A multilayer circuit fabrication approach and circuitized substrate are presented wherein at least two conductive layers are formed over a substrate. The conductive layers are separated by a first dielectric layer and the structure is encapsulated with a second dielectric layer. The first dielectric layer includes open areas exposing a portion of the underlying support structure aligned to those areas where contact points are to reside in the second conductive layer. The first dielectric layer comprises a blanket dielectric layer such that recesses are defined in the upper surface thereof aligned to the open areas of the first conductive layer. The second conductive layer thus resides in two planes, both of which comprise planes other than a plane of the first conductive layer. A plurality of openings can be simultaneously formed to expose contact points in both the first and second conductive layers.

Multilayer circuits are well known and are typically fabricated by providing a first conductive layer over a substrate, covering the first conductive layer with a dielectric blanket, then providing a second conductive layer over the dielectric blanket. The second conductive layer is circuitized with two photolithographic and wet etching process steps. A first photo pass provides "personality", where circuitry is defined, while a second photo pass is a "select" pass where solderable locations are defined. Vias in the dielectric blanket may be formed either prior to formation of the second conductive layer or after the personality of the second conductive layer is defined.
By way of more specific example, an existing process for producing a circuitized substrate designed to receive an integrated circuit chip might include circuitizing a first metal layer over a substrate, applying a dielectric layer over the first metal layer, forming a second metal layer over the dielectric layer and then personalizing the second metal layer to define individual circuit wires and pads. Conventionally, this personalization of the second metal layer, as well as the first metal layer, comprises a photolithographic etching process. After the second metal layer is personalized, the photoresist is stripped.
Often, the first metal layer and second metal layer will each comprise multiple films or layers. For example, the first metal layer and the second metal layer may each comprise a copper layer with a top film of chromium. This chromium acts as a solder dam for solder bumps to be formed on exposed portions of the first metal layer and the second metal layer. Since the solder bumps must directly contact the copper layer, it is necessary to selectively etch the top chromium films from exposed portions of the first metal layer and the second metal layer. Conventionally, this etching of the chromium films is accomplished by applying a second photoresist layer, which after photolithographic processing, provides openings exposing the areas to be etched and the areas to be laser ablated (to provide vias). The photoresist openings with the vias formed allow the top chromium film of both conductive layers to be etched simultaneously, thereby exposing the underlying copper layers. In a second pass, the second photoresist is stripped from the structure and electrical testing is conducted.
The disadvantage with the above-outlined approach is that consecutive photoresist and wet etching steps occur, each occurrence of which involves a number of processing steps. Further, wet etching chemistry inherently has disposal costs associated therewith.
Thus, the present invention is directed towards providing an improved fabrication method and multilayer circuitized structure which is less complex and costly to manufacture.

Multilayered circuitized substrate and method of fabrication

International Business Machines Corporation


A display apparatus for displaying adjustment data for a video display on an on-screen display includes video signal processing circuitry, input circuitry for entering user adjustment data, a microcomputer for receiving the user adjustment data and for controlling the video signal processing circuitry based on the user adjustment data, a memory connected to the microcomputer for storing the user adjustment data and factory preset data for the video display, a display screen connected to the video signal processing circuitry, and an on-screen display portion for displaying the user adjustment data and the factory preset data simultaneously on the display screen. Also, a method for displaying a representation of user adjustment data simultaneously with a representation of factory preset adjustment data for a video display device, includes the steps of writing the factory preset adjustment data in a non-volatile memory section, receiving an input video signal for display on a video screen, receiving the representation of user adjustment data for a video display device parameter to be adjusted, writing the user adjustment data in another non-volatile memory section, generating an on-screen display video signal for displaying on a on-screen display portion of the video screen, thereby giving a user a reference adjustment position during the adjustment of the video display device parameter.

The present invention relates to a video display apparatus and method for use with, for example, a color television receiver or a multiscan computer monitor.
Currently there are computer monitors and television receivers which in addition to displaying an input video signal can display various monitor parameters that can be adjusted by displaying characters, numerals, graphics or a combination thereof. This capability to display the parameters to be adjusted is called "on-screen display" (hereinafter "OSD").
These video display devices having OSD capability are designed to allow the user to adjust parameters related to the video display operation. These parameters include the size and center position of the picture screen (raster) displayed upon under-scanning, the rotational distortion and the pincushion distortion of the screen resulting from geomagnetism, convergence, brightness, contrast and other parameters.
Such parameters are digitally adjusted by using operation keys for controlling the adjustment amount of the parameters. When these operation keys are used, graphs representing the current adjustments of the parameters are displayed and changed to reflect the new settings on the OSD portion of the display screen, thereby giving the user a visual feedback.
When the user adjusts the parameters, data indicating the adjusted amount is stored in a nonvolatile memory so that when the power supply is cycled the last adjusted parameters can be retrieved.
When parameters are adjusted as described above, a reference adjustment position for the parameter is not available. This lack of reference position creates a problem for the user by making it difficult to judge whether the current adjustment amount is proper or is too large or too small. Therefore, the user is forced to adjust the elements based on only a visual feedback of the screen leading to misadjustment and potential frustration of the user.

Video display apparatus and method for adjusting parameters on an on-screen display


The invention relates to a microporous membrane having a relatively low heat shrinkage values along planar axes of the membrane. The invention also relates to a battery separator formed by such microporous membrane, and a battery comprising such a separator. Another aspect of the invention relates to a method for making the multi-layer, microporous polyolefin membrane, a method for making a battery using such a membrane as a separator, and a method for using such a battery.

Microporous membranes can be used as battery separators in, e.g., primary and secondary lithium batteries, lithium polymer batteries, nickel-hydrogen batteries, nickel-cadmium batteries, nickel-zinc batteries, silver-zinc secondary batteries, etc. When microporous polyolefin membranes are used for battery separators, particularly lithium ion battery separators, the membranes' characteristics significantly affect the properties, productivity and performance of the batteries. Accordingly, it is desirable for the microporous membrane to have resistance to thermal shrinkage, particularly at elevated temperature. Resistance to heat shrinkage can improve the battery's protection against internal short circuiting that might otherwise occur as the separator shrinks away from the edges of the battery's electrodes at elevated temperature.
European Patent Application Publication No. EP 1 905 586, published Feb. 2, 2008, discloses multi-layer polymeric membranes useful as battery separator film. Among the membranes exemplified are those having (i) a rupture temperature of 180° C., a machine direction heat shrinkage of 3% at 105° C., and a transverse direction heat shrinkage of 4% at 105° C.; and (ii) a rupture temperature of 175° C., a machine direction heat shrinkage of 2% at 105° C., and a transverse direction heat shrinkage of 2% at 105° C. membranes.
Japanese patent document JP2000198866 (published Jul. 18, 2000) discloses multi-layer battery separator films having heat shrinkage values of 10%. The membrane comprises layers containing alpha-olefin-CO copolymers and an inorganic species (cross-linked silicone powders).
PCT publication WO2007-049568 (published May 3, 2007) also discloses multi-layer battery separator films having a machine direction heat-shrinkage value of 4% and a transverse direction heat shrinkage value of 3%. The films of this reference comprise a core layer containing heat-resistant polymers or an inorganic filler.
U.S. Patent Publication 2007/0218271 discloses monolayer microporous films having machine and transverse direction heat shrinkage values of 4% or less. The films of this reference are produced from high density polyethylene having a weight-average molecular weight of 2×105 to 4×105, containing not more than 5 wt. % of molecules with a molecular weight of 1×104 or less and not more than 5 wt. % of molecules having a molecular weight of 1×106 or more.
Japanese Patent Application Laid Open No. JP2001-192467 discloses monolayer microporous membranes having transverse direction heat shrinkage values as low as 1.8%, but at a relatively low permeability (Gurley value of 684 seconds). Similarly, Japanese Patent Application Laid Open No. and JP2001-172420 discloses monolayer microporous membranes having transverse direction heat shrinkage values as low as 1.1%, but at a Gurley value above 800.
While improvements have been made, there is still a need for battery separator film having increased resistance to heat shrinkage.

