A process for selective separation of niobium from proton irradiated molybdenum targets is provided and includes dissolving the molybdenum target in a hydrogen peroxide solution to form a first ion-containing solution, contacting the first ion-containing solution with a cationic resin whereby ions selected form the group consisting of molybdenum, biobium, technetium, selenium, vanadium, arsenic, germanium, zirconium and rubidium remain in a second ion-containing solution while ions selected from the group consisting of rubidium, zinc, beryllium, cobalt, iron, manganese, chromium, strontium, yttrium and zirconium are selectively adsorbed by the cationic resin; adjusting the pH of the second ion-containing solution to within a range of from about 5.0 to about 6.0; contacting the pH adjusting second ion-containing solution with a dextran-based material for a time to selectively separate niobium from the solution and recovering the niobium from the dextran-based material.

Positron emission tomography (PET) is rapidly becoming essential in diagnosis of heart and neurological conditions and is also useful in the staging and assessment of cancer treatments. PET is also a valuable research tool for studying in vivo biochemical functions during either normal or disease states. A drawback to PET is the necessity of a large capital investment. Still, the growth of PET as a procedure and the acquisition of PET scanners by medical centers is expected to grow rapidly over the next few years and the development of mobile PET units may be near.
Every PET scanner or instrument must be calibrated using radioisotope sources containing a positron emitter. Additionally, virtually every clinical scan must be accompanied by a patient "transmission scan" to permit proper image interpretation. All of the commercial calibration and transmission sources for current clinical PET scanners use germanium-68.
Germanium-68 has a half-life of about 271 days, decays by electron capture to gallium-68, and lacks any significant photon emissions. Gallium-68 decays by positron emission. These properties make germanium-68 an ideal isotope for calibration and transmission sources. Additionally, gallium-labelled imaging agents such as disclosed in U.S. Pat. No. 5,079,346 can employ gallium-68 produced from a germanium-68/gallium-68 generator. Thus, the availability of the long-lived parent, germanium-68, is of significant interest because of its generation of the shorter-lived gallium metal activity. The useful shelf-life is determined by the activity of the germanium-68, while the short half-life of the gallium-68, about 68 minutes, minimizes the radiation dose to technicians during calibration of PET scanners and the patient transmission scans.
Previously, germanium-68 has been recovered from an irradiated rubidium target. In such a recovery process,, the rubidium target is generally dissolved in 4 Normal (N) to 9 N HCl, followed by distillation of the germanium and other volatiles such as arsenic and selenium. The germanium is then selectively recovered from the distillate by extraction with carbon tetrachloride. A second extraction of the carbon tetrachloride solution with water yields an aqueous solution of the germanium. While this process proves suitable for recovery of the germanium from the rubidium targets, other sources of germanium are not as easily processed by this procedure.
Irradiated molybdenum targets have generally served as a source for the separation of strontium, yttrium, zirconium and rubidium isotopes. Such irradiated molybdenum targets have now been found to contain a significant amount of germanium-68 that has previously gone unrecovered. Such irradiated targets also contain quantities of niobium and arsenic that may also be sought to be recovered. Recovery of these isotopes would provide additional supplies for the medical community. Optionally, recovery of germanium via an organic solvent-free process may be desirable to minimize waste.
Accordingly, it is an object of this invention to provide a process for the recovery of germanium-68 from irradiated molybdenum targets.
Another object of this invention is to provide a process for selectively separating both the niobium and the germanium from irradiated molybdenum targets.
Yet another object of this invention is to provide a process for selectively separating both the germanium and the arsenic from irradiated molybdenum targets.
Still another object of this invention is to provide a process for selectively separating the niobium, arsenic and germanium from irradiated molybdenum targets.
It is a further object of this invention to provide an organic solvent-free process for recovery of germanium-68.

Recovery of niobium from irradiated targets

The United States of America as represented by United States Department of Energy


A toy computer includes a keyboard housing and a monitor housing pivotally secured by a hinge coupler. A depressible keyboard unit is pivotally supported by the keyboard housing and is coupled to a movable slider within the interior of the keyboard housing. A return spring is coupled to the slider and is operative to pivot the slider such that a ratchet engaging tooth is raised to its engagement position in the absence of a keyboard unit stroke. An endless belt display utilizes a cylindrical lens element array together with a segmented image formed on the endless belt to provide apparent motion of the image as the endless belt is moved. A ratchet coupling system is coupled between the slider and the movable belt to provide incremental belt motions in response to each keyboard stroke.

Toys utilizing sound or other action together with visual displays have, through the years, developed into an extremely popular type of toy with children of broad age ranges. Many such toys have been developed which provide music, rotating carousels, illuminated projections and the like often resembling music boxes. Still others have been provided which imitate radios or television sets in their general appearance with corresponding functional characteristics which simulate their operation. Within such devices, the display systems used very substantially. Some devices utilize a scrolling belt-like roll bearing a series of images together with a moving mechanism which scrolls the images past an aperture or other viewing area. Some devices utilize a plurality of movable cards often centrally disposed about a rotating shaft to be flipped into a visible alignment in accordance with shaft rotation. Still others utilize illuminated drums or other movable, rotatable image bearing structures together with a light source to provide a series of viewable pictures.
One of the more interesting types of toy display systems used is that provided by a segmented lenticular system in which an image roll having a parallel series of image lines formed in multiple segments thereon is continuously scrolled past a lens system. The lens system typically utilizes a plurality of parallel cylindrical lens overlying at least a portion of the moving picture roll. The alternate magnifying and obscuring of the underlying segments of the picture roll as the picture moves beneath the lens system together with the arrangement and character of the picture image segments provides the illusion of image motion.
Thus, a great variety of display systems in toy devices have been provided by the art. For example, U.S. Pat. No. 4,182,071 issued to Todokoro sets forth a TOY TELEVISION SET which is also set forth in U.S. Pat. No. 4,215,511 also issued to Todokoro and entitled TOY TELEVISION SET WITH MUSICAL BOX. The toy television sets set forth therein employs a housing defining a viewing screen aperture behind which a rotatable shaft is generally centered and extends horizontally. A plurality of image cards are loosely secured to the centered shaft and are displayed in pairs to generally fill the image screen as the shaft is rotated. An indexing member controls the card position to provide sequential exposure of each card as the cards are flipped into visible position by rotation of the shaft.
U.S. Pat. No. 3,590,525 issued to Tomaro sets forth a TOY MOVING PICTURE AND AUDIO SYNCHRONIZING MECHANISM in which a story telling toy includes a housing having an interior cavity supporting a rotating image bearing drum behind a viewing aperture simulating a television viewing screen. An audio play device is operative within the housing to replay the audio track of a prerecorded story. The drum is rotated in synchronism with the audio information on the recorded story track to provide simultaneous image and audio information.
U.S. Pat. No. 5,032,099 issued to Chan sets forth a TOY MUSICAL BOX which is also the subject of a counterpart British Application No. 2236490. The toy musical box includes electronic musical sound reproduction systems together with an electric drive motor for moving an endless band carrying a continuous past a window. The music box may resemble a television set in general appearance. The operation of the sound reproduction circuit and the motor are remotely controlled by sound impulses from a separate hand-held device. A lenticular system comprising a plurality of cylindrical lenses in parallel array is formed upon the simulated television viewing screen and the continuous picture is segmented to provide the appearance of motion as it is continuously moved past the cylindrical lens system.
U.S. Pat. No. 3,114,216 issued to Crawford et al sets forth a SOUND AND PICTURE TOY having a rectangular housing within which a rotatable disk is supported and coupled to a forwardly extending knob. An aperture is positioned in the frontal portion of the housing to frame a single segment of the disk which bears a plurality of images radially spaced about the outer portion of the disk. A musical drive system rotates the disk moving the images past the viewing window and playing music.
U.S. Pat. No. 3,388,499 issued to Mercorelli sets forth a SIMULATED TELEVISION SET INCLUDING DIORAMA AND MUSIC BOX in which a housing replicating a television receiver and defining a viewing screen aperture supports a pair of parallel rollers between which an image bearing belt is scrolled past the viewing aperture.
While the foregoing described prior art systems have provided some measure of enjoyment and entertainment and have improved visual display toys generally, there remains nonetheless a continuing need in the art for ever improved toy display systems.

Incrementally moved cylindrical lens display system for toy


An optical scan device having an optical deflector reflecting a light beam from a light beam source so as to deflect the light beam and having a surface to be scanned on which information is written such that the light beam deflected by the deflector scans the surface is disclosed. Optical detectors are arranged at least in two locations, a start side of writing and an end side of writing, which locations are outside an effective writing area. A measuring part measures a scan time required by the light beam deflected by the optical deflector to scan a range between the optical detectors. A correcting part corrects each dot position of image data in the effective writing area to an arbitrary position based on a variation amount of the measured scan time.

