors: Michalopoulos Demetrios A.
Published: November 2005

One of the challenging fields of computer science is the computer graphics field which, because of its relatively high cost, has not been used extensively for educational purposes. Recent hardware developments in the graphics technology and price breakthroughs in digital equipment are beginning to influence the educational uses of computer graphics. If “a picture is worth a thousand words” and if the cost is not at this ratio, one can provide the student, not necessarily of computer sciences, with the possibility of a continuous interaction in which the student can see the results of his decision and thus allows him to experiment and practice with ideas not completely understood yet.

This paper presents a design for an interactive educational system incorporating the recent development of the video-disc.
A functional model of instructional programs
Authors: Salako Abimbola
Published: November 2005

A functional model of instructional programs (for Computer Assisted Instruction - CAI) that describes all program types as being essentially composed of a set of primitive building blocks is proposed. The variables that account for the apparent distinguishing characteristics of these programs are then interpreted in the light of this model and a procedure is provided for reducing the different program types to their elementary building blocks. Starting with the primitive building blocks, it is shown how programs of varying descriptions can be generated by an appropriate choice of parameter values. This model provides better insight on the requirements and structure of application-oriented CAI languages, software, and systems. Furthermore, the model provides an easy means of generating CAI synthetic programs for the purpose of simulation modeling directed towards instructional systems design, analysis, and performance evaluation.
Computer based systems in boiling water reactors
Authors: Shukla J. N. , Iubelt J. A.
Published: November 2005

This paper describes the application of computers to the General Electric Company's Boilling Water Reactor (BWR) type nuclear power plants. In the GE BWR plants, computers are used for Real Time Process Monitoring, Nuclear Steam Supply Systemn Performance and Core Limit Evaluation, Balance of Plant Performance Evaluation, Historical Recording, and Control Rod Pattern Enforcement. These functions are performed by different systems and subsystems each consisting of one or more computers. This paper discusses the following:Basic design objectives of each System Major Functions performed by each system simplified systems configurations system operation system evaluation and testsThis paper concludes with a brief discussion of computer control and comments on a few anticipated control applications. It suggests that the architecture of the display control system is adaptable to control applications.
Six models for the social accountability of computing
Authors: Kling Rob
Published: November 2005

This paper briefly examines six public policy strategies for including the "social accountability of computing". "Social accountability" denotes ways of organizing computer specialists, organized groups that develop, manufacture, sell or use computer-based systems, and their markets, so that the broader public is well served. The six models which are examined here include:1. Market arrangements2. Administrative authority3. Professional control4. Regulatory commissions to administer legislative acts5. Judical enforcement and review of legislative acts6. Citizen actionEach is applicable to a different context in which computer-based services are provided. And collectively, they span the set of policy instruments available in liberal democracies. While these models have been extensively developed and examined in a variety of settings, their appropriateness for computing is usually tacitly assumed, rather than grounded in careful analyses. Upon close inspection, each model is found to have severe problems in either its practical effectiveness or its appropriateness for computing.
Computer-based analytic grading for German grammar instruction
Authors: Levine David R.
Published: November 2005

This dissertation is motivated by a concern for an essential aspect of teaching, particularly of teaching by computer: the necessity of grading the student's response to a question posed by the teacher. By grading, I mean analyzing for correctness, diagnosing what has been done both correctly and incorrectly. My work concentrates on language teaching, specifically the teaching of German grammar, and works at analyzing sentence-sized responses. In the restricted area of pattern practice and controlled translation, in the rules of the game, I have produced a computer program which can do an indepth grading analysis. The program is given two inputs: a description of the expected response, and the sentence actually constructed by the student. Using its built-in knowledge of German grammar, it analyzes the student sentence for conformity to both the expected response and the applicable rules of German grammar, and produces a comprhensive diagnostic report.
Computer-assisted instruction
Authors: Goldberg Adele
Published: November 2005