Microporous films, methods for their production, and applications thereof


A watercraft having a bow rider-type configuration wherein the forwardmost riders' seats are canted slightly inwardly toward the longitudinal centerline of the watercraft so as to permit adequate leg room without overly extending the length of the hull. A pass-through connects the bow riders' portion to a main seating portion in which a bench-type seat that is adapted to accommodate three riders is provided. The pass-through between the seating portions is not significantly wider than one of the seats. Various arrangements for a storage compartment and engine and jet pump clean-out and flushing access are also provided.

This invention relates to a watercraft and more particularly to an improved seat arrangement, passenger compartment, storage and service access arrangement for a watercraft.
The design of watercraft and particularly the passenger's area thereof presents considerable challenges to the designer, particularly in the class of watercraft that is designed primarily to a accommodate a relatively few (for example, less than 8 passengers). The watercraft should be designed so as to provide comfortable seating area for each passenger. In addition, the passenger should be seated in positions wherein each of them can enjoy the view with obstructions from the others. In addition to this, there must be some provision provided in the watercraft for carrying paraphernalia used by boaters such as coolers, beverages, food, water skiing equipment and other such devices.
Of course, these requirements can be met by merely making the size of the watercraft larger. However, as the size of the watercraft is increased, then the power requirements in order to drive it are also increased. This adds to the cost of the assembly and further makes it difficult to trailer the watercraft from one location to another.
It is, therefore, a principal object to this invention to provide an improved watercraft and passenger's compartment therefore.
It is a further object of this invention to provide an improved watercraft passenger's area wherein each rider can be comfortably seated.
One type of watercraft which is becoming relatively popular is the so-called "bow rider" type of watercraft. With this type of watercraft there is a main passenger's compartment positioned at approximately mid-ships and wherein the operator's control position is located. The bow of the watercraft is provided with a further passenger's area and frequently a pass-through is provided between the main passenger's area and the bow area.
For convenient and efficient hull configuration, however, the bow area generally tapers inwardly toward the tip or nose of the bow. Thus, the foot area for passengers seated in the bow area can be restricted.
It is, therefore, a still further object of this invention to provide an improved seating area for utilization in a peripheral edge of the watercraft where the watercraft tapers to a point and which will still offer adequate leg room for the passengers.
As should be apparent from the foregoing description, with this type of watercraft it is also desirable to permit access between the two rider's areas without the rider having to climb over the portion of the hull which separates the two areas. Pass-throughs can be provided but these pass-throughs then restrict the available seating area in the bow portion as well as its effectiveness.
It is, therefore, a still further object of this invention to provide an improved passenger's compartment arrangement for a bow rider type of watercraft.
As has been previously noted, it is also desirable to provide storage and other areas in the hull where paraphernalia utilized by the riders can be stored. However, these areas should also offer free and easy access.
It is, therefore, a still further object of this invention to provide an improved storage arrangement for a watercraft of this general type wherein the storage area can be easily accessed.
In addition to having storage areas, there is also the problem of positioning the propulsion system for the watercraft. Although outboard motor arrangements can be utilized and do provide a greater facility for storage areas, there are a number of disadvantages to such arrangements. Furthermore, an inboard propulsion system offers a much neater appearing watercraft and in some regards provides one which will handle and can be controlled better. However, there is then provided the problem of being able to access the propulsion unit for servicing.
It is, therefore, a still further object of this invention to provide an improved storage and access arrangement for a watercraft.
It is a further object of this invention to provide an improved jet propelled watercraft having a convenient arrangement for accessing the propulsion unit for servicing without necessitating removal of the watercraft from the body of water in which the watercraft operates.
In connection with the servicing of the engine, it is frequently desirable to provide an arrangement for flushing the cooling system of the engine. This is done when the watercraft is not in use and is done primarily for the purpose of purging salt water from the engine cooling system. In many instances, the water for the engine cooling system is circulated by diverting a portion of the water pumped by a jet propulsion unit for the watercraft through the engine cooling system. Although purging systems may be provided for purging the engine cooling jacket, there is not a convenient arrangement normally provided that would permit also the jet propulsion unit to be purged of salt water.
It is, therefore, a still further object of this invention to provide an improved purging system for a jet propelled watercraft propelled by a water-cooled engine wherein both the jet propulsion unit and the engine cooling jacket may be purged through the same flushing source.


A method and apparatus for handling internet access telephone calls made via cable company telephone services. A head end data terminal receives cable signals and converts them into individual signals. An intelligent switch detects signals destined for an internet service provider and routes those signals on a separate path to the internet service provider. A central switch routes the other signals along a telephone network. A computer program can control the steps of receiving cable signals, converting them into voice band signals, routing the signals that are not for the intended recipient to a central switch, multiplexing the signals for the intended recipient together, and sending the multiplexed signals to the intended recipient.

1. Field of the Invention
Embodiments of the present invention relate to telephony networks accessed via cable. Embodiments of the present invention specifically relate to methods and apparatuses that reduce loads on central switches caused by internet access through dial up cable telephone service.
2. Description of the Related Art
Cable companies have begun expanding their services beyond offering cable television programs. Many now offer customers services such as cable modem internet access and cable telephone service. While cable modem internet access is beneficial, some users are reluctant to pay the higher costs associated with that service. Thus, some users will opt for their cable company's telephone service but not cable modem internet access. When those users connect to the internet, they use their cable company's telephone services to directly dial their internet service provider.
Providing telephone service to large numbers of voice telephony users is usually not a significant problem. Most telephones are not in use at any one time, and most voice calls are relatively short, averaging around 4 to 5 minutes. However, that is not the case with a computer user who may stay in communication with his internet service provider for long periods of time, possibly many hours on end. Such long duration calls increase the costs associated with the telephone network since the telephone network must provide the required telephone lines and switching devices. Additionally, such long duration calls can congest the telephone network, which is designed using statistical data associated with the frequency and duration of voice calls. It has been demonstrated that such congestion can adversely impact even emergency services like 911 calling.
Therefore, it would be beneficial to reduce the costs and congestion effects associated with long duration internet access telephone calls made via cable company telephone services.


A server chassis includes a base defining an opening, a rotating plate, a sliding plate, and first and second elastic members. The base includes a middle plate opposite to the opening and defines a space communicating with the opening. The rotating plate defines a plurality of first air holes. The sliding plate defines a plurality of second air holes. The rotating plate is rotated toward the middle plate when the functional module is inserted into the space, the sliding plate abuts against the middle plate and slides toward the opening, and the second air holes align with the first air holes. The second elastic member restores the rotating plate to obstruct the opening when the functional module is drawn out, and the first elastic member restores the sliding plate to make the second air holes be staggered with the first air holes.

1. Field of the Invention
The present invention relates to server chassis, and particularly to a server chassis having an access flap.
2. Description of Related Art
Generally, a functional module, such as a power supply, can be inserted into or drawn out of a server chassis through an opening. The opening of the server chassis is not shielded when the functional module is removed from the server chassis, allowing air outside the server chassis to flow into the server chassis, thereby interfering with the normal airflow in the server chassis. This potentially impairs an efficiency of heat dissipation in the server chassis. A shielding apparatus is typically attached to the chassis by a plurality of screws, which makes the installation and detachment of the shielding apparatus tedious and time-consuming.
What is needed, therefore, is a server chassis which overcomes the above-mentioned problems.

Hong Fu Jin Precision Industry (ShenZhen) Co., Ltd.