1. Field of the Invention
The present invention generally relates to image forming apparatuses such as laser printers, laser facsimiles, and digital copying machines, optical scan devices used for such image forming apparatuses, and image forming methods, and more particularly, to an image forming apparatus and image forming method that perform correction of a shift (displacement) of a scan position of laser scan, and pixel position control of optical scan devices.
2. Description of the Related Art
A color laser printer is equipped with a laser scan optical device having laser scan optical units corresponding to four colors (Y: yellow, M: magenta, C: cyan, and BK: black). Each of the laser scan optical units includes a laser diode emitting a laser light beam, a polygon mirror deflecting the laser beam, and the like.
The laser beam emitted from-the laser diode is deflected by the polygon mirror after modulation based on image data, and scanned on a photo conductor line by line. This is called main scan, and a 2-dimensional image is formed on the photo conductor by the main scan and sub scan by rotation of the photo conductor. Such a color laser printer has advantages in that modulation for each dot is easy, there is little unevenness of an image in the main scan direction, and the like.
By the way, each of the laser scan optical units corresponding to each of the colors has a different linearity property in the main scan direction according to variations in lens performance and in mounting of the lens. In addition, the linearity property is varied by elongation of a component according to temperature changes. Such variations in the linearity property cause variations in registration.
(Prior Art 1)
For this reason, in order to correct the variation in registration, a conventional color laser printer prints a pattern for detecting the variation in registration, reads the pattern by a CCD or the like, and detects the amount of variation in registration. Then, adjustment of registration is performed by modulating a dot clock and correcting the variation in registration so that shift (displacement) of the print position in the main scan direction is eliminated.
In addition, in a case of a tandem laser scan optical device, color matching of respective laser scan optical units is performed by standardizing the temperature characteristic of each of the laser scan optical units.
However, in the above-described conventional method of adjusting the registration, errors in reading the pattern for detecting the variation in registration are considerable. Thus, there is a problem in that the registration correction cannot be correctly performed, and thus it is impossible to obtain a high quality image. Additionally, since a CCD or the like for reading is required, there is also a problem in that the size of each of the laser scan optical units is increased and cost increases.
Further, in the method of standardizing the temperature characteristic of each of the laser scan optical units so as to perform the color matching of each of the laser scan optical units of the laser scan optical device, it is difficult to standardize the temperature characteristics due to limitations of accuracy of components. That is, the scan position of a laser beam on the photo conductor is shifted according to the temperature changes for each of the laser scan optical units.
A problem will not be caused if the scan position of the laser beam shifted by the temperature changes is the same in each of the laser scan optical units. However, the scan position of the laser beam of each of the laser scan optical units varies according to the characteristic of each of the laser scan optical units and the difference of temperatures between the laser scan optical units. This causes color shift. Especially, the shift of scan position introduced by the difference between the thermal expansion of the lens and that of the chassis or the like has a great influence.
(Prior Art 2)
In Japanese Laid-Open Patent Application No. 2-50176, recording shift is corrected by generating a pattern designation signal corresponding to a detected temperature, generating a line designation signal with a pattern designated by the pattern designation signal during 1-line main scan, and scanning according to image data of a line designated by the line designation signal.
However, in such a correction method, though it is possible to correct the shift in the sub scan direction introduced by the temperature change, there is a problem in that it is impossible to perform correction of shift of registration in the main scan direction.
(Prior Art 3)
Considering such a condition, in the invention in Japanese Laid-Open Patent Application No. 2001-201702, correction of print position is performed such that, in a tandem laser scan optical device, a laser scan optical unit having a temperature sensor is provided for each of the colors Y, M, C and K, the linearity characteristic and data of temperature gradient in the main scan direction that are measured for each of the laser scan optical units are maintained, an amount of correction of print position difference according to an error in mounting fθ lens and temperature changes is calculated, and based on the calculated amount, the modulation of a dot clock and correction of the print position difference are performed.
However, in the prior art 3, the cost is high since the tandem laser scan optical device includes four sets of a light source, a polygon motor, a fθ lens, and a temperature sensor for four colors, that is, Y, M, C and K.
In addition, the tandem laser scan optical device further includes four polygon mirror motors that are heat sources therein. Thus, the tandem laser scan optical device increases the temperature by self-generating heat, and performs correction by detecting the temperature for each of the laser scan optical units. Accordingly, energy saving is not achieved.
Further, correction control is complex since the tandem laser scan optical device uses as many as four temperature sensors.
Concerning such aspects, as mentioned above, the print position difference occurs according to the characteristic of each of the laser scan optical units and the difference of temperature between the laser scan optical units. However, by arranging a plurality of scan optical systems close together, it does not matter if the temperature changes of the scan optical systems are regarded as the same. Thus, it is possible to manage with a smaller number of temperature sensors than the number of the laser scan optical units. Hence, the correction control can be simplified.
Moreover, in the prior art 3, a modulation means of the dot clock for performing printing correction is not specified. Thus, the prior art 3 lacks specifics for realization.
By the way, an image forming apparatus such as a laser printer, a laser facsimile, and a digital copying machine includes an optical writing device or an optical scan device having an optical deflector and a surface to be scanned. The optical deflector deflects (reflects) a beam from a light source. Information is written on the surface to be scanned by scanning the surface with the beam deflected by the optical deflector. Generally, a laser light source such as a semiconductor laser is used for the light source. Hereinafter, the optical scan device is referred to as a "laser scan device", and an optical system thereof is referred to as a "laser scan optical system".
As a factor that degrades writing quality or quality of forming images, there is variation in scan speed on the surface to be scanned, which surface is constituted by a surface of a photo conductor. When there is variation in the scan speed, as a result, shifts of dot positions (hereinafter referred to as "dot position shifts") occur. Especially, in color images, the variation in the scan speed causes color shift, resulting in degradation in color reproduction characteristics and resolution. Thus, in order to obtain high-quality images, one condition to be met is that the variation in the scan speed be eliminated. However, in prior art, there is a limit to eliminating the variation in the scan speed. The factors that cause the variation in the scan speed in the laser scan optical systems are as follows.
1. fθ characteristic of a scan lens is not sufficiently corrected
2. degradation in precision of optical components of the laser scan optical systems and accuracy in mounting to a housing
3. fθ characteristic is degraded due to variation in focal distance, which variation is caused by deformation of the optical components and variation in refraction factors of the optical components, according to variation in the environment such as temperature and moisture in an image forming apparatus
In particular, it is possible to avoid the dot position shift in the main scan direction caused by the environmental variation (#3 of above factors), even if optical tuning or electrical correction is performed on the image forming apparatus before shipping. In order to meet the needs for higher quality these days, it is necessary to solve this problem. More specifically, in color image forming apparatuses such as color laser printers that scan with a light beam for each of a plurality of colors, the dot position shift in the main scan direction is a great factor for degrading image quality. Thus, it is important to eliminate the dot position shift so as to maintain image quality.
Prior art for correcting the dot position shift in the main scan direction are as follows. As an example of including a means for correcting a start position for writing of an image forming position of each color with an error within 1 clock, there is an invention described in Japanese Laid-Open Patent Application No. 2000-238319. As an example of adjusting the start position and end position for writing in the main scan direction, there is an invention described in Japanese Laid-Open Patent Application No 2000-289251.
However, in neither of the inventions described in the above-described applications, is it possible to correct the influence of the dot position shift in the main scan direction caused by optical systems and deflectors.

Image forming method, image forming apparatus, optical scan device, and image forming apparatus using the same


A cleaning sheet (29) is formed with a trough-hole (29a) at a portion corresponding to a cavity of a mold along with a slit (29b) or a flow cavity cut (29c) at every corner at an outer periphery of the through-hole (29a) and is placed between a first mold half and a second mold half of the mold to clean the inside of the mold, thereby improving the cleaning effect of the mold.

In the resin molding step for resin molded-type semiconductor devices, resin molding is repeated several times, so that resin burrs and dirt, such as oil or dust, are accumulated in the inside of the mold, in which a molding resin is filled, or in the cavities, runners and air vents of a pair of top and bottom halves constituting the mold and also in a cull block and its neighbor.
Such dirt adversely influences the quality of moldings and leads to a lowering of releasability when a product is removed from the mold. Accordingly, it is necessary for a worker to clean the mold at intervals of given shots.
However, the cleaning of a mold by a worker is a manual work, which requires much time. Thus, there is a demand for a technique wherein a mold can be cleaned within a short time.
For a technique meeting the requirement, a method has been carried out, as stated in Japanese Laid-open Patent Application No. Hei 1 (1989)-95010, wherein a lead frame not mounting a semiconductor chip (hereinafter referred to as dummy lead frame) is clamped between the main surfaces (faces) of a mold, and a cleaning resin formed of a melamine resin or the like is charged into the mold and hardened to cause dirt to be deposited on the cleaning resin surface, thereby removing the dirt along with the cleaning resin.
Alternatively, there is known a method of directly pouring a cleaning resin into the cavity at a high pressure or normal pressure without use of any dummy lead frame or the like.
However, according to the first-mentioned technique, an expensive dummy lead frame has to be used for cleaning, and not only this is poor in economy, but also a dummy lead frame of a specific shape matched with a mold has to be set in position and clamped, so that precise positioning between the mold and the dummy lead frame becomes necessary. Moreover, with a molded resin for cleaning, the resin formed at cull and runner portions is separated out of the lead frame and the removal of this separated resin from the mold requires much time, thus being poor in working property. In addition, the separated cull and runner may be caught in a sliding portion of a molding apparatus, with the possibility of causing mechanical breakdown.
In order to solve such problems as stated hereinabove, a technique set out below has been proposed.
As described in Japanese Laid-open Patent Application No. Hei 6 (1994)-254866, the technique comprises the steps of clamping a sheet-shaped cleaning member made of cotton cloth (non-woven fabric), in which a cleaning resin can be impregnated and permeated, between opened mold halves, and filling a cleaning resin in a molten state in the cavity of the closed mold.
As described in the known instance, when a cleaning resin in a fluid form is charged in such a state that the sheet, in which a cleaning resin and chemicals are able to be impregnated therein and permeated therethrough, is placed between the main surfaces (faces) of the top and bottom mold halves, an advantage is offered in that not only the positioning accuracy required between the mold and the sheet can be lowered, but also the cleaning resin and chemicals can be infiltrated at a portion where the sheet is sandwiched between the main surfaces of the top and bottom mold halves, thereby permitting the mold to be cleaned.
In the technique, however, when the cleaning resin is filled in the cavity, the sheet-shaped member is vertically moved (lifted) within the cavity. This causes a phenomenon wherein the sheet-shaped member becomes resistant to the flow of the cleaning resin, not allowing the cleaning resin to be run to all corners of the cavity.
Eventually, dirt is left at the corners of the cavity, with the attendant problem that cleaning within the cavity becomes unsatisfactory.
It should be noted that the faces of the mold have recesses, such as a flow cavity (capable of escaping air or a molding resin to prevent air from being entrained from a gate and ensure well-balanced filling of the molding resin in the cavity) and an air vent, in communication therewith formed at corners of the outer periphery of the cavity.
However, where the molding is subjected to cleaning with use of a cleaning sheet for a mold, the cleaning resin is unlikely to creep in the corners of the cavity and vicinities thereof. As a result, the cleaning resin does not enter into the flow cavity and air vent, and thus the flow cavity and air vent cannot be cleaned. This arises the problem of shortage of a molding resin being filled into the cavity upon molding of a product after cleaning.
Further, if the molding resin is unlikely to creep in the corners of the cavity and vicinities thereof, the cleaning resin is not stuck at portions of the molding cleaning sheet corresponding to the cavity corners and vicinities thereof. This presents the problem that after completion of the cleaning, when the cleaning resin is removed from the faces of the mold along with the mold cleaning sheet, the cleaning resin is partly left, which takes much time in removing the mold cleaning sheet and the cleaning resin from the faces.
In the faces of a mold for molding of SOP (small outline package) having an elongated portion to be molded and QFN (quad flat non-leaded package) using a matrix frame, where the distance between the outer edge of a cavity and the margin of the face is relatively small (e.g. where the distance is 10 mm or below), the cleaning resin leaked from the cavity runs out of the mold cleaning sheet upon cleaning of the mold and attaches to over the side surfaces contiguous to the faces of the mold.
In this case, it takes much time to remove the cleaning resin from the side surfaces of the mold, with the attendant problem that the efficiency of the cleaning work lowers.
An object of the invention is to provide a mold cleaning sheet which is able to improve the cleaning effect of a mold and also improve productivity through the reduction in time of a cleaning work and also a method of producing semiconductor devices using the mold cleaning sheet.
The above and other objects and novel features of the invention will become apparent from the description of the present specification and the attached drawings.