In a CAI system for teachig elementary mathematical logic, in order to provide tutorial advice similar to the suggestions a human tutor might give, a theorem-prover is employed as a proof-analyzer to generate appropriate dialogue with students who need help with a proof. It is shows that the heuristically programmed theorem-prover, by embodying techniques thought to be used by the students, constructs derivations for expressions in the elementary theory of Abelian groups within the constraints on rule usage imposed on these students. To demonstrate its capabilities, the theoremprover was tested on a list of theorems and problems chosen arbitrarily from a standard curriculum in elementary algebra. The proof-analyzer mocks the adaptive behavior of a human tutor; it can determine relevant hints when a student requires help in completing a soultion paths. The proof-analyzer is incorporated in a new instructional system or mathematical logic, an examle of a "student-oriented" CAI system which emphasizes active participation of the students with the computer by providing methods by which a student can initially specify or extend the axiomatic theory he is studying, while still retaining the error analysis and teaching facilities of an interactive proof-checker.
A plan for research toward computer-aided instruction with natural English, teachnical memorandum, TM-3623
Authors: Simmons Robert S. , Silberman Harry F.
Published: November 2005

A research program was planned to develop a first, experimental computer-assisted instruction system that would permit interaction with students in a subset of natural English. At the base of this system was a model of cognition that would represent the knowledge content of the material to be taught and the student's current knowledge of it. A comparison of the model of student current knowledge and the model of the material to be taught offered a basis for feeding back appropriate information to the student to move him toward the eventual training goal. The research was planned in two concurrent phases. The first developed language processing technology based on Protosynthex III. The second used tutorial studies to discover appropriate methods for training the students. The first appendix consists of material outlining the Cognitive Structure Model for Verbal Understanding, and the second is a Sample of the Minimal Lesson Structure. (Author/GO).
Computer science contributions to learning and teaching
Authors: Zinn Karl L.
Published: November 2005

At the ACM Annual Conference in 1970 the Special Interest Group on Computer Uses in Education (SlGCUE) organized two sessions on computers in the instructional process. Recommendations for action by computer professionals were formulated and printed in the October issue of the SIGCUE Bulletin on Computer Uses in Education (V4, #5, pp. 26--33). Consistent with program planning for ACM 70 and 71, SIGCUE has organized a session for this year which in part should answer some of the questions raised last year. The Bulletin should again be a vehicle for supplementary statements and reporting of outcomes after the Conference.
Integrated data base as key to computer assisted instruction
Authors: Ting T. C.
Published: November 2005

A general purpose interactive computer assisted instructional system is described. It uses an integrated data base to store the instructional materials, the student records, the system statistics, and the system control data. A control program is employed to interact with learners at remote terminals, to direct the instructional process, and to retrieve the appropriate instructional materials.Instructional materials are organized and stored as English text in the data base. No computer programming is necessary for implementing and revising the course materials. The data base is organized as a direct access file allowing (in auxaliary storage media) large quantities of instructional information to be stored at a minimal cost. Every basic instructional material unit, a frame, in the data base is equally accessible to the control program. This permits the lesson designer to link any frame at any particular sequence. Branches between the courses are feasible for remedial instruction or multiple use of materials. Several types of response modes are provided, and additional desirable responsivenesses can be added with minimal difficulty. Detailed student background and historical learning data are available for intelligently controlling the instructional sequences.The system is now operational on an IBM system/360 model 65/50 ASP general purpose computational system in a multiprogramming environment under CPS. The same concept can be used to develop a dedicated CAI system using a smaller hardware configuration.
All About the Blog
Authors: Grimes Sara M.
Published: November 2005

The world order of child and youth media has traditionally been one
in which adults create the media content that is then selected and
consumed by young people and their families. Much of the debate
surrounding children's media concerns the author's responsibility
to produce moral, educational, and healthy media messages, which
are believed to have varying levels of influence on childhood
development and socialization processes. Less attention is paid to
the cultural content and artifacts that children themselves create
and communicate. This participatory aspect of children's culture is
becoming increasingly prominent, however, through the expansion of
information and communication technologies (ICTs) and, more
specifically, the Internet. Youth-created websites, chatrooms and
weblogs make up a significant component of children and teens'
on-line experiences, and as more young people gain access to the
necessary tools and skills, their presence will only continue to
exert itself in the new media landscape.
Ecto-ADP-ribose Transferases: Cell-Surface Response to Local Tissue Injury
Authors: Zolkiewska Anna
Published: November 2005