Embodiments of a showerhead for use in a substrate processing chamber are provided herein. In some embodiments, a showerhead for use in a substrate processing chamber includes an upper plate having an outer gas inlet fluidly coupled to an outer recursive gas path and an inner gas inlet fluidly coupled to an inner recursive gas path; and a lower plate having an upper surface bonded to the upper plate and a lower surface having a plurality of outer gas distribution holes and a plurality of inner gas distribution holes, wherein the upper surface includes an outer recess to define an outer annular gas plenum fluidly coupled to the outer gas inlet and to the plurality of outer gas distribution holes and an inner recess to define one or more inner annular gas plenums fluidly coupled to the inner gas inlet and to the plurality of inner gas distribution holes.

Conventional showerheads utilized in semiconductor process chambers (e.g., deposition chambers, etch chambers, or the like) typically include a showerhead body disposed between a gas distribution plate and a chill plate. However, for high power applications (e.g., power greater than 22 kW), the inventors have observed that a showerhead temperature becomes difficult to control and an area between the showerhead body and a center region of the gas distribution plate becomes prone to light up.
Accordingly, the inventors have provided embodiments of an improved showerhead.

High power showerhead with recursive gas flow distribution


The present invention relates generally to compositions and methods of killing biofilm using a surface plasmon coupled to a photosensitizer. A nanostructure (10) may include a silver nanoparticle core (12), a mesoporous silica shell (14), and a photosensitizer (16). A method of killing biofilm may include contacting biofilm with a nanostructure (10) including a silver nanoparticle core (12), a mesoporous silica shell (14), and a photosensitizer (16) to form a blend and exposing the blend to light.

Singlet oxygen plays a central role in many applications, such as photodynamic inactivation of microorganisms, photodynamic therapy of cancers, photoinduced oxidation, photodegradation of polymers, wastewater treatment, and fine chemical synthesis. Photodynamic inactivation (PDI) of bacteria has become an emerging and evolving strategy against infectious diseases, especially those related to multidrug resistance, because microorganisms do not appear to readily develop resistance toward PDI. In this regard, multidrug-resistant bacterial strains are shown to be killed by PDI as easily as their naïve counterparts. During PDI and when the level of the reactive oxygen species (ROS) produced exceeds bacterial detoxification and repair capabilities, the ROS can damage intracellular DNA, RNA, proteins, lipids, and cytoplasmic membrane, which leads to bacteria death.
Gram-positive and Gram-negative bacteria differ in membrane permeability due to the difference in the outer membrane structures. Gram-positive bacteria can easily take up most neutral or anionic photosensitizers and be readily photoinactivated, which is not the case for Gram-negative bacteria. This difference has led the development of photosensitizers toward polycationic conjugates or cationic photosensitizers to facilitate uptake by the bacterial cells. Importantly, some studies have shown that singlet oxygen, when produced sufficiently close to the bacteria, can diffuse into the bacteria cells causing fatal damage to the cells. Accordingly, photosensitizers with enhanced singlet oxygen production efficiency are highly desired, regardless of their charge properties.
The ground electronic state of molecular oxygen is a spin triplet. Ground-state (triplet) oxygen is not very reactive. However, triplet oxygen can be activated by the addition of energy and transformed into reactive oxygen species. The two electronically excited singlet states are O2(1Δg) and O2(1Σg+), at 94 and 157 kJ/mol above the ground state, respectively. The O2(1Σg+) state has a rather short lifetime, due to the spin-allowed transition to the O2(1Δg) state. The O2(1Δg) state is commonly referred to as singlet oxygen. Singlet oxygen has a relatively long lifetime (e.g. 10−6 to 10−3 seconds in solution) because of the spin-forbidden transition to the triplet state O2(3Σg−). Singlet oxygen can be observed experimentally in the absorption and emission at about 1270 nm.
The most convenient method of singlet oxygen production is the photosensitization of sensitizing molecules in the presence of light and oxygen. Great progress has been made in identifying, designing and synthesizing molecules as efficient photosensitizers. Even noble metal nanostructures have demonstrated the capability of singlet oxygen production. Still, the ability of noble metal nanostructures to enhance the production of singlet oxygen has remained largely unexploited. Since singlet oxygen plays a very important role in cell damage, an abundant supply of singlet oxygen is required.
Photodynamic inactivation of bacteria, among other applications that utilize singlet oxygen, is currently limited by the insufficient generation of singlet oxygen while reacting with biological targets. Accordingly, improved compositions and methods of producing singlet oxygen are needed to address the shortcomings of existing methods. More particularly, new compositions and methods are needed that increase the efficiency of the production of singlet oxygen.
Fungi are a large group of eukaryotic organisms distantly related to mammals, yet with similarities in the plasma membrane to that of mammalian cells. Most fungi have a rigid cell membrane including polysaccharides, such as chitin and ergosterol, whereas in mammalian cell membranes ergosterol is replaced by cholesterol. The similarities that exist between fungal and mammalian cell membranes render it challenging to develop antifungal drugs with low toxicity to humans.
Tricophyton rubrum, herein T. rubrum, is a dermatophytic fungus that commonly causes nail, skin and hair infections, i.e. dermatophytoses, due to its ability to utilize keratin. Fungal nail infection is the most common T. rubrum infection in humans worldwide, affecting 2%-13% of the world population. T. rubrum infections have indeed become a global phenomenon.
Fungal nail infection may be caused by a number of reasons, including less hygienic lifestyles, contact with infected skin scales, or contact with the fungi in wet areas such as swimming pools, showers and locker rooms. Infected patients may experience embarrassment in social and work situations, and carry the danger of transmitting the infection to others. Patients with diabetes, weakened immune system due to diseases such as HIV, and patients undergoing nail surgeries or cancer therapy, are highly susceptible to fungal nail infections, which could be serious, even fatal.
One drawback of existing drugs used to treat fungal infections is the relatively long-term treatments (some requiring up to 18 months to cure), and adverse side effects such as liver damage or drug interactions. Furthermore, the lack of targeted delivery of drugs may lead to less effective cure, as evidenced by slow and incomplete clearance of the infections. While molecular photosensitizers, such as methylene blue, toluidine blue, protoporphyrin and hematoporphyrin, have been shown to treat T. rubrum infections noninvasively, the use of molecular photosensitizers in PDI suffers from the drawback that most of the photosensitizers are highly hydrophobic and tend to aggregate in aqueous media, which reduces the efficiency of ROS generation and thus the efficacy of PDI.
Device-based treatments for fungal infections, such as laser treatments, iontophoresis, ultrasound treatments and photodynamic therapy, have been reported with varying degrees of success. So far, only laser treatments for cosmetic uses are FDA-approved. However, more studies are needed to validate the technique. The use of ultrasound devices has been investigated using a canine nail model. Still, the device itself seems complicated, and further studies will be required to assess it as a modality of antifungal treatment. Therefore, there is an ongoing need for noninvasive and user-friendly methods for treating of fungal infections.
Eighty percent of all bacterial infections, such as chronic wound and prosthetic joint infections, are caused by biofilms. Biofilms are defined as matrix-embedded microbial communities attached to biological or non-biological surfaces. Their key component is the extracellular polymeric substance (EPS), which accounts for 90% of the biofilm weight and is responsible for conferring adhesion capabilities and extra-resistance to treatments. Due to its increased defense system, infections caused by biofilms require 10 to 1000 times higher levels of antibiotics to treat, when compared to infections caused by planktonic pathogens. Therefore, there is a great need to better understand and treat the bacterial infections caused by biofilms.

This patent is subject to a terminal disclaimer.

Silver nanoparticle-enhanced photosensitizers as antibiofilm agents


A network storage server has a non-volatile mass storage facility, a main cache and a victim cache. A technique of efficient, non-blocking storage of data in the victim cache includes, responding to a caller process by, without blocking the caller process, selecting a first storage unit for eviction from the main cache, destaging the first storage unit for storage in the victim cache without copying the first storage unit, and identifying a second storage unit to the caller process as available to be overwritten in the main cache.