This patent is subject to a terminal disclaimer.

Mold cleaning sheet and method of producing semiconductor devices using the same


A device, a control method, and a program to increase the accuracy of voice read-out and text mining by automatically structuring a presentation file. The arrangement and practice of the invention involves an overlap grouping part for extracting overlap information between objects in a presentation file and grouping the objects as a parent-child relationship; a graph dividing grouping part for grouping the objects as a sibling relationship by representing the objects as nodes of a graph and by recursively dividing the graph so that a predefined cost between the nodes is minimized; a distance information grouping part for further grouping the objects as a sibling relationship if distance information between the objects is below a threshold determined by a predefined computation from a distribution histogram of the distance information; and a link information extraction part for extracting arrow graphics that represents a link relationship and generating link information including the link relationship and a link label. The resulting structured data is output as meta-information.

1. Field of the invention
The present invention relates to a method, program, and device for analyzing a document structure, and more specifically to a method, a program, and a device for analyzing a structure of a presentation document.
2. History of Related Art
In recent years, it has been common to use a presentation tool in a personal computer (PC) environment to create documents for use in making a presentation (presentation files).
A presentation file typically includes information such as text, graphics, images, and sounds, and it is created and stored by a presentation tool in various file formats. To expand the range of utilization of many presentation files created in this manner, methods are emerging that convert a presentation file into a form convenient for voice access (read-out) or for searching a file database.
For example, a tool for converting a file of Microsoft PowerPoint (®) (simply referred to as PowerPoint hereafter) into an HTML and a tool for extracting text (e.g., http://www.rdpslides.com/pptools/ppt2html/index.html and http://cita.disability.uiuc.edu/software/office/), and a technique for efficiently searching for presentation files (e.g., Published Unexamined Patent Application No. 2004-265097) are known.
Adding meta-information to document information allows an improved accuracy of document searches and of text mining techniques, which leads to efficient management of a large amount of information. For a text file, meta-information can be simply added to the file such as by extracting keywords. However, for a file like a presentation file in which a user may arbitrarily place objects such as text, graphics, and images, the document information as well as the position of the objects on a page has important meanings. Therefore, extracting the position information is essential.
Consider the slide shown in FIG. 1 as an example. If a structured text output such as one indicated below is obtained based on the position of the objects, dependency relationships among the texts can be understood. A "dependency relationship" as used herein refers to: a parent-child relationship (inclusion relationship) detected based on an overlap between objects; a sibling relationship (also referred to as a parallel relationship or sibling) detected based on the position of objects relative to each other; or a link origin and link target relationship between objects represented by graphics such as an arrow.
Exemplary Structured Text Output                Main image: Car                    ∘ FIG. 1                            □ Space Shuttle                                    ∘ FIG. 2                            □ Airplane                                    ∘ FIG. 3                            Motorcycle
However, no techniques are known that extract such positional information and generate structured data that is readily applicable to voice access or text mining. Text mining as used herein refers to a technique of analyzing and mining a large amount of data to derive useful information. In view of the above issues, the present invention aims to solve the following problems (1) to (4) in conventional art.
(1) Problem with the Read-out Order
Since presentation files are created by different users in different formats, it is difficult to understand the content of the files with voice access (automatic read-out). For example, screen readers (software for providing voice output of GUI screens) can only read out objects on a slide one-dimensionally in order of depth of the objects (this direction is referred to as the Z coordinate herein, which is a third coordinate relative to the X and Y coordinates). The slide of FIG. 1 will then be read out in the order in which the objects were generated, as in the following example.                Airplane        Space Shuttle        Motorcycle        Main image: Car        FIG. 1        FIG. 2        FIG. 3
This voice output alone cannot provide positional information about the visual document structure, so that it is difficult to understand the content of the document. For a presentation file created without much thought, the screen reader will read out the objects in the order in which they were generated. Typically, a user does not necessarily create a presentation file in conceptual order. Therefore, it is difficult to understand the content of the presentation file by causing the screen reader to read out the file.
To solve this, the first of the above-mentioned tools (PPT2HTML) has a function to sort along the Z coordinate as shown in the left part of FIG. 2. This tool allows changing the read-out order by selecting an object in a select box for which changing the read-out order is desired, and by moving the object in the select box using up and down buttons. However, this tool still requires changing the order for each object, which is a cumbersome task. Therefore, the ability of sorting a plurality of objects as a conceptual unit would reduce burdens on the user.
(2) Problem with Reading out Diagrams
In order for a diagram contained in a presentation file to be read out, a technique is typically used that replaces the diagram with text briefly describing the diagram, i.e., what is called alternative text (Alt text). However, inserting the Alt text into all objects in a presentation file is a laborious task.
For example, in the second of the above-mentioned tools (cita.disability.uiuc.edu/software/office/—Illinois Web Publishing Wizard), data must be entered to a wizard (a mechanism that facilitates operation on sophisticated application software by presenting questions to be interactively answered) on a screen as shown in FIG. 3 in order to insert the Alt text into all objects. This is a time-consuming task for a slide on which many complicated diagrams appear. Therefore, the ability of dealing with a diagram made up of a plurality of objects as a group would also reduce burdens on the user in inserting the Alt text.
(3) Problem with Acquiring Information about Positional Relationships between Objects
Conventional art does not allow effective use of graphics helpful for understanding the relationships between objects, such as "arrows," unless the Alt text is inserted into the graphics.
(4) Applications of Presentation Files to the Field of Natural Language Processing
In analyzing a presentation file using a technique such as text mining, there has been no way other than to separately analyze text obtained for each object on a slide. If the above-mentioned dependency relationships among objects on the slide were found, text obtained from objects related to each other would be able to be collectively analyzed. Therefore, an improvement of accuracy of techniques such as text mining could be expected.

Method, program, and device for analyzing document structure

International Business Machines Corporation


The present invention is directed to polyisocyanates and polyurethanes derived therefrom. In various embodiments, the present invention provides polyisocyanates, methods of making the polyisocyanates from fused bicyclic alcohols, polyurethanes, and methods of making the polyurethanes from the polyisocyanates.

Polyurethanes are a versatile class of polymers that are used in a wide range of applications, for example: plastics, elastomers, flexible or rigid foams, gaskets and seals, coatings, fibers, and adhesives. Polyurethanes can be made by combining polyols and polyisocyanates, such as diisocyanates, optionally including chain-extenders such as diols, diamines, and the like. Polyols and polyisocyanates are typically derived from petroleum-based materials. There has been work in recent years to replace the petroleum-derived polyols with polyols derived from non-petroleum sources, such as vegetable oil, soybean oil, and castor oil. However, little attention has been paid to development of polyisocyanates from renewable non-petroleum sources.

Polyisocyanates from fused bicyclic polyols and polyurethanes therefrom

Iowa State University Research Foundation, Inc.


Means and methods for treating tumors in a mammal, in particular, malignant solid tumors, using adenovirus derived material and interleukin-3 (xe2x80x9cIL-3 xe2x80x9d). Tthe adenovirus derived material preferably encodes IL-3 activity. Such an adenovirus is preferably administered systemically to the mammal, optionally in an isolated perfusion setting. In preferred embodiments, IL-3 activity is combined with other cytotoxic activity.