Ecto-ADP-ribose transferases (ecto-ARTs) catalyze the transfer of ADP-ribose from NAD+to arginine residues in cell-surface proteins. Since the concentration of extracellular NAD+is very low under normal physiological conditions but rises significantly upon tissue injury or membrane stress, it is postulated that the main role of ecto-ARTs is to ADP-ribosylate and regulate the function of certain membrane receptors in response to elevated levels of NAD+.
Acid Acclimation byHelicobacter pylori
Authors: Sachs George , Weeks David L. , Wen Yi , Marcus Elizabeth A. , Scott David R. , Melchers Klaus
Published: November 2005

Helicobacter pylori is a Gram-negative neutralophile associated with peptic ulcers and gastric cancer. It has a unique ability to colonize the human stomach by acid acclimation. It uses the pH-gated urea channel, UreI, to enhance urea access to intrabacterial urease and a membrane-anchored periplasmic carbonic anhydrase to regulate periplasmic pH to ~6.1 in acidic media, whereas other neutralophiles cannot regulate periplasmic pH and thus only transit the stomach.
Ubiquitylation of Ion Channels
Authors: Abriel Hugues , Staub Olivier
Published: November 2005

Ubiquitylation (i.e., covalent attachment of ubiquitin moieties to proteins) of ion channels allows regulation of their activity and fate. Nedd4/Nedd4-like ubiquitin-protein ligases bind to, ubiquitylate, and modulate the internalization of several channels bearing PY motifs, whereas endoplasmic reticulum-associated degradation (involving ubiquitylation) plays an important role in the biogenesis of normal and defective channels.
Ras-Related Signaling Pathways in Valve Development: Ebb and Flow
Authors: Yutzey Katherine E. , Colbert Melissa , Robbins Jeffrey
Published: November 2005

Congenital heart defects affect ~1 in every 100 live births, and deficits in the formation of the mitral, tricuspid, and outflow tract valves account for 20–25% of all cardiac malformations. Mutations in genes that affect Ras signaling have been identified in individuals with congenital valve disease associated with Noonan syndrome and neurofibromatosis type 1. Dissection of Ras-related signaling pathways during valvulogenesis provides seminal insight into cellular and molecular mechanisms that contribute to congenital heart disease.
Role of Acid/Base Transporters in the Male Reproductive Tract and Potential Consequences of Their Malfunction
Authors: Pastor-Soler Nuria , Piétrement Christine , Breton Sylvie
Published: November 2005

Acid/base transporters play a key role in establishing an acidic luminal environment for sperm maturation and storage in the male reproductive tract. Impairment of the acidification capacity of the epididymis, via either genetic mutations or exposure to environmental factors, may have profound consequences on male fertility.
Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor κB Activation and Subsequently Suppressed Ovarian Cancer Dissemination
Authors: Kobayashi Hiroshi , Yagyu Tatsuo , Kondo Toshiharu , Kurita Noriyuki , Inagaki Kiyokazu , Haruta Shoji , Kawaguchi Ryuji , Kitanaka Takashi , Sakamoto Yoshiharu , Yamada Yoshihiko , Kanayama Naohiro , Terao Toshihiko
Published: November 2005

Thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. It has been shown previously that increased levels of urokinase-type plasminogen activator receptor (uPAR) correlate well with higher invasive phenotype. We examined whether thalidomide is able to suppress the expression of uPAR mRNA and protein in human ovarian cancer cell line HRA and human chondrosarcoma cell line HCS-2/8. Here, we show that: (a) thalidomide suppresses the expression of constitutive and transforming growth factor-β1 (TGF-β1)–induced uPAR mRNA and protein; (b) a nuclear factor κB (NF-κB) activation system (phosphorylation of IκB-α and degradation of IκB-α) is necessary for the TGF-β1-induced increase in uPAR expression, because l-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-κB inhibitor, reduced the uPAR production as well as mRNA expression; (c) thalidomide failed to further strengthen l-1-tosylamido-2-phenylethyl chloromethyl ketone's action; (d) the once-daily i.p. administration of thalidomide (400 μg/g body weight/d) decreased progressive growth of HRA tumors and ascites formation in an in vivo animal model; and (e) the once-daily i.p. administration of thalidomide in combination with paclitaxel (i.p., 100 μg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. We conclude that thalidomide down-regulates constitutive and TGF-β1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-κB activation. Furthermore, combination therapy with thalidomide plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian cancer dissemination.
Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma
Authors: Shiftan Liora , Israely Tomer , Cohen Miriam , Frydman Veronica , Dafni Hagit , Stern Robert , Neeman Michal
Published: November 2005

Hyaluronan, a high molecular weight, negatively charged polysaccharide, is a major constituent of the extracellular matrix. High molecular weight hyaluronan is antiangiogenic, but its degradation by hyaluronidase generates proangiogenic breakdown products. Thus, by expression of hyaluronidase, cancer cells can tilt the angiogenic balance of their microenvironment. Indeed, hyaluronidase-mediated breakdown of hyaluronan correlates with aggressiveness and invasiveness of ovarian cancer metastasis and with tumor angiogenesis. The goal of this work was to develop a novel smart contrast material for detection of hyaluronidase activity by magnetic resonance imaging (MRI). Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) covalently linked to hyaluronan on the surface of agarose beads showed attenuated relaxivity. Hyaluronidase, either purified from bovine testes or secreted by ES-2 and OVCAR-3 human epithelial ovarian carcinoma cells, activated the hyaluronan-GdDTPA-beads by rapidly altering the R1 and R2 relaxation rates. The change in relaxation rates was consistent with the different levels of biologically active hyaluronidase secreted by those cells. Hyaluronan-GdDTPA-beads were further used for demonstration of MRI detection of hyaluronidase activity in the proximity of s.c. ES-2 ovarian carcinoma tumors in nude mice. Thus, hyaluronan-GdDTPA-beads could allow noninvasive molecular imaging of hyaluronidase-mediated tilt of the peritumor angiogenic balance.
Mutation of the PIK3CA Gene in Anaplastic Thyroid Cancer
Authors: García-Rostán Ginesa , Costa Angela M. , Pereira-Castro Isabel , Salvatore Giuliana , Hernandez Radhames , Hermsem Mario J.A. , Herrero Agustin , Fusco Alfredo , Cameselle-Teijeiro Jose , Santoro Massimo
Published: November 2005

The phosphatidylinositol 3′-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.
HLA-G Proteins in Cancer: Do They Provide Tumor Cells with an Escape Mechanism?
Authors: Rouas-Freiss Nathalie , Moreau Philippe , Ferrone Soldano , Carosella Edgardo D.
Published: November 2005

Convincing clinical evidence indicates that the limited success of T-cell–based immunotherapy of malignant diseases is caused, at least in part, by the ability of malignant cells to escape from immune recognition and destruction. Among the multiple escape mechanisms identified, a major role is played by changes in the expression and/or function of HLA antigens expressed by tumor cells, because they may markedly affect tumor cell-host's immune system interactions. In this article, we review the data about the aberrant expression of the nonclassical HLA class I antigen HLA-G by tumor cells. Furthermore, we discuss the possible reasons for the conflicting information in the literature about HLA-G antigen expression by malignant cells. Lastly, in light of the well-documented immunotolerant function of HLA-G, we discuss the potential role of these antigens in the escape of tumor cells from immune recognition and destruction and in the clinical course of malignant diseases.
Laminin α5 Chain Metastasis- and Angiogenesis-Inhibiting Peptide Blocks Fibroblast Growth Factor 2 Activity by Binding to the Heparan Sulfate Chains of CD44
Authors: Hibino Suguru , Shibuya Masahiko , Hoffman Matthew P. , Engbring Jean A. , Hossain Rydhwana , Mochizuki Mayumi , Kudoh Shoji , Nomizu Motoyoshi , Kleinman Hynda K.
Published: November 2005