Various forms of network storage systems exist today, including network attached storage (NAS), storage area networks (SANs), and others. Network storage systems are commonly used for a variety of purposes, such as backing up critical data, data mirroring, providing multiple users with access to shared data, etc.
A network storage system includes at least one storage server, which is a processing system configured to store and retrieve data on behalf of one or more client processing systems ("clients") that are used by users of the network storage system. In the context of NAS, a storage server is commonly a file server, which is sometimes called a "filer". A filer operates on behalf of one or more clients to store and manage shared files. The files are stored in a non-volatile mass storage subsystem (which is typically external to the storage server, but does not have to be) which may include one or more arrays of non-volatile mass storage devices, such as magnetic or optical disks or tapes, by using RAID (Redundant Array of Inexpensive Disks). Hence, the mass storage devices in each array may be organized into one or more separate RAID groups.
In a SAN context, a storage server provides clients with access to stored data at a sub-file level of granularity, such as block-level access, rather than file-level access. Some storage servers are capable of providing clients with both file-level access and block-level access, such as certain Filers made by Network Appliance, Inc. (NetApp®) of Sunnyvale, Calif.
Caching is a technique that is commonly used to reduce latency associated with accessing data in computer-related applications, including in network storage systems. For example, the main memory (i.e., random access memory (RAM)) of a storage server is often used as a cache logically between the storage server's main central processing unit (CPU) and the non-volatile mass storage (e.g., disk) subsystem, since the RAM which forms the main memory generally has a much smaller access latency than the disk subsystem. Accordingly, the main memory of a storage server is sometimes called the "buffer cache" or, simply, the "cache". Note that this kind of cache should not be confused with other forms of cache memory, known as level 1 ("L1") cache, level-2 ("L2") cache, etc., which are commonly used by a microprocessor (and typically implemented on the same chip or the same motherboard as the microprocessor) to reduce the number of accesses to main memory. In the context of this document, the buffer cache (or simply "cache") of a storage server is the main memory itself.
Some network storage servers also employ an additional level of caching logically between the buffer cache (main memory) and the non-volatile mass storage subsystem. This additional cache is known as a "victim cache". In the context of this document, a "victim cache" is a cache that holds some of the data blocks ("victims") most recently evicted from a main or primary cache, which in this context is main memory of the storage server. The main memory in a storage server is in certain instances called the "main cache" in this document, to distinguish it from the victim cache.
A victim cache in a storage server is generally a medium-size auxiliary storage facility that is faster than normal RAID disk storage, but slower than main memory. Such a victim cache might be implemented on, for example, an external memory card, using solid state disks (SSDs) or other types of storage devices. The size of such a cache can range from, for example, a few GBytes up to hundreds of GBytes or more. When a data block, or "buffer", is needed but not found in main memory, the victim cache is consulted prior to loading the buffer from RAID disks. Note that the terms "buffer" and "data block" (or simply "block") are used herein interchangeably. A data block, or "buffer", is the basic unit of data transfer of the file system in a storage server. Buffers are commonly 4 Kbytes in size, though different storage systems may use buffers of different sizes.
The process of finding an old buffer in the main cache and then evicting it is known as "buffer scavenging". This process is often expected to return another buffer for the storage server to immediately overwrite (reuse) in the main cache. For optimal system performance, the buffer scavenging process should not be blocking; that is, the process which invokes (calls) the scavenging process should not be prevented from doing something else while the scavenging process executes (i.e., until a reusable buffer is returned). However, when a victim cache is used, there is generally latency associated with performing a write to the victim cache and then waiting for the response. Thus, there is a tension between the desire for fast, efficient scavenging and the need to preserve the evicted buffer and its contents until it has been successfully stored in the victim cache.

Efficient non-blocking storage of data in a storage server victim cache


Disclosed herein is a gift wrap ensemble that includes a first end cap and a second end cap. Each of the first and second end caps includes a base member and a plurality of depressions extending therefrom. A plurality of gift wrap rolls are provided that form a chamber therebetween and that receive the depressions. A decorative item, such as a ribbon, bow, tissue paper and/or a gift tag, is positioned within the chamber. Packaging such as shrink wrap, a container, etc. encloses the decorative item within the chamber, and the decorative item is visually-perceptible from outside the packaging.

Gift wrap is typically packaged as a long continuous paper sheet rolled onto a cylindrical cardboard tube, and decorative items, such as bows, ribbons, etc., are typically packaged and purchased separately therefrom. However, separate packaging impacts manufacturing costs and may inhibit sales, particularly with respect to those consumers who would prefer to purchase a single package at a lower cost. Furthermore, some packaging of the prior art is problematic, because the edges of the rolled gift wrap are typically exposed at the ends thereof so that the ends are vulnerable to being damaged during storage, handling, and shipping.
It is known in the art to use protective holders as packaging for the ends of rolled gift wrap. For example, U.S. Pat. No. 3,441,127 to Manning (the "Manning '127 Patent") discloses a gift wrapping ensemble having a holder adapted for engaging two rolls of gift wrap. The holder includes a rectangular frame that has members depending therefrom for retaining the two rolls of gift wrap. Each of the depending members frictionally engages one of the rolls. Although the Manning '127 Patent further provides that gift tags may be contained by the ensemble, the Manning '127 Patent teaches that the holder has a compartment formed as a part thereof and that the tags are contained within the small space of the compartment.


Intestinal content sampling device having a capsule which is adapted to be swallowed and to pass through the intestinal tract. The capsule has an opening through which a sample can pass and a closure member for closing off the opening once a sample has been obtained. The closure member is held in an open position against a closing force by a magnetically actuated latch which, in the disclosed embodiments, comprises a pendulum which is set into vibration by an externally applied magnetic field to release the latch.

1. Field of the Invention
This invention pertains generally to medical devices and, more particularly, to a device for obtaining a sample from the intestinal tract of a person.
2. Description of Related Art
Heretofore, there have been some attempts to obtain samples from the intestinal tracts of human beings by means of relatively small capsules which are swallowed, then opened to collect a sample as they pass through the intestinal tract. Such devices are particularly useful in the small intestine where it is otherwise difficult to obtain samples for chemical and microbiological analysis.
One example of a swallowable capsule for obtaining samples of gastric and/or intestinal fluids is found in U.S. Pat. No. 4,481,952. That capsule has an inner chamber with an inlet port which is normally sealed off by a film or coating which is dissolved by the fluids in the portion of the body from which the sample is to be obtained. The capsule also has a spring-actuated closure which is held in an open position relative to the port by a restraint fabricated of a material which is dissolved by the sampled fluid. Thus, the capsule is intended to open when it reaches the area in which the sample is to be taken, then close after the sample is obtained to contain the sample and protect it from contamination as capsule continues its passage through other parts of the body. One problem with this type of device is that it does not provide very precise control over the closing of the capsule, with the result that the sample may be lost or become contaminated before the closing occurs.
U.S. Pat. No. 4,239,040 discloses a capsule for discharging drugs into or collecting samples from the body, which utilizes a meltable thread to hold a pistonlike element against the force of a spring. Movement of the piston-like element serves to push drugs out of or draw a sample into the capsule, and the thread is melted by a heater which is energized by a an electric circuit including a tunable receiver which responds to an externally transmitted electric signal.
U.S. Pat. Nos. 4,439,197 and 4,507,115 shows capsules for discharging medicine or obtaining samples, utilizing shape memory elements to move piston-like elements in response to temperature changes. In the '197 patent, the capsule contains a power source, a switching circuit, and a radio receiver which respond to radio frequency signals to control the temperature of the shape memory element, and in the '115 patent, the shape memory element is heated ultrasonically.