The present invention lies in the field of anti-cancer (gene) therapy. In particular, the invention relates to selective killing of (solid) tumor cells in a mammal by gene delivery via the blood circulation.
Many different kinds of solid tumors occur in the body of mammals, including humans. In many cases these tumors are extremely difficult to treat, especially in advanced cancer with metastases. Currently available therapies include surgery, radiation therapy, chemotherapy, radio-immunotherapy, cytokine treatment and hyperthermia. All these therapies have important limitations and disadvantages. E.g., surgery can only be performed on localized, accessible tumors; radiation and chemotherapy are associated with both acute and latent toxicity, and responses are often limited; radio-immunotherapy and hyperthermia have limited application and effectivity; and cytokine administration is often associated with toxicity and evokes many pleiotropic side-effects. Often said therapies are combined to improve efficacy and to decrease toxic side-effects. However, in general, the effectivity of said therapies and their combinations is still unsatisfactory.
More recently, gene therapy has been proposed as a novel approach to treat malignancies. The concept of gene therapy comprises the introduction of a molecule carrying genetic information into cells of a host, whereby said genetic information has a functional format. Said genetic information may comprise a nucleic acid molecule that encodes a protein. In this case said functional format means that the protein can be expressed by the machinery of the host cell. The genetic information may also comprise or encode nucleic acid molecules with a sequence that is complementary to that of a nucleic acid molecule present in the host cell. The functional format in this case is that the introduced nucleic acid molecule or copies made thereof in situ are capable of base pairing with the complementary nucleic acid molecule present in the host cell. Said genetic information may furthermore comprise a nucleic acid molecule that encodes or is itself a so-called ribozyme or deoxyribozyme. In this case said functional format means that said nucleic acid molecule or copies made thereof in situ are capable of specifically cleaving a nucleic acid molecule present in the host cell. Said genetic information may furthermore comprise a nucleic acid molecule that encodes or is itself a so-called decoy molecule. In this case said functional format means that said nucleic acid molecule or copies made thereof in situ (nucleic acid molecules or proteins) are capable of specifically binding a peptide molecule present in the host cell.
Said introduction of a molecule carrying genetic information into cells of a host is achieved by various methods known in the art. Said methods include, but are not limited to, direct injection of naked DNA constructs, bombardment with gold particles loaded with said constructs, and macromolecule mediated gene transfer using, e.g., liposomes, biopolymers, and the like. Preferred methods use gene delivery vehicles derived from viruses, including but not limited to adenoviruses, retroviruses, vaccinia viruses and adeno associated viruses. Because of the much higher efficiency as compared to e.g. vectors derived from retroviruses, vectors derived from adenoviruses (so-called adenoviral vectors) are the preferred gene delivery vehicles for transferring nucleic acid molecules into host cells in vivo.
The adenovirus genome is a linear double-stranded DNA molecule of approximately 36000 base pairs. The adenovirus DNA contains identical Inverted Terminal Repeats (ITR) of approximately 100 base pairs with the exact length depending on the serotype. The viral origins of replication are within the ITRs exactly at the genome ends. Adenoviruses can be rendered replication defective by deletion of the early-region 1 (E1) of their genome. Vectors derived from human adenoviruses (so-called adenoviral vectors), in which at least the E1 region has been deleted and replaced by a gene-of-interest, have been used extensively for gene therapy experiments in both pre-clinical and clinical phase. Apart from replication defective adenoviral vectors, helper independent or replication competent vectors, either or not containing a gene-of-interest, can also be used for gene therapy purposes. Adenoviral vectors have a number of features that make them particularly useful for gene therapy for malignancies. These features include (1) the biology of adenoviruses is characterized in detail, (2) adenoviruses are not associated with severe human pathology, (3) adenoviruses are extremely efficient in introducing their DNA into host cells, (4) adenoviruses can infect a wide variety of cells and have a broad host-range, (5) adenoviral vectors allow insertion of relatively large fragments of foreign DNA, (6) adenoviruses can be produced in large quantities with relative ease, and (7) adenoviral vectors are capable of transferring nucleic acid molecules very efficiently into host cells in vivo (Brody and Crystal, Ann. N. Y. Acad. Sci. 716(1994):90-101).
The present inventors and their coworkers as well as others have demonstrated that recombinant adenoviral vectors efficiently transfer nucleic acid molecules to the liver of rats (Herz and Gerard, Proc. Natl. Acad. Sci. U.S.A., 96 (1993):2812-2816) and to airway epithelium of rhesus monkeys (Bout et al., Gene Ther., 1 (1994):385-394; Bout et al., Hum. Gene Ther., 5(1994):3-10). In addition, the present inventors, their coworkers and others have observed a very efficient in vivo adenoviral vector mediated gene transfer into a variety of established solid tumors in animal models (lung tumors, glioma) and into human solid tumor xenografts in immune-deficient mice (lung) (Haddada et al., Biochem. Biophys. Res. Comm. 195 (1993):1174-1183; Vincent et al., Hum. Gene Ther., 7 (1996):197-205; reviewed by Blaese et al., Cancer Gene Ther., 2 (1995):291-297. Thus, preferred methods for in vivo gene transfer into tumor cells of nucleic acid molecules that encode molecules that can be used to kill said tumor cells make use of adenoviral vectors as gene delivery vehicles.
Said molecules that can be used to kill tumor cells include but are not restricted to suicide enzymes that convert a non-toxic prodrug into a toxic compound (e.g. the HSV-tk/ganciclovir system), cytokines, antisense nucleic acid molecules, ribozymes, and tumor suppressor proteins. In addition, treatment of cancer by gene therapy methods also includes the delivery of replicating vectors that are toxic to the tumor cells by themselves.
Gene therapy by introduction of nucleic acid molecules encoding suicide enzymes has been widely tested on a variety of tumor models. Especially the transfer of the Herpes simplex virus thymidine kinase (HSV-tk) gene into tumor cells in conjunction with systemic administration of the non-toxic substrate ganciclovir has proven to be an effective way of killing tumor cells in vivo (Esandi et al., Gene Ther., 4 (1997) :280-287; Vincent et al., J. Neurosurg., 85 (1996) :648-654; Vincent et al., Hum. Gene Ther., 7 (1996) :197-205). An important advantage of the HSV-tk/ganciclovir system is that upon ganciclovir treatment HSV-tk transduced tumor cells mediate a significant killing effect on neighboring untransduced tumor cells, the so-called bystander effect (Culver et al, Science 256 (1992) :1550-1552). Thus, using this approach there is no absolute need for gene transfer into every individual cell in a solid tumor to achieve successful gene therapy. A limitation of this approach, however, is that the effect remains local. Consequently, the HSV-tk gene needs to be delivered into every individual solid tumor or metastasis throughout the body.
Gene therapy for cancer by the introduction of nucleic acid molecules encoding cytokines is based on the concept of enhancing the immune response against the tumor cells. The ultimate goal of this approach is to obtain regression of the treated tumor and simultaneously induce such a high degree of immunity that coexisting metastases are also destroyed. The mechanism by which the cytokine enhances the immune response against the tumor cells most likely in many cases involves eliciting an inflammatory type cell infiltration that results in improved antigen presentation. During the local inflammation invading cells may lyse the tumor cells, releasing tumor antigens in a form that can be presented by other subpopulations of the invaders to T lymphocytes. These, in their turn could act against coexisting metastases. Compared to administration of a cytokine protein the gene transfer approach has the important advantage of high-level production of the cytokine at the site of the tumor, while systemic concentrations of the cytokine remain low. This avoids any pleiotropic and toxic side effects associated with said cytokine. Signs of (partially) successful cancer treatment have been obtained with tumor cells expressing IL-2 (Fearon et al., Cell 60: 397-401, 1990; Gansbacher et al., J. Exp. Med. 172:1217, 1990), IL-4 (Golumbek et al., Science 254:713-716, 1991; Platzer et al., Eur. J. Immunol. 22:1729-1733, 1992), interferon-gamma (Gansbacher et al., Cancer Res. 50:7820-7824, 1990), interferon-alpha (Ferrantini et al., Cancer Res. 53:1107-1112, 1993), TNF alpha (Blankenstein et al., J. Exp. Med. 173:1047-1052, 1991), IL-7 (Hock et al., J. Exp. Med. 174:1291-1298, 1991; McBride et al., Cancer Res. 52:3931-3937, 1992), G-CSF (Colombo et al., J. Exp. Med. 173:889-897, 1991), GM-CSF (Dranoff et al., Proc. Natl. Acad. Sci. U.S.A. 90:3539-3543, 1993), IL-12 (Tahara et al., Cancer Res. 54:182-189, 1994), IL-1 (Apte et al., In: Cytokine-induced tumor immunogenicity, Acad. Press, London, pp. 97-112, 1994; Apte et al., Folia Biol. Praha 40:1-18, 1994; Douvdevani et al., Int. J. Cancer 51:822-830, 1992; Nakata et al., Cancer Res. 48:584-588, 1988; Zxc3x6ller et al., Int. J. Cancer 50:443-449, 1992) and IL-3 (McBride et al., Folia Biol. Praha 40:62-73, 1993; Pulaski et al., Cancer Res. 53:2112-2117, 1993). The present inventors and their coworkers have previously observed partial regression of a non-immunogenic solid tumor (L42 non small cell lung cancer; Kal et al., NCI Monographs 6:111-114, 1988; Kal et al., Radiother. Oncol. 6:231-238, 1986; Kal et al., J. Natl. Cancer Inst. 76:943-946, 1986) growing subcutaneously in WAG/Rij rats after intra-tumor injection of adenoviral vectors expressing IL-1a or IL-3. This regression occurred both in the injected tumor and in an untreated distant (contralateral) L42 tumor (patent application EP 96.202725, incorporated herein by reference).
Interleukin-3 (IL-3) is a cytokine well described as a hematopoietic growth factor that has a wide range of target cells including progenitor cells of every lineage, excluding cells committed to the T and B lymphoid lineage (Schrader et al., In: Lymphokines, Acad. Press, San Diego, 1988). The main production of IL-3 by activated T cells has led to the hypothesis that IL-3 is not involved in steady-state hematopoiesis but functions as a link between on one hand the T lymphocytes of the immune system, which sense invasion of the body by foreign materials, and on the other hand the hematopoietic system which generates the cellular elements that mediate defense and repair responses (Ihle, In: Immunoregulatory cytokines and cell growth, Karger, Basel, 1989). IL-3 exerts a broad spectrum of biological properties (Ihle et al ., J. Immunol. 131:282, 1983), including stimulatory activity on several myeloid leukemia cell lines, formation of granulocyte-macrophage colonies, mast cell growth factor activity, P cell-stimulating activity and histamine producing cell-stimulating factor activity. In addition, IL-3 is capable of promoting the proliferation of megakaryocyte colony-forming cells, of supporting the differentiation of eosinophils and pre-B-cell precursors, of supporting proliferation of Natural Cytotoxic (NC) cells but not Natural Killer (NK) cells and of promoting the formation of osteoclasts. IL-3 also stimulates the effector functions of monocytes, eosinophils and basophils, thereby having the potential to regulate inflammation and allergy (Elliott et al., J. Immunol. 145:167, 1990; Haak-Frendesco et al., J. Clin. Invest. 82:17, 1988; Lopez et al., J. Cell. Physiol. 145:69, 1990). Human endothelial cells express the IL-3 receptor which expression is enhanced by tumor necrosis factor alpha (TNF-xcex1). IL-3 stimulation of TNF-xcex1-activated endothelial cells enhances IL-8 production, E-selectin expression and neutrophil transmigration (Korpelainen et al., Proc. Natl. Acad. Sci. U.S.A. 90:11137, 1993). This suggests that IL-3 plays a role in inflammation not only by stimulating effector functions of mature leukocytes but also by regulating their localization to sites of inflammation through its action on the endothelium.
There are several ways to administer recombinant adenoviral vectors with therapeutic genes into solid tumors that grow in a mammalian animal body. Currently, cancer gene therapy protocols predominantly use direct injection of the recombinant vector into the tumor (e.g., Haddada et al., Biochem. Biophys. Res. Comm. 195:1174-1183, 1993; Vincent et al., Hum. Gene Ther. 7:197-205, 1996). The major disadavantage of this application route is that metastases, and in particular micrometastases, in advanced cancer are practically impossible to reach with this approach. Therefore, such a gene therapy relies solely on a distant (immune mediated) effect of the introduced genetic information. Using current technology, said distant effect may not be expected to be complete and, consequently, may not be expected to cure the disease.
An alternative, and possibly better way of delivering genetic material into solid tumors and/or their metastases could be by administering the recombinant adenovector via the blood or lymphatic circulation. All established tumors, both primary and metastatized, that are larger than a few millimeter in diameter are vascularized (Folkman et al., J. Nat. Cancer Inst. 82:4, 1990; Folkman and Shing, J. Biol. Chem. 267:10931-10934, 1992). In addition, distant metastases usually emerge after migration of tumor cells from the primary tumor through the blood or lymphatic circulation. Thus, all solid tumors are in close contact with the circulation and, in priciple, could be reached via the circulation. Moreover, killing of a solid tumor does not neccessarily depend on gene transfer into the tumor cells themselves. Gene therapy strategies have been proposed where genetic material (e.g., the HSV-tk gene) is introduced into endothelial cells of the tumor vasculature (e.g., WO96/21416). This should result in destruction of the tumor vasculature, ultimately leading to tumor necrosis.