Recently, we reported that the laminin α5 synthetic peptide A5G27 (RLVSYNGIIFFLK, residues 2,892-2,904) binds to the CD44 receptor of B16-F10 melanoma cells via the glycosaminoglycans on CD44 and inhibits tumor cell migration, invasion, and angiogenesis in a dominant-negative manner. Here, we have identified the potential mechanism of A5G27 activity using WiDr human colorectal carcinoma cells. WiDr cells bound to the laminin A5G27 peptide via the heparin-like and chondroitin sulfate B glycosaminoglycan side chains of CD44. Cell binding to fibroblast growth factor (FGF2) was blocked by laminin peptide A5G27 but not by either a scrambled version of this peptide or by another laminin peptide known to bind cell surface proteoglycans. FGF2 signaling involving tyrosine phosphorylation was also blocked by laminin peptide A5G27 but was not affected by peptide controls. Finally, we have shown that peptide A5G27 directly blocks FGF2 binding to heparin. Peptide A5G27 has sequence homology to a region on FGF2 that binds heparin and the FGF receptor and is important in FGF2 central cavity formation. We conclude that peptide A5G27 inhibits metastasis and angiogenesis by blocking FGF2 binding to the heparan sulfate side chains of CD44 variant 3, thus decreasing FGF2 bioactivity.
Expression Microarray Analysis and Oligo Array Comparative Genomic Hybridization of Acquired Gemcitabine Resistance in Mouse Colon Reveals Selection for Chromosomal Aberrations
Authors: van de Wiel Mark A. , Costa Jose L. , Smid Kees , Oudejans Cees B.M. , Bergman Andries M. , Meijer Gerrit A. , Peters Godefridus J. , Ylstra Bauke
Published: November 2005

Gemcitabine is a commonly used therapy for many solid tumors. Acquired resistance to this nucleoside analogue, however, diminishes the long-term effectiveness in a majority of patients. To better define the molecular background of gemcitabine resistance, a mouse colon tumor was selected during successive rounds of transplantation with continued treatment of gemcitabine. Expression microarray analysis was applied to determine which genes are consistently and highly overexpressed or underexpressed in the resistant versus the nonresistant tumor. For the statistical interpretation of the microarray data, a parametric model was implemented, which returns model-based differential gene expression (log-) ratios and their uncertainties. This defined a set of 13 genes, putatively responsible for the gemcitabine resistance in solid tumors. One of these, RRM1, was previously identified as an important marker for gemcitabine resistance in human cell lines. Five of the 13 genes, including RRM1, are located within a 3 Mb region at chromosome 7E1 of which four are highly overexpressed, suggesting a chromosomal amplification. Therefore, chromosomal copy number changes were measured, using oligo array comparative genomic hybridization. A narrow and high amplification area was identified on 7E1 that encompassed all five genes. In addition, reduced RNA expression of two other genes at 8E1 encoding COX4I1 and RPL13 could be explained by a decrease in chromosomal copy number on chromosome 8. In conclusion, the array comparative genomic hybridization biologically validates our statistical approach and shows that gemcitabine is capable to select for chromosomally aberrant tumor cells, where changed gene expression levels lead to drug resistance.
Interleukin-8 Differentially Regulates Migration of Tumor-Associated and Normal Human Brain Endothelial Cells
Authors: Charalambous Christiana , Pen Ligaya B. , Su Yuzhuang S. , Milan Johanna , Chen Thomas C. , Hofman Florence M.
Published: November 2005