Externally controlled intestinal content sampler


A method includes: setting up, by a first network device, a MACSec channel to a second network device according to the MACSec protocol; and sending, by the first network device, an ACP packet to the second network device by using the MACSec channel, where the ACP packet is carried in a MACSec frame, and a frame header of the MACSec frame carries identification information used to identify the ACP packet. By means of the packet transmission method, a MACSec channel is set up between adjacent nodes in a self-organizing network according to the MACSec protocol, and an ACP packet is transmitted between the adjacent nodes by using the MACSec channel and processed.

A self-organizing network supports self-management, so as to reduce intervention of an administrator and improve automation of the network, thereby alleviating network management workload, facilitating deployment of new services, lowering a probability of a configuration error, and reducing an operating expense (OPEX).
In an important aspect of the self-organizing network, a device can be "plug-and-play", and supports bootup and self-configuration. One of key technologies of the self-organizing network is setup of an autonomic control plane (ACP). The ACP is characterized in that participation of an administrator is not required, and such a control plane is automatically generated and automatically grows up (a new device automatically joins). Setup of an end-to-end connection is completely "zero-touch (zero-touch)", and the ACP is not affected by incorrect configuration of an administrator, so as to implement secure information exchange.
In an existing solution, setup of an ACP relies on IPv6, but most devices in an existing network support IPv4. Development of an IPv4-based ACP provides a better compatibility with the existing network and can reduce deployment barriers. If a secure tunnel is to be set up by using a link-local address similar to an IPv6 link-local address (link-local-IP) (169.254.0.0/16), when an ACP having an IPSec channel is set up based on IPv4, an IPv4 link-local address needs to be used. However, different from IPv6, Request For Comments RFC (Request For Comments) 3927 recommends that an IPv4 link-local address is used only when there is no routable IPv4 interface address. Consequently, usually, no layer 3 tunnel corresponding to the IPv6 link-local-IP can be used in this case, and an IPv4-based ACP having an IPSec channel cannot be set up.

Autonomic control plane packet transmission method, apparatus, and system


There is disclosed a method and apparatus for polishing a surface of a magnetic recording medium in which a magnetic layer surface of a magnetic tape is brought into contact with a polishing tape which is wound on a contact roll and travelled, and the magnetic tape and the polishing tape are travelled in opposite directions to polish the magnetic layer surface of the magnetic tape. In this invention, in surface polishing, a curvature of the contact roll at a position where the magnetic tape is brought into contact with the polishing tape at first is set to be 0.1 to 10 mm. In order to set the curvature of the contact roll at the position where the magnetic tape is brought into contact with the polishing tape at first to be 0.1 to 10 mm, for example, the curvature of the contact roll is continuously changed. More specifically, in consideration of the sectional shape of the contact blade, first and second curves which have different curvature radii are continuously formed from the supply side of the magnetic tape, and the curvature radius of the first curve is set to be smaller than the curvature radius of the second curve. Otherwise, a composite cylindrical roll having a shape obtained by combining a large-diameter roll and a small-diameter roll to each other is used.

For a magnetic tape such as a video tape or an audio tape, either a so-called coating type magnetic recording medium or a metal thin-film type magnetic recording medium is proposed. That is, according to the former, a magnetic coating material, which is prepared in such a manner that a powdery magnetic material, a binder, and various additives are dispersed and kneaded together with an organic solvent, is coated on a non-magnetic support member and then dried. According to the later, a magnetic layer is formed in such a manner that a metal magnetic material is directly coated on a non-magnetic support member by using a vacuum thin film forming technique.
In this case, a recording/reproducing operation of an information signal with respect to each of these magnetic tapes is performed while the magnetic layer side of the magnetic tape is slidably moved on a magnetic head. For this reason, if surface projections are unexpectedly formed on the magnetic layer surface of the magnetic tape, the surface projections are sheared and broken by slidably moving between the magnetic head and the magnetic tape and are interposed as a fine magnetic powder (to be referred to as an abrasion powder hereinafter) between the magnetic tape and the magnetic head. The abrasion powder interposed between the magnetic tape and the magnetic head causes dropouts, for example, causes image degradation, sound skipping, or the like and, in the worst case, causes head clogging to make it impossible to record/reproduce data.
Therefore, in a conventional magnetic tape described above, a magnetic layer is formed on a non-magnetic support member, and then subjected to a surface process in which the magnetic layer surface is polished with a magnetic tape. A polishing apparatus for performing the surface process is shown in FIG. 1.
The polishing apparatus 101 has a polishing tape 103 and a contact roll 102, having a diameter of about 30 mm, for pushing the polishing tape 103 against the a magnetic tape 104.
The polishing tape 103 is wound on the contact roll 102 at an arbitrary holding angle to cause its polishing layer to face outside. The holding angle of the polishing tape 103 wound on the contact roll 102 is controlled in such a manner that the polishing tape 103 is looped between a pair of winding rolls 105a and 105b arranged parallel to each other near the contact roll 102.
Guide rolls 106a and 106b are arranged on both the sides of the contact roll 102 on which the polishing tape 103 is wound, respectively. The guide rolls 106a and 106b are used to guide the continuously traveling magnetic tape 104 to a position where the magnetic tape 104 is brought into contact with the polishing tape 103 wound on the contact roll 102.
In this polishing apparatus 101, a feeding roll and a take-up roll (not shown) are arranged for each of the polishing tape and the magnetic tape. The end portions of the polishing tape 103 are attached to the feeding roll and the take-up roll, respectively, and the end portions of the magnetic tape 104 are attached to the feeding roll and the take-up roll, respectively.
In the polishing apparatus 101 as described above, when the feeding roll and the take-up roll for the polishing tape and the magnetic tape are rotatably driven, the polishing tape travels in an X direction in FIG. 1, and, in contrast to this, the magnetic tape travels in a Y direction in FIG. 1. In this manner, the magnetic layer surface of the magnetic tape is polished by the polishing tape, and the surface projections on the magnetic layer surface are cut and removed.
However, in the polishing apparatus, when the magnetic tape and the polishing tape are traveled in opposite directions, respectively, air is inserted between the magnetic tape and the polishing tape to form an air film, and the magnetic tape is in incomplete contact with the polishing tape. For this reason, the magnetic layer surface cannot be sufficiently polished by a single process. When a high-quality magnetic tape is to be manufactured, the surface process must be performed a plurality of times to sufficiently polish the magnetic layer surface. Since the thickness of the air film formed between the magnetic tape and the polishing tape increases with a process speed, a process speed is limited to bring the magnetic tape and the polishing tape into sufficient contact with each other. Therefore, the process speed cannot be easily increased. For these reasons, a sufficiently long period of time is required to perform the surface polishing process, thereby preventing productivity of magnetic tapes from being improved.

Method and apparatus for polishing surface of magnetic recording medium


A carrier for use in a pneumatic tube transport system includes first and second shell members, at least a first hinge for pivotally interconnecting the first and second shell members such that the shell members can move relative to one another between open and closed positions, and at least a first seal band interconnected to at least one of fore and aft portions of the first and second shell members. At least the first seal band includes a plurality of fibers mountable on a first backing strip, the fibers having a modulus of elasticity of at least about 1.times.10.sup.5 psi, being mounted perpendicularly relative to the first backing strip, and uniformly distributed on the first backing strip.

Generally, pneumatic tube transport systems are used to transport or convey materials between discrete points or stations. Many products, documents, and other items may be placed in a carrier which is positionable within a number of substantially hermetically sealed tubes of the pneumatic tube transport system. The carrier may then be propelled through the tube by creating a zone of relatively higher pressure behind the carrier than in front of the carrier. This pressure differential may be accomplished by creating a vacuum or zone of negative pressure in front of the carrier or by creating a zone of positive pressure behind the carrier.
Accelerator rings or seal bands have been provided on carriers to prevent excessive mass transfer of air between the front of the carrier and the rear of the carrier. Such seal bands thus create differential pressure between the front and rear portions of a carrier, which provides the force necessary to propel the carrier through the pneumatic tube system. Such accelerator rings or seal bands typically engage the inner surface of the transport tube to support the carrier body and to inhibit air flow between the front and rear portions of the carrier. In this regard, it is important to minimize friction between the seal bands and the inner wall of the tube to enable the carrier to move through the tube without requiring high differential pressures between the front and rear of the carrier. Such a desire for minimizing friction must also be balanced with providing an adequate seal to inhibit mass transfer of air between the front and the rear of the carriers. In this regard, a "loose" seal band which does not provide a good seal may travel freely, but may also perform erratically for varying payloads within the carrier. On the other hand, while a "tight" seal will inhibit mass transfer of air between the front and rear portions of the carrier, friction forces between the seal band and tube may be high, thus requiring increased system pressures of the transport tube. Such tight seals may also generate an excessive amount of debris from wear on the seal bands, which can degrade performance of the tube transport system and/or components, such as blowers and optical sensors therein.


Methods, compositions and kits are disclosed directed at haptens, immunogens and immunoassays for buprenorphine (BUP) and nor buprenorphine (norBUP). The method comprises providing in combination in a medium (i) a sample suspected of containing buprenorphine (BUP) or norbuprenorphine (norBUP) and (ii) an antibody raised against an immunogen of buprenorphine (BUP) or norbuprenorphine (norBUP). The medium is examined for the presence of a complex comprising a labeled hapten of buprenorphine (BUP) or norbuprenorphine (norBUP) where the presence of such as complex indicates the presence of the compound in the sample.

The clinical diagnostic field has seen a broad expansion in recent years, both as to the variety of materials of interest that may be readily and accurately determined, as well as the methods for the determination. Over the last decade, testing for drugs of abuse has become commonplace. This testing is not only for the monitoring of criminal offenders and drug addicts, but employers also use it for the screening of workers. In recent years, immunoassay based on the reaction of an antibody with an antigen has been extensively investigated for this purpose. Some categories of immunoassays include a radioimmunoassay, using a radioactive isotope, an enzyme-based immunoassay (EIA) using an enzyme, and luminescence assays, using fluorescent labels, e.g., fluorescence polarization, and chemiluminescent labels.
The clinically important and potent analgesic buprenorphine, a semi-synthetic narcotic derived from thebaine, has attracted attention as a potential pharmacotherapy for opiate abuse and dependence. At times of shortage of heroin, buprenorphine, BUP hereinafter may be used as the substitute drug of choice. BUP's unique effects and pharmacology make it an attractive and clinically helpful treatment option. The unique pharmacology of buprenorphine at the mu-opioid receptor (i.e. high affinity, low intrinsic activity and slow dissociation) results in buprenorphine having: (1) a good safety profile, (2) low physical dependence, and (3) flexibility in dose scheduling. Further, BUP produces less euphoria than morphine and heroin. When compared with other opiates, it also causes a significantly lower degree of sedation and respiratory depression, the slowing down of breathing that makes heroin overdoses so dangerous.
On the other hand, BUP has been chosen by the National Institute on Drug Abuse as one of the medications for the treatment of opiate dependence. Norbuprenorphine, norBUP hereinafter, is a major dealkylated metabolite of BUP and displays similar but distinct properties. These limited side effects can be attributed to the fact that BUP and norBUP are partial mu agonists. Agonists are chemicals that bind to and stimulate opiate receptors. Antagonists block the effects of opiates by binding to receptors without stimulating them. By stimulating mu opiate receptors in the brain, mu agonists produce the effects associated with morphine: analgesia, euphoria, sedation, and respiratory depression. Because BUP is a partial mu agonist, it also readily binds to mu opiate receptors. However, BUP activates these receptors to a lesser degree than full mu receptor agonists such as morphine and heroin. Both norBUP and BUP are potent partial agonists, with norBUP having moderate efficacy and BUP having low efficacy. BUP also is released slowly from the mu receptor, producing a long-lasting effect. Therefore, it may be possible to give BUP to patients every other day, rather than in the daily doses that methadone patients must receive. Some studies also suggest that withdrawal effects are less severe with BUP than with methadone. From both a drug of abuse and therapeutic drug monitoring view point, it is important to have available reliable immunoassays for BUP and its metabolite, norBUP. HPLC-MS methods for the detection of buprenorphine and norbuprenorphine are disclosed in the literature [Kronstrand, R.; Selden G.; Josefsson, M. "Analysis of buprenorphine, norbuprenorphine, and their glucuronides in urine by liquid chromatography-mass spectrometry", J. Anal. Toxicol., 2003, 27, (7), p464–70.], and two immunoassays have also been disclosed [Cirimele, V.; Kintz, P.; Lohner, S; Ludes, B. "Enzyme immunoassay validation for the detection of buprenorphine in urine", J. Anal. Toxicol., 2003, 27, (2), p103–5, and Tiong, G. K. L.; Olley, J. E. "Enzyme immunoassay of buprenorphine", Naunyn-Schmiedeberg's Arch Pharmacol 1988, 338, 202] However, these assays are not suitable for use in automated clinical analyzers. There is, therefore, a need for assays for the detection of the aforementioned drugs and, in some instances, their major metabolites. The assays should be able to detect these drugs in order to monitor and treat addicted patients.

Immunoassays for buprenorphine and norbuprenorphine


A thin film transistor is provided. The transistor includes a gate; a first passivation layer covering the gate; a channel layer disposed on the first passivation layer; a source and a drain that are disposed on the first passivation layer and contact two sides of the channel layer; a second passivation layer covering the channel layer, the source, and the drain; first and second transparent electrode layers that are disposed on the second passivation layer and spaced apart from each other; a first transparent conductive via that penetrates the second passivation layer and connects the source and the first transparent electrode layer; and a second transparent conductive via that penetrates the second passivation layer and connects the drain and the second transparent electrode layer. A cross-sectional area of the gate is larger than a cross-sectional area of the channel layer, the source, and the drain combined.

1. Field
The present disclosure relates to a thin film transistor and a display panel employing the same.
2. Description of the Related Art
Thin film transistors are used in various applications. In particular, thin film transistors are used as switching and driving devices in a display field.
Recently, a thin film transistor used as an optical sensing device of an optical touch screen apparatus has been proposed. In a touch screen apparatus, if a user touches a specific position on a display screen by using a finger or a pen, a specific process may be performed by using software to determine the position, and thus the touch screen apparatus may directly receive input data on the display screen. An existing touch screen apparatus that is widely used uses a direct-touch method in which a user directly touches a screen of a display apparatus by using a finger, a pen, or the like. However, as display apparatuses become larger, when a distance between a user and a display apparatus is increased, it may be difficult to use such a direct-touch method. Optical touch screen apparatuses may perform the same function as an existing touch screen by sensing light instead of a finger or a pen. Optical touch screen apparatuses are expected to be advantageous for communication between users as well as communication between a user and a terminal.
As such, when a thin film transistor is used in a display device, performance of the thin film transistor greatly depends on a semiconductor material forming a channel layer, and performance of the channel layer greatly deteriorates due to external light or temperature. Also, when a liquid crystal display device, which is a non-emissive display device, is used as a display device, a backlight may further be included as an image forming light source. When light is incident on a channel layer, performance of the channel layer may deteriorate.

Thin film transistor and display panel employing the same


A lifting mechanism and spacer block arrangement is disclosed to include a magnetically attractive lifting mechanism installed in a lifting jack and driven to move a lifting rod vertically, and a plurality of magnetically attractive spacer blocks for attaching to the lifting mechanism at the bottom in a stack to space the lifting mechanism above the floor, each spacer block having a top side mounted with a magnet in a flush manner, and a bottom side fitting the top side for enabling the spacer blocks to be arranged in a stack and secured to the bottom side of the lifting mechanism.

(a) Field of the Invention
The present invention relates generally to a lifting jack and more particularly, to a lifting mechanism and spacer block arrangement for use in a hydraulic/air lifting jack.
(b) Description of the Prior Art
When wishing to lift a load, for example, a machine, lathe, construction, etc., or to support a first member on a second member at the desired pitch, a small hydraulic/air lifting jack may be used. A small hydraulic/air lifting jack is highly movable, however it has a limited lifting stroke. When lifting a load, the user may have to operate the hydraulic/air lifting jack to lift the load to the desired elevation through several lifting stokes. Further, after each lifting stroke during a lifting operation, a respective movable support block is used to support the load in position and a spacer block is inserted under the lifting mechanism of the hydraulic/air lifting jack so that the lifting mechanism of the hydraulic/air lifting jack can be operated to lift the load again. If the spacer block in use can not be positively maintained in position, the load and the lifting mechanism may fall, thereby resulting in an accident.

Lifting mechanism and spacer block arrangement for lifting jack


A welding accessory system for a welder that includes a welder having a welder housing and at least one welding accessory support connected to the welder housing to support at least one welding accessory of a welder. The one or more welding accessory supports include a cable holder, an electrode holder, a cooling fluid holder, a cylinder gas holder, a cable connector box, and/or a tool holder.

A wide variety of welding machines are used to perform a variety of welding functions in the workplace. Typically, a welding machine includes a welder housing which encases a welding circuit. On the welding housing there is typically a series of control switches to control the output of the welder. The welder housing also includes a connector for a welding gun or torch. Depending on the type of welder and/or the magnitude of the current generated by the welder, various types of accessories are connected to the welder or used in association with the welder. The accessories can include welding gases, shielding gases, cooling fluids, consumable electrodes, and the like. In addition to the various accessories associated with a particular welding operation, the welder requires tools to facilitate in the maintenance and operation of the welder. Such tools can include wrenches, screw drivers, wire cutters, welding tips, tape, clamps, etc. The use of these various accessories and tools require a welding operator to carry a tool chest for the various tools used with the welder, and to also separately transport the welding gas and/or shielding gases, the cooling fluid, welding cable, welding gun or torch, and/or electrodes. As a result, the initial set up of a welder in a particular location and/or the movement of the welder to various locations is both difficult and time consuming. In addition, there sometimes is difficulty finding a suitable location for all the accessories used with the welder. Commonly, welding operations take place in small locations and/or on unlevel ground. As a result, it is sometimes difficult to find a suitable location to position the welder and the various accessories about the welder so that a welding operation can proceed.
Many welders include a welding cable which attaches the welding gun or torch to the welder. This welding cable is typically several feet long. When a welding operation is terminated and/or the welder is to be moved to another location, typically, the welding cable is bunched up into a pile about the welder and/or placed on top of the welder. Bunching up the welding cable can result in damage to the fluid tubes and/or electrical connections inside the cable. In addition, laying the welding gun or torch on the ground and/or placing the welding gun or torch on the top of a welder can result in damage to the welding gun or torch if the welding gun or torch is inadvertently stepped on and/or falls off the top of the welder. During the transport of the welder to various locations, the welding cable typically must be disconnected from the welder and separately transported, since there is no convenient manner of transporting the welding gun or torch and welding cable with the welder without exposing the welding cable and welding gun or torch to damage.
In view of the present state of the art of welders, there is a need for a welder or welding assembly which can easily and conveniently transport one or more welding accessories associated with the welder to reduce the burden and time of set-up and the time necessary to transport the welder to a new location.


The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

Gliomas
Glial cells, the most abundant cell type in the central nervous system, are cells that surround neurons and provide support for and insulation between them. Unlike neurons, glial cells do not conduct electrical impulses. There are two major classes of glial cells in the central nervous system: astrocytes and oligodendrocytes (Kandel E R, et al., Principles of Neural Science, 4th Ed. McGraw-Hill New York (2000), Ch. 2, pp. 20-21).
Glial cells in the vertebrate nervous system are divided into two major classes: microglia and macroglia. Microglia are phagocytes that are mobilized after infection, injury or disease, which arise from macrophages outside the nervous system. Three types of macroglial cells predominate in the vertebrate nervous system: oligodendrocytes, Schwann cells, and astrocytes. Astrocytes, the most numerous of glial cells in the central nervous system characterized by their star-like shape and the broad end-feet on their processes, are thought to play a nutritive role, and help form an impermeable lining in the brains capillaries and venules—the blood brain barrier—that prevents toxic substances in the blood from entering the brain. Oligodendrocytes, small cells with relatively few processes, and Schwann cells produce the myelin used to insulate nerve cell axons.
The term "glioma" encompasses all tumors thought to originate in the glial cell linage. (Veliz, I. et al., "Advances and challenges in the molecular biology and treatment of glioblastoma—is there any hope for the future?" Ann. Trans. Med. 3(1): 7. Doi: 10.3978/j.issn.2305-5939.2014.10.06. The location of the tumor depends on the type of cells from which it originates.
Malignant gliomas exhibit properties that resemble astrocytes or oligodendrocytes, hence the designation as astrocytomas and oligodendrogliomas. These tumors are graded on a scale from I to IV, based on how normal or abnormal the cells look. Of numerous grading systems in use, the most common is the World Health Organization (WHO) grading system for glioma (Louis D N, et al., Acta Neuropathol, 2007, 114(2):97-109). Grade I tumors are slow-growing, nonmalignant, and associated with long-term survival. Grade II tumors are relatively slow-growing but sometimes recur as higher grade tumors. They can be nonmalignant or malignant. Grade III tumors are malignant and often recur as higher grade tumors. Grade IV tumors reproduce rapidly and are very aggressive malignant tumors.
Low grade astrocytomas usually are localized and grow slowly. High grade astrocytomas grow at a rapid pace and are infiltrative. Astrocytomas can appear in various parts of the brain and nervous system, including the cerebellum, the cerebrum, the central areas of the brain, the brainstem, and the spinal cord.
Pilocytic Astrocytoma (also called Juvenile Pilocytic Astrocytoma), are grade I astrocytomas, which typically stay in the area where they started and do not spread. They are considered the "most benign" (noncancerous) of all the astrocytomas. Two other, less well known grade I astrocytomas are cerebellar astrocytoma and desmoplastic infantile astrocytoma.
Diffuse Astrocytoma (also called Low-Grade or Astrocytoma Grade II) (e.g., Fibrillary, Gemistocytic, Protoplasmic Astrocytoma) tend to invade surrounding tissue and grow at a relatively slow pace.
An anaplastic astrocytoma is a grade III tumor. These rare tumors require more aggressive treatment than benign pilocytic astrocytoma.
Astrocytoma Grade IV (also called Glioblastoma, previously named "Glioblastoma Multiforme," "Grade IV Glioblastoma," and "GBM"). There are two types of astrocytoma grade IV—primary, or de novo, and secondary. Primary tumors are very aggressive and the most common form of astrocytoma grade IV. The secondary tumors are those which originate as a lower-grade tumor and evolve into a grade IV tumor.
Subependymal Giant Cell Astrocytoma—Subependymal giant cell astrocytomas are ventricular tumors associated with tuberous sclerosis.
Oligodendrogliomas can be found anywhere within the cerebral hemisphere of the brain, although the frontal and temporal lobes are the most common locations. Sometimes oligodendrogliomas are mixed with other cell types. These tumors may be graded using an "A to D" system, which is based on microscopic features of the individual tumor cells. The grade indicates how quickly the tumor cells reproduce and how aggressive the tumor is. About 4% of primary brain tumors are oligodendrogliomas, representing about 10-15% of the gliomas. Only 6% of these tumors are found in infants and children. Most oligodendrogliomas occur in adults ages 50-60, and are found in men more often than women.
Mixed glioma (or oligoastrocytoma) usually contain a high proportion of more than one type of cell, most often astrocytes and oligodendrocytes. Occasionally, ependymal cells are also found. The behavior of a mixed glioma appears to depend on the grade of the tumor. It is less clear whether their behavior is based on that of the most abundant cell type.
Ependymal cells line the ventricles of the brain and the center of the spinal cord. These tumors are divided into four major types: subependymomas (grade I), typically slow growing tumors; myxopapillary ependymomas (grade I), typically slow growing tumors; Ependymomas (grade II), the most common of the ependymal tumors, which can be further divided into the following subtypes, including cellular ependymomas, papillary ependymomas, clear cell ependymomas, and tancytic ependymomas; and anaplastic ependymomas (grade III), typically faster growing tumors. The various types of ependymomas appear in different locations within the brain and spinal column. Subependymomas usually appear near a ventricle. Myxopapillary ependymomas tend to occur in the lower part of the spinal column. Ependymomas are usually located along, within, or next to the ventricular system. Anaplastic ependymomas are most commonly found in the brain in adults and in the lower back part of the skull (posterior fossa) in children. They are rarely found in the spinal cord. Ependymomas are relatively rare tumors in adults, accounting for 2-3% of primary brain tumors. However, they are the sixth most common brain tumor in children. About 30% of pediatric ependymomas are diagnosed in children younger than 3 years of age.
Optic gliomas may involve any part of the optic pathway, and they have the potential to spread along these pathways. Most of these tumors occur in children under the age of 10. Grade I pilocytic astrocytoma and grade II fibrillary astrocytoma are the most common tumors affecting these structures. Higher-grade tumors may also arise in this location. Twenty percent of children with neurofibromatosis (NF-1) will develop an optic glioma. These gliomas are typically grade I, pilocytic astrocytomas. Children with optic glioma are usually screened for NF-1 for this reason. Adults with NF-1 typically do not develop optic gliomas.
Gliomatosis Cerebri is an uncommon brain tumor that is most frequently pediatric and features widespread glial tumor cells in the brain. This tumor is different from other gliomas because it is scattered and widespread, typically involving two or more lobes of the brain. It could be considered a "widespread low-grade glioma" because it does not have the malignant features seen in high-grade tumors.
Glioblastoma
Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, classification name "glioblastoma", is the most common and most aggressive primary brain tumor in adults. GBM accounts for 40%-60% of all diffuse astrocytic tumors and 10%-15% of all intracranial neoplastic lesions. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. (Nakada, M. et al., Cancers, 2011, 3: 3242-3278). GBM is composed of poorly differentiated neoplastic astrocytes. The presence of microvascular proliferation and/or necrosis is essential for histopathological diagnosis of GBM.
GBM is one of the most aggressive human cancers and is very difficult to treat due to several complicating factors: the tumor cells are very resistant to conventional therapies; the brain is susceptible to damage by conventional therapy; the brain has a very limited capacity to repair itself; and many drugs cannot cross the blood-brain barrier to act on the tumor.
Although treatment can involve radiation, surgery and chemotherapy with temozolomide, which is an alkylating agent (P. J. Noughton et al. Clin. Cancer Res. (2000) 6:4110-4118), decades of surgical therapy, radiotherapy, and chemotherapy have failed to drastically change survival for GBM. The medium survival of patients with GBM in clinical trial populations treated with multimodal treatment approaches is approximately 12-15 months, with only 3%-5% of patients surviving longer than 36 months. (McNamara. M. G. et al., Cancers, 2013, 5: 1103-1119).
Glioblastoma multiforme has at least four distinct molecular subtypes. Tumor variants can be classified on the basis of somatic mutations in isocitrate dehydrogenase (IDH) ½ and TP53; transcriptional signature (classical, mesenchymal, neural or proneural), copy number variation, including co-deletion of chromosomes 1p and 19q; and amplification or mutation of the epidermal growth factor receptor (EGFR) and increased DNA hypermethylation of promoter-associated CpG islands. (Parker, N. R. et al., "Molecular heterogeneity in glioblastoma: potential clinical implications," Frontiers in Oncology 5, article 55 (March 2015)).
Classical GBM tumors are characterized by abnormally high levels of epidermal growth factor receptor (EGFR) which is a protein found on the surface of some cells that, when bound by epidermal growth factor, sends signals for the cell to keep growing in number (proliferation). The Cancer Genome Atlas (TCGA) Research Network, Nature 455: 1061-1068 (2008).
EGFR abnormalities occur at a much lower rate in the three other GBM subtypes. The TP53 gene codes for tumor protein p53 that normally suppresses tumor growth. TP53 is rarely mutated in classical GBM tumors subtype, but is the most frequently mutated gene in other subtypes of GBM.
Proneural GBM tumors are characterized by alterations of platelet derived growing factor receptor A (PDGFRA) and point mutations in IDH1, the gene that encodes isocitrate dehydrogenase 1. The gene IDH1, when mutated, codes for a protein that can contribute to abnormal cell growth. PDGFRA, which plays an important role in cell proliferation, cell migration, and angiogenesis, was also found to be mutated and expressed in abnormally high amounts. PDGFRA alteration only occurs in Proneural tumors and not in any other subtypes. When PDGFRA is altered, too much of its protein can be produced, leading to uncontrolled tumor growth. The patients of this subtype tend to be younger and to survive longer than in other subtypes.
The Mesenchymal subgroup contains the most frequent number of mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Frequent mutations in the PTEN (phosphatase and tensin homolog) and TP53 tumor suppressor genes also occur in the Mesenchymal subgroup. PTEN protein acts as a tumor suppressor, helping regulate the cycle of cell division.
While the Neural subgroup has mutations in many of the same genes as the other groups, the group does not stand out from the others as having significantly higher or lower rates of mutations. The Neural group is characterized by the expression of several markers that are also typical of the brain's normal, noncancerous nerve cells, or neurons, such as NEFL, GABRA1, SYT1 and SLC12A5.
While classical and mesenchymal GBMs express gene expression profiles reminiscent of NSCs, IDH-mutant gliomas display a proneural phenotype. (Ilkanizadeh, et al., "Glial Progenitors as Targets for Transformation in Glioma," Adv. Cancer Res. 121: 1-65 (2014)).
Based on clinical experience, two subgroups of otherwise histologically indistinguishable GBMs have been established: primary glioblastoma and secondary glioblastoma. Primary glioblastoma, which comprises more than 90% of biopsied or resected cases, arise de novo without antecedent history of low-grade disease, whereas secondary glioblastoma progresses from previously diagnosed low-grade gliomas. Primary glioblastomas display classical mesenchymal and neural phenotypes, whereas secondary glioblastomas tend to display a proneural phenotype that shifts toward a mesenchymal phenotype with recurrence. (Parker, N. R. et al., "Molecular heterogeneity in glioblastoma: potential clinical implications," Frontiers in Oncology 5, article 55 (March 2015)).
These molecular subtypes of glioblastoma multliforme appear to differ in their clinical courses and therapeutic responses. For example, the different subtypes show varying responses to aggressive chemotherapy and radiotherapy, with a difference of around 50% between the subtypes. It has been suggested that the pathology of each subtype might begin from different types of cells, which might explain the variation in response to therapy. The greatest benefit was seen in the Classical and Mesenchymal subtypes, where intensive therapy has significantly reduced mortality; and there was a suggestion of efficacy in the Neural subtype; but the Proneural subtype was less responsive to intensive therapy including conventional chemotherapy or chemo-radiation therapy. (Verhaak, R G, et al., Cancer Cell, 17(1):98-110, 2010))
Major Glioma Signaling Pathways
Several major signaling pathways have been associated with Glioma (Nakada, M. et al., Cancers, 2011, 3: 3242-3278).
1. Receptor Tyrosine Kinase Pathway (RTK