The total capillary surface area in an adult human is approximately 100 m2 comprising approximately 1012 endothelial cells, whereas the endothelial cell content of the vasculature of a solid tumor is about 4-log less (Chan and Harris, In: The Internet book of Gene Therapy. Cancer Therapeutics, eds. R. E. Sobol and K. J. Scanlon, 1995, Appleton and Lange, CT, pp. 211-227). Based on these estimations, intravascularly administered adenoviral vectors only have a 0.01% chance of interacting with endothelial cells in the vasculature of a distant tumor. The proliferation index of endothelial cells in the vasculature of a tumor is about 100-fold higher than that of normal endothelial cells (Hobson and Denekamp, Br. J. Cancer, 1984, 49:405-413). Thus, if gene delivery would preferentially occur into actively proliferating cells, the gene transfer efficiency into the chosen target cells could be raised to approximately 1%. However, because adenoviral vectors, in contrast to retroviral vectors, transduce both replicating and non-replicating cells, the estimate of 0.01% gene transfer into cells of the tumor vasculature is more realistic. In any event, administering the adenovector via the circulation is expected to result in at least 99% of the adenoviral vectors interacting and possibly being taken up by cells in normal tissues. This is highly undesirable with respect to toxic side-effects of the procedure. E.g., the introduction and expression of a suicide gene or an inflammation eliciting cytokine gene should obviously not take place in the endothelium of the normal vasculature. Therefore, until the present invention the common belief in the field has been that administering the adenovector to the tumor via the circulation requires some sort of specific targeting of the adenovector to the tumor or its vasculature (e.g., WO 96/25947). Said specific targeting may include specific interaction with and uptake by the intended target cells, as well as specific expression of the introduced genetic information in the intended target cells. Said specific targeting was felt to be necessary to ensure efficient gene transfer and to avoid toxic side-effects in other tissues. Many different molecules that are specifically expressed or upregulated on the cell surface of tumor cells or their vascular endothelial cells have been proposed as targets for specific uptake of gene transfer vectors. Examples of such molecules are carcinoembryonic antigen (CEA; Walther et al., Head-Neck 15:230-235, 1993), surface-bound vascular endothelial growth factor (VEGF; Plate et al., Int. J, Cancer 59(1994):520-529; Brown et al., Hum. Pathol. 26(1995):86-91), the avb3 integrin (Brooks et al., Science 264(1994):569-571), endosialin (Rettig et al., Proc. Natl. Acad.Sci. USA 89(1992):10832-10826) and radiation-induced E-selectin (WO 96/25947). However, said specific interaction with and uptake by the intended target cells is extremely difficult to achieve, for two reasons; i.e. (1) most of the proposed target molecules are also expressed on normal tissue, albeit at lower levels, and (2) it is difficult to construct targeted gene delivery vehicles. Many years of research have been invested by many different investigators in devising targeted gene delivery vehicles for this purpose, without significant success. Perhaps eventually this goal will be reached, but not without a major research effort and significant investment.
As a further alternative way to accomplish functional expression of genetic material in the vasculature of tumors, it has been proposed to transfer said genetic material into cultured endothelial cells ex vivo, followed by administration of said cultured endothelial cells via the circulation (WO 93/13807). This should result in selective incorporation of said cultured endothelial cells at sites of active angiogenesis, including the vasculature of solid tumors. However, such a selective incorporation into the vasculature of solid tumors has not been shown to occur.
Furthermore, the disadvantage of this approach is that it involves the isolation, ex vivo manipulation, and readministration of endothelial cells.
The present invention provides an effective and safe treatment of (solid) tumors in the body of mammals. This is accomplished by administration via the circulation of recombinant adenoviral vectors with wild-type infection spectrum that carry an interleukin-3 gene in a functional format.
Thus the invention provides the use of a recombinant adenoviral vector encoding IL-3 activity for manufacturing a pharmaceutical composition for the systemic treatment of tumors. For the present invention IL-3 activity is defined as the protein itself, derivatives and/or fragments thereof having at least, but preferably most or all of the biological functions of IL-3, although the amounts of activity displayed by these derivatives and/or fragments may vary. It is preferred that the systemic treatment is restricted to certain tissues, organs, or extremities, or certain combinations thereof, because adenovirus is in principle capable of infecting almost any cells in the host, so that the restriction enables to avoid unnecessary infection, as well as higher probability of infection of the proper targets. Thus in a preferred embodiment the invention provides a systemic treatment which includes isolated tissue perfusion. Tissue perfusion is intended to read on isolated tissues as well as organs and/or extremities or any combination thereof. Two approaches of isolated perfusion are provided, one whereby the isolated perfunded tissue includes the tumor and one whereby the isolated perfunded tissue excludes the tumor. In the second case organs or body parts which are liable to be damaged by the treatment or which are likely to influence the uptake of virus by the target cells can be excluded from the system to which the adenoviral vector encoding IL-3 activity is provided. A preferred organ to be excluded according to the invention is the liver.
In the other isolated perfusion route the vector is delivered to the isolated part only. It is preferred to deliver the vector in the form of a virus-like particle.
This means that the vector is packed in an adenovirus shell. The most preferred virus-like particle is the human homolog of recombinant adenovirus IG.Ad.CMV.rIL-3 deposited at the ECACC under accession number V96071634 or a functional derivative thereof.
IL-3 is not only capable of inducing regression of tumors, but it is also capable of retarding or halting the growth of tumors over prolonged periods of time. Many cytostaic agents are also capable of accomplishing regression of tumors, but are not capable of holding the regressed tumor in check over a prolonged period of time. It is therefor advantageous to make combinations of IL-3 activity and other cytostatic activity to have the best of both worlds. Regression of the tumor by administration of one or a number of doses of a cytotoxic agent and obtaining further regression as well as retarding or halting the growth of the regressed tumor by providing IL-3 activity.
Thus the invention further provides a means for treating tumors comprising a pharmaceutical composition comprising I1-3 activity and a pharmaceutical composition comprising cytostatic activity. Preferably, the IL-3 activity is provided by a recombinant adenoviral vector, (preferably in a virus-like particle) encoding said activity to be given systemically, either in an isolated perfusion format or not. Preferably the pharmaceutical composition comprising cytostatic activity is in a single dosage unit for injection into a solid tumor, to be given once or several times until the required dosage is reached.
Typically the virus-like particle is present in an amount of from about 106 to 5.109 iu in a perfusion fluid.
It is of course also possible that both activities are present in one composition.
Preferably the cytostatic or cytotoxic activity is TNF-activity, Melphalan, or adriamycin. The invention further provides a pharmaceutical composition for systemic treatment of tumors comprising IL-3 activity provided by a recombinant adenoviral vector encoding such activity, whereby said pharmaceutical composition is a perfusion fluid. Preferably the recombinant adenoviral vector is provided in the form of virus-like particles. Preferably said virus-like particles are present in an amount of about 106 to 5109 iu.
The most preferred virus is the human homolog of recombinant adenovirus IG.Ad.CMV.rIL-3 deposited at the ECACC under accession number V96071634 or a functional derivative thereof.
The invention further provides a kit of parts for the treatment of tumors comprising a pharmaceutical composition comprising IL-3 activity, means for isolating certain tissues, and means for perfunding said isolated tissues. Hereby the essential elements for performing a method of treatment according to the invention are given. The means for perfunding are preferably heart-lung machines or other equipment capable of perfunding and preferably oxygenating. Means for excluding certain organs, limbs and/or tissues are known in the art and references thereto can be found herein. If it is possible to exclude then it is of course also possible to limit perfusion to said organs, tissues or limbs which can be excluded. Of course the IL-3 activity in the kit of parts is again preferably provided by a recombinant adenoviral vector encoding said activity, preferably in the form of a virus-like particle, preferably present in an amount of about 106 to 5.109 iu. Preferably the kit of parts further comprises a pharmaceutical composition comprising cytostatic activity for the reasons already disclosed herein.
Despite the high potential of cancer gene therapy, the results of experimental treatment of solid tumors have until now been very disappointing. Direct injection of gene delivery vectors, mostly adenoviral vectors, carrying therapeutic genetic information into solid tumors has resulted in efficient gene transfer into tumor cells and has shown some, although still incomplete, tumor regression (e.g., see patent applications WO 95/05835 and EP 0 707071). The major limitation of this approach, however, has been that every solid tumor has to be individually injected. This makes clinical application of such a treatment far from realistic for most cancers, in particular for advanced cancers with metastases. The alternative approach, i.e. therapeutic gene delivery via the circulation after systemic intravascular administration of said gene delivery vector, has been associated with extremely low gene transfer efficiency into the tumor. The common belief in the field has been, therefore, that the gene transfer efficiency should be increased to obtain a significant therapeutic effect. It is also generally accepted that this should not be done by administering more gene delivery vectors, but by promoting the specific uptake of said gene delivery vector into the tumor cells or into the endothelial cells aligning the tumor vasculature. The reason for this is that high concentrations of untargeted gene delivery vectors cause (1) a stronger immune response, and (2) more toxicity due to delivery of the anti-tumor gene to other tissues. Furthermore, it is difficult and expensive to produce extremely high concentrations of gene delivery vectors.
The present inventors have made the surprising observation that adenoviral vector mediated delivery of an interleukin-3 gene through administration via the circulation into the vasculature of solid tumors results in a very effective cancer treatment. Said circulation is meant to include both the blood circulation and the lymphatic circulation. Said adenoviral vector is not treated in any way to promote its specific uptake by the solid tumor cells or the endothelial cells aligning the tumor vasculature. The therapeutic effect of said delivery is much more dramatic than could be expected from the low transduction efficiency (less than 1% transduced cells) that is obtained with said administration via the circulation. Established solid tumors growing in relevant animal models regressed completely. Said therapeutic effect is shown to be dependent on both said administration via the circulation and the biological activity of the interleukin-3 encoded by the introduced gene.
The present invention among other things provides a recombinant adenoviral vector that carries a nucleic acid molecule that encodes interleukin-3 or a functional derivative or a fragment thereof. Said nucleic acid molecule is provided with a format that allows functional expression of said interleukin-3 in solid tumor cells and/or in endothelial cells of the vasculature of a solid tumor in the body of a mammal after administration of said recombinant adenoviral vector to the circulation of said mammal. The term xe2x80x9cfunctional expressionxe2x80x9d is understood to mean production of said interleukin-3 with biological activity that leads to killing of said solid tumor cells. Said format is conferred upon said nucleic acid molecule by including upstream of said nucleic acid molecule an activator (promoter and/or enhancer) nucleic acid molecule that preferably interacts with one or more trans-activating transcription factors that are present in tumor cells or in cells of the vasculature of a tumor and downstream of said nucleic acid molecule a eukaryotic polyadenylation signal. Said activator molecule may be derived from the adenovirus used to construct said adenoviral vector or from a different adenovirus. Alternatively, said activator molecule is of exogenous origin. Useful activator molecules in this aspect of the invention are derived from, e.g. the Cytomegalovirus Immediate Early promoter/enhancer, the Rous Sarcoma Virus LTR promoter/enhancer, but may also be derived from other activator molecules known in the art. In this aspect of the invention it is preferred that said nucleic acid molecule encoding interleukin-3 is a functional derivative from or includes at least a functional fragment of a nucleic acid molecule isolated from the same species as said mammal. Because in most applications of the invention said mammal is a human, it is in most applications of the invention preferred that said nucleic acid molecule is a functional derivative from or includes at least a functional fragment of a nucleic acid molecule isolated from a human. The terms xe2x80x9cfunctional derivativexe2x80x9d and xe2x80x9cfunctional fragmentxe2x80x9d are used here to indicate that said nucleic acid molecule encodes a peptide molecule with the same biological activity in kind, but not necessarily in amount, as said interleukin-3. Many different examples of nucleic acid molecules encoding mutants of human interleukin-3 with functional interleukin-3 activity are given in European patent EP 0 413 383. It is furthermore preferred that the biological activity of said interleukin-3 includes the elicitation of an intense local inflammation associated with an inflammatory type cell infiltration. The recombinant adenoviral vectors according to the invention may be derived from any wild-type adenovirus serotype that allows the functional expression of said interleukin-3 in solid tumor cells and/or in endothelial cells of the vasculature of a solid tumor in the body of a mammal after administration of said recombinant adenoviral vector to the circulation of said mammal. In the examples given infra to illustrate the present invention said recombinant adenoviral vectors are derived from human adenovirus type 5. It is to be understood, however, that those skilled in the art will be able to apply other recombinant adenoviral vectors without departing from the invention. Methods for the construction of recombinant adenoviral vectors according to the invention and for their propagation on useful packaging cells have been described in patent applications EP 0 707 071 and WO 97/00326, incorporated herein by reference. Other examples of vectors and packaging systems useful in the invention include, but are not limited to, those given in patent applications WO 93/19191, WO 94/28152, WO 96/10642, and WO 97/04119.
The present invention furthermore provides a pharmaceutical composition that comprises the recombinant adenoviral vector defined supra in combination with a diluent that is not toxic to the recipient mammal at the dosage used and that retains sufficient stability of the infectivity of said recombinant adenoviral vector for a time long enough to allow uptake of said recombinant adenoviral vector into the solid tumor cells and/or endothelial cells of the vasculature of a solid tumor after administration of said composition to the circulation of the recipient mammal.
A typical non-limiting example of a diluent according to this aspect of the invention is an isotonic saline solution that is sterile and that is buffered at a physiological pH. Preferably, said diluent furthermore contains serum-substituting ingredients. In the examples given infra to illustrate the present invention Haemaccel (Behring Pharma) is used as a suitable diluent. It is to be understood, however, that those skilled in the art will be able to apply other diluents without departing from the invention. For some applications of the invention it is furthermore preferred that said pharmaceutical composition is oxygenated prior to administration. Optionally, said recombinant adenoviral vector (or virus) is prepared in lyophilized form. In the latter case, said recombinant adenoviral vector is suspended in solution to obtain said pharmaceutical composition before administering said pharmaceutical composition to the circulation of the recipient mammal. Typically, a pharmaceutical composition comprising one dose contains at least about 106, preferably about 108 infectious units (iu) of the adenoviral vector of the invention, but in certain conditions it is preferred that it contains at least about 109, more preferred 1010, or even more preferred 1011 iu. The amount of virus to be provided depends on many parameters. As disclosed herein only a very limited portion of the administered virus actually infects the target cells. This may be one reason to increase the amount of virus to be administered. Also the size of the tumor and/or the degree of its vascularization will influence the amount of virus required to get an effect. Another important aspect is of course the amount of IL-3 activity expressed by a cell infected with one or more viruses. This of course depends on the cell, but also on the promoter that drives the expression and its interaction with cell components of the expression machinery, etc.
Based on the rat studies, where a CMV promoter is driving the rat IL-3 gene, anti-tumor activity was measured after perfusion with 109 i.u. of IG.Ad.CMV.rIL-3. Perfusion time was 15 minutes. The size of this tumor was approximately 1 cm3 . Dose finding studies are performed, where the range of administered [perfused] will increase from 106 up to 1010 iu. Anti-tumor activity is measured according to the methods described. The lowest dose resulting in a maximal anti-tumor effect will be used to calculate the dose to be delivered to human tumors, assuming that the same promoter are used in the adenoviral vector harboring the human IL-3 gene or a derivative thereof. It is assumed that the infection of human cells by recombinant adenoviral vectors is 10xc3x97 more efficient than rat cells. Furthermore, we assume the vascular bed or the tumor to be proportional to the tumor volume. Therefore, the optimal dose assessed in the rat model is extrapolated to the human situation by the following calculation:       dose              xe2x80x83            delivered              xe2x80x83            to              xe2x80x83            humans    =                    [                  effective                                xe2x80x83                              dose                                xe2x80x83                              in                                xe2x80x83                              rat                ]            xc3x97              [                  tumor                                xe2x80x83                              volume                                xe2x80x83                                          (            human            )                          ]                    [              10        xc3x97        tumor                          xe2x80x83                        volume                          xe2x80x83                                  (          rat          )                    ]
In another aspect, the invention provides a method to deliver said nucleic acid molecule that encodes interleukin-3 to solid tumor cells and/or endothelial cells of the vasculature of a solid tumor in the body of a mammal, whereby the adenoviral vector or pharmaceutical composition defined supra is administered to a site in the circulation of said mammal. Said circulation is meant to include both the blood circulation and the lymphatic circulation. Thus, the administration is performed to any site in the body of the recipient mammal where the blood or lymph fluids of said mammal pass. Preferred sites of administration are intravenous or intra-arterial, where it is further preferred that said administration is into an artery located upstream of the tumor vasculature. There are several means to perform said administration to the circulation. One of said means is by injection using, e.g., a syringe, a catheter or another infusion system known in the art. Preferably, said injection is performed at a controlled infusion rate. A much preferred means to perform said administration to the circulation is by perfusion. Perfusion is a technique whereby said administered pharmaceutical composition is caused to pass through said circulation or through a part of said circulation. When the administration is performed by perfusion it is furthermore preferred that said perfusion is done multiple times by creating a closed circuit and repassaging said pharmaceutical composition through said circulation or said part of circulation. Typically, said causing to pass is done by using a pump device and perfusion is performed at a rate depending on the species of the mammal to which said pharmaceutical composition is being administered. For humans, said rate is often in the range of approximately 40-80 ml/min and said perfusion is continued for a period of 60-90 minutes, but depending on patient, type of tumor, location thereof, these parameters may vary. For short treatment times (approximately 5-30 minutes) with the adenoviral construct an anoxic perfusion can be performed by those skilled in the art by using balloon catheters to make a closed circuit. No heart-lung machine is necessary.
In this aspect of the invention, said part of the circulation comprises the vasculature of the tumor or tumors to which gene delivery is performed. For optimal delivery of said nucleic acid molecule that encodes interleukin-3 to solid tumor cells and/or endothelial cells of the vasculature of a solid tumor it is preferred that the adenoviral vector or composition of the invention does not pass through the liver or a part of the liver of the recipient mammal. Thus, said part of the circulation does preferably not include the circulation of the liver or of a part of the liver, except when the tumor is located in or very close to the liver. For optimal delivery of said nucleic acid molecule that encodes interleukin-3 to solid tumor cells and/or endothelial cells of the vasculature of a solid tumor it is furthermore preferred that the blood of the mammal is first washed away from said closed circuit (e.g., by precirculation with the diluent of the pharmaceutical composition only) before said pharmaceutical composition is administered. Optionally, the blood that is washed away is collected and readministered at the end of the procedure. Surgical techniques for perfusion of parts of the circulation according to the present invention are under development and are already available for various specific parts of the circulation, such as, e.g., the liver (Fraker, D L et al., Circulatory shock, 44, p.45-50, 1994), the lung (Progrebniak H W et al., Ann. Thorac. Surg.,57, p.1477-83, 1994), and the kidney (Veen van de AH et al., Eur. J. Surg. Oncol. 20, p.404-405, 1994). A typical nonlimiting example of a routine perfusion technique useful in the invention is isolated limb perfusion (ILP), where a closed circuit is created between the femoral artery and the femoral vein. Alternatively, essentially the same perfusion techniques can be employed in the invention to exclude the delivery of said nucleic acid molecule to a part or parts of the circulation. In this aspect of the invention, the part or parts of the circulation to which said delivery is unwanted are perfused with a diluent according to the invention while said pharmaceutical composition is administered to the circulation systemically (hence, outside the perfusion circulation). An important example of this embodiment of the invention is exclusion of the liver circulation from delivery of said nucleic acid molecule.
The invention furthermore provides genetically modified solid tumor cells and cells of the vasculature of a solid tumor expressing said interleukin-3 in the body of a mammal. These cells expressing said interleukin-3 are obtained by administering the composition containing the adenoviral vector according to the invention using the method according to the invention via the circulation of said mammal.
The expression of said interleukin-3 in said solid tumor cells or cells of the vasculature of a solid tumor results in an effective killing of said cells. Thus, the present invention also provides a gene therapy treatment for solid tumors. All tumors that are in close contact with the circulation can be treated according to the invention. Although leukemias and lymphomas are not excluded, vascularized solid tumors are especially suited for treatment according to the invention. Examples of types of said solid tumors include, but are not limited to, carcinomas (e.g., of the lung, bladder, kidney, breast, stomach, pancreas, urogenital tract, and intestine), sarcomas (e.g., soft tissue sarcomas, osteogenic sarcomas, or Kaposi""s sarcoma), gliomas and melanomas. Also benign types of tumors, such as, e.g., angiomas and fibrocytomas can be treated according to the invention. It is to be understood, however, that the scope of the present invention is not to be limited to the treatment of any particular type of tumor.
It is furthermore to be understood that the cancer treatment according to the invention may be combined with other methods of cancer treatment known in the art. Such treatment combinations are also part of the present invention.
The invention is illustrated by means of the following examples. It is to be understood that said examples are not meant to limit the scope of the invention in any way.
Example 1 teaches the production of adenoviral vectors and pharmaceutical compositions according to the invention.
Example 2 teaches the cloning and production of an adenoviral vector with the human IL-3 gene and the pharmaceutical composition according to the invention.
Example 3 and 4 show the gene transfer efficiency that is obtained when adenoviral vectors are administered to a solid tumor via the circulation or by direct intra-tumor injection, as well as the unwanted gene transfer into non-tumor cells in both cases, and the type of cells in the tumor that are transduced using these administration methods. It is shown that the direct injection results in approximately 87-times more expression of the introduced gene in the tumor than administration via the circulation. The direct injection efficiently transduces many tumor cells along the needle tract, whereas administration via the circulation mainly transduces endothelial cells of the tumor vasculature, a few solid tumor cells adjacent to the vascular endothelial cells and some cells in or near the capsule of the tumor. Gene transfer into tissues other than the tumor hardly occurs using either method.
Examples 5, 6, 7 and 8 clearly demonstrate the effective anti-tumor effect that is accomplished by administering an adenoviral vector carrying the interleukin-3 gene into two types of solid tumors via the circulation. Complete regression of said tumors occur. Experiments show that this effective anti-tumor effect is not obtained by direct intra-tumor injection or by using an adenoviral vector that expresses the IL-3 gene at low levels. Control isolated limb perfusion experiments show that this effective anti-tumor effect is not obtained by a isolated limb perfusion without addition of said adenoviral vector with the interleukin-3 gene or by treatment with an adenoviral vector without effector gene. After the latter treatment some delay in tumor growth is observed when ROS-1 osteosarcomas were used, but the tumors do not regress. The latter growth delay is not observed when BN175 tumors were treated. Example 5 shows that the anti-tumor effect is specific for the activity of the interleukin-3 gene. Anti-cancer treatment by administering adenoviral vectors expressing the HSV-tk gene via the circulation followed by ganciclovir injections show only incomplete effects.
Example 9, 10 and 12 demonstrate that in the rats with the two tumor models studied the optimal dose for administering of the adenoviral vector carrying the interleukin-3 gene via the circulation is 1.09 iu (infectious units). And that a 15 minutes perfusion results in good antitumor effects.
Example 11 clearly demonstrates that the administration via the circulation of 1.109 iu of the adenoviral vector carrying the interleukin-3 gene is at least as efficient as the established combination therapy with TNF( and Melphalan).


Memory devices are described along with methods for manufacturing. A memory device as described herein includes a plurality of memory cells located between word lines and bit lines. Each memory cell comprises a diode and a plurality of memory elements each comprising one or more metal-oxygen compounds, the diode and the plurality of memory elements arranged in electrical series along a current path between a corresponding word line and a corresponding bit line.

1. Field of the Invention
The present invention relates to memory devices and methods for manufacturing memory devices, and more particularly to high density three-dimensional (3D) memory devices having a plurality of programmable resistive memory elements based on metal-oxygen compounds.
2. Description of Related Art
Metal oxide based nonvolatile resistive random access memory RRAM has attracted much attention because of its simple structure and excellent properties such as low power, high speed, and a large memory window between resistive states.
Tungsten-oxygen WOx based RRAM can be caused to change resistance between two or more stable ranges by application of electrical pulses at levels suitable for implementation in integrated circuits, and the resistance can be read and written with random access to indicate stored data. See, U.S. patent application Ser. No. 11/955,137 entitled "Memory Devices Having an Embedded Resistance Memory with Tungsten Compound and Manufacturing Methods", filed 12 Dec. 2007 and incorporated by reference herein.
Multi-level operation comprises changing the resistance of the metal-oxide material between more than two resistance states and is desirable since the data storage density can be increased.
Additionally, in order to achieve higher density it is desirable to reduce the cross-sectional area or footprint of individual memory cells in an array of memory cells. However, problems have arisen in manufacturing devices with very small dimensions, and with variations in manufacturing processes needed to meet the tight tolerance requirements necessary for large-scale high-density memory devices.
It is therefore desirable to provide a metal-oxide based memory cell structure for use in high-density memory devices having multi-level operation, as well as methods for manufacturing which address the tight process requirements needed for manufacturing large-scale high density devices.

High density resistance based semiconductor device


In a menu display apparatus, when a user selects a desirable item from a large number of items displayed in a drawing unit image on a display screen, the user can have such a feeling that the user actually uses a storage cabinet. The menu display apparatus is arranged by: image display means for displaying an image represented by such an image structure that a plurality of drawings are stored into storage units thereof; operation detecting means for detecting a drawing amount of a desirable drawing unit when an instruction is issued so as to draw the desirable drawing unit among the plurality of drawing units displayed within the image; display control means for displaying the drawing-instructed desirable drawing unit in a display size defined in response to the detected drawing amount; and item display means for displaying the respective items related to the drawing-instructed desirable drawing unit within the desirable drawing unit in such a display form in accordance with the display size of the desirable drawing unit. As a result, the menu display apparatus displays a menu used to select the respective items related to the desirable drawing unit.

1. Field of the Invention
The present invention generally relates to a menu display apparatus for displaying a menu used to arbitrary select a desirable item, and a program storage medium. More specifically, the present invention is directed to a data processing apparatus capable of varying a menu display area and also a total menu item number displayed on a cabinet holder image in response to a user instruction, and is directed to a storage medium for storing thereinto a program of this data processing apparatus.
2. Description of the Related Art
Conventionally, as menu screens for application software, there are typically two different menu formats. That is, in a hierarchical structure type menu format process modes are moved from upper-grade menus to lower-grade menus. In a list-shaped menu format, all of menus are simply arranged in a list shape irrespective of process modes. In the first-mentioned hierarchical structure type menu format, when an arbitrary menu icon is selectively designated under such a condition that icons corresponding to menu items of an upper-grade layer are displayed in a list form, the menu screen is switched from the menu screen of the upper-grade layer to the menu screen of the lower grade screen. In the list-mentioned list-shaped menu format, the menu screen is switched in the unit of a page while manipulating a preceding page key and/or a succeeding page key.
However, these conventional menu formats own the below-mentioned problems. That is, in the list-shaped menu format, the larger the item number of the menu is increased, the larger the total page number thereof is increased. As a result, the user must switch the pages many times. Also, in the hierarchical structure type menu format, under such a condition that the present menu screen is switched to the menu screen of the lower-grade layer, the menu item of the upper-grade layer corresponding thereto cannot be confirmed. Furthermore, when the present menu screen is moved from the lower-grade layer to the high-grade layer, the present menu screen must be once returned to the menu screen of the upper-grade layer. As previously described, the menu screens must be switched so as to display a desirable menu screen in any of these conventional menu formats. As a consequence, cumbersome operations are necessarily required, and also the user cannot readily grasp the entire menu structure.
The present invention has been made to solve the above-described problems, and therefore, has an object to provide such a data processing apparatus capable of selecting a necessary item from a large number of items, while having such a feeling that a user actually uses a storage cabinet.
Furthermore, the present invention has another object to provide a data processing apparatus capable of freely increasing/decreasing a dimension of a menu display area and also a total number of menu items in response to an operation instruction issued to this menu display area in such a case that an arbitrary menu item is selected from a plurality of menu items.
In accordance with the data processing apparatus of the present invention, under such a condition that a cabinet image is displayed and this cabinet image is represented by such an image structure that a drawing unit is stored into a cabinet main body, this drawing unit is displayed as being drawn with respect to the cabinet main body in response to an operation instruction issued to this drawing unit. Also, identifiers of the respective items related to this drawing unit are indicated in a list form within this drawing unit. Then, a desirable item identifier is selectively designated from the respective item identifiers listed in this drawing unit.
As a consequence, the user can select the necessary item from a large number of items, while having such a feeling that the storage cabinet is actually used. Therefore, the item selection can be visually grasped, and a desirable item can be effectively selected.
Also, in accordance with the present invention, such an image is displayed which is represented by an image structure that a plurality of drawing units are stored into a storage unit, and when a drawing instruction is issued to a desirable drawing unit, a drawing amount of this desirable drawing unit is detected. Then, this drawing unit is displayed with such a display size defined in correspondence to this detected drawing amount. The respective items related to this desirable drawing unit are displayed within this desirable drawing unit by a display form in accordance with the display size of the desirable drawing unit.
As a consequence, in such a case that an arbitrary item is selected from a large number of items, while the display forms of the items classified by the plural drawing units are adjusted in a readable shape, the desirable item can be effectively selected.
Also, the dimension of the menu display area is changed in response to an operation instruction issued to this menu display area, and also the plural menu items whose total number is equal to the dimension of this menu display area are indicated within this menu display area. Then, a desirable item is selectively designated from the respective menu items displayed in this menu display area.
As a consequence, when an arbitrary menu item is selected from a plurality of menu items, the dimension of the menu display area and the total number of menu items can be freely increased/decreased in response to the operation instruction with respect to the menu display area. Therefore, the user can visually grasp the selected item and also can effectively select the desirable item.

Menu display apparatus capable of varying menu display area and total menu item number displayed on cabinet holder image, and program storage medium


The present invention provides a transport or conveyor belt structure, particularly for use in heavy duty environments such as mining, aggregate and ore handling and other industrial conditions, where the belt preferably comprises a carcass that is made from identical cross-shaped interengaging metal links embedded within the body of the belt so as to provide both strength and flexibility. A method of making such a belt comprising building up layers of belt material and links is also described as are unique structures for joining and splicing belt ends or sections.

This invention relates to conveyor belts for carrying bulk material and in particular conveyor belts which are supported on conventional troughing rolls. Such belts are required to be strong and almost inextensible in the longitudinal direction and to have a moderate stiffness transversely, so that the longitudinal driving loads will be sustained and the belts will bend into the desired trough shape while bridging the angles between the several troughing rolls in each group.
A great many combinations of reinforcing materials have been proposed to impart the desired properties to conveyor belts of rubber or other elastomers for carrying bulk materials, but the majority of such belts continue to be reinforced with multiple plies of woven fabrics, or a multi-ply woven fabric having a plurality of layers of longitudinal yarns, or, alternatively, uniformly spaced longitudinal cords or cables combined with a transverse stiffener. Such belts, when carefully made, track satisfactorily over the head and tail pulleys and the intervening idler rolls, but require closely spaced expensive troughing rolls to provide adequate support and to prevent spillage. One of the main factors leading to spillage seems to be the flattening of the belt between idlers brought about by the high tension required to drive such belts and the inherent flexibility of woven fabrics, cords or cables embedded within the rubber or elastomer forming the body of the belt.
Attempts have been made to control spillage by adding upstanding rubber flanges to the edges of belts which are otherwise of conventional construction, but such flanges not only do not prevent transverse flattening between successive troughing idlers, but present other problems such as difficulties in passing around end pulleys, particularly if the flanges are high enough to be of significant benefit in preventing spillage.
In addition, proposals have been made to provide supports for conveyor belts omitting longitudinal reinforcements over a part or all of their width. Thus, so-called "cable belts," made without longitudinal tension members, ride on a pair of moving steel cables, which permits elimination of inclined troughing rolls but requires addition of separate sheaves for guiding and transmitting power to the cables. Other proposals are to omit some of the longitudinal reinforcement at a particular zone, such as an edge or the center of the belt, but the remaining reinforcement in such cases is of a conventional kind and located in a conventional relation to the transverse reinforcement.
Belts having metal cores or carcasses have been proposed in the past. However, such belts do not provide the desired longitudinal and lateral strength and flexibility of the present invention.
For example, one of the earliest examples, Emery, U.S. Pat. No. 420,779, provides two layers of an ordinary leather belt with parallel metal strips arranged in the longitudinal direction and cemented between the layers. No lateral connection between the strips is evident.
Similarly Harley, U.S. Pat. No. 757,919, provides a longitudinal metal band between two layers of belt material with the edges of the belt material stitched to enclose the band. When a wide belt is constructed, a plurality of bands are provided and the belt material stitched between the bands. As with Emery, there is no lateral connection providing no lateral stiffness to the belt.
Pattee, U.S. Pat. No. 1,204,816, discloses a belt which is constructed of a plurality of interwound spiral coils disposed parallel to each other in a lateral arrangement across the belt. The coils are secured to endless flexible cables disposed along the longitudinal edges of the belt. When the belt body is made of rubber it fills the interstices of the coils embedding them within the rubber body.
Shiner, U.S. Pat. No. 1,360,456, discloses a reinforced belt where the reinforcing element is a link chain of the type consisting of U-shaped links with the arms of each link being apertured to receive the bend of the adjacent link. The chains are embedded within the belt material in parallel rows along the longitudinal axis of the belt.
Paul, U.S. Pat. No. 1,527,912, discloses a belt core consisting of a strip of metal provided with a plurality of pairs of slits with the metal between the slits being pressed outwardly in opposite directions to form transversely extending circular openings.