Interleukin-8 (IL-8) is a chemokine involved in angiogenesis, a process vital to tumor growth. Previously, we showed that endothelial cells derived from human tumor tissue have different functional and phenotypic properties compared with normal endothelial cells. This study analyzes the role of IL-8 in regulating angiogenesis of tumor-associated brain endothelial cells (TuBEC). Results show that TuBECs have a higher baseline migration rate compared with normal brain endothelial cells (BEC). TuBECs are unaffected when stimulated with IL-8 whereas BECs are activated. This lack of response of TuBECs to IL-8 is due to the constitutive production of IL-8. Endogenously produced IL-8 activates TuBECs in an autocrine manner as shown by IL-8 receptor inhibition. Blocking either CXCR1 or CXCR2 partially reduces TuBEC migration, whereas blocking both receptors further reduces migration. Treatment with antibody against vascular endothelial growth factor (VEGF) shows that production of IL-8 by TuBECs is dependent on VEGF. Transforming growth factor-β1 (TGF-β1), shown to down-regulate IL-8 production in BECs, does not inhibit IL-8 production in TuBECs. In summary, these studies show that TuBECs constitutively secrete IL-8 and autocrine activation by IL-8 is the result of VEGF stimulation. Furthermore, TuBECs do not respond to the feedback inhibition normally induced by TGF-β1. These data emphasize the functional uniqueness of TuBECs. Understanding the functions and regulatory processes of tumor-associated endothelial cells is critical for developing appropriate antiangiogenic therapies.
Transforming Growth Factor-β Activation of Phosphatidylinositol 3-Kinase Is Independent of Smad2 and Smad3 and Regulates Fibroblast Responses via p21-Activated Kinase-2
Authors: Wilkes Mark C. , Mitchell Hugh , Penheiter Sumedha Gulati , Doré Jules J. , Suzuki Kaori , Edens Maryanne , Sharma Deepak K. , Pagano Richard E. , Leof Edward B.
Published: November 2005

Transforming growth factor-β (TGF-β) stimulates cellular proliferation and transformation to a myofibroblast phenotype in vivo and in a subset of fibroblast cell lines. As the Smad pathway is activated by TGF-β in essentially all cell types, it is unlikely to be the sole mediator of cell type–specific outcomes to TGF-β stimulation. In the current study, we determined that TGF-β receptor signaling activates phosphatidylinositol 3-kinase (PI3K) in several fibroblast but not epithelial cultures independently of Smad2 and Smad3. PI3K activation occurs in the presence of dominant-negative dynamin and is required for p21-activated kinase-2 kinase activity and the increased proliferation and morphologic change induced by TGF-β in vitro.
Uncoupling between Epidermal Growth Factor Receptor and Downstream Signals Defines Resistance to the Antiproliferative Effect of Gefitinib in Bladder Cancer Cells
Authors: Kassouf Wassim , Dinney Colin P.N. , Brown Gordon , McConkey David J. , Diehl Alan J. , Bar-Eli Menashe , Adam Liana
Published: November 2005

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways, such as phosphatidylinositol-3 kinase/Akt and Ras/mitogen-activated protein kinase (MAPK), have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the urogenital tumors. To investigate the mechanism of resistance to EGFR inhibition in bladder cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-3β (GSK-3β). We found that the resistance to the antiproliferative effects of gefitinib, in vitro as well as in vivo in nude mice models, was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-3β activation and degradation of its target cyclin D1 were indicators of a high cell sensitivity to gefitinib. Further analysis of one phenotypic sensitive (253J B-V) and resistant (UM-UC13) cell lines revealed that platelet-derived growth factor receptor-β (PDGFRβ) activation was responsible for short circuiting the EGFR/MAPK pathway for mitogenic stimuli. However, invasion as well as actin dynamics were efficiently reduced by EGFR inhibition in UM-UC13. Chemical disruption of signaling pathways or of PDGFR kinase activity significantly reduced the inactive pool of cellular GSK-3β in UM-UC13 cells. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in bladder cancer. Although this uncoupling may arise through different mechanisms, we suggest that the resistance of bladder cancer cells to EGFR blockade can be predicted early in the course of treatment by measuring the activation of GSK-3β and of nuclear cyclin D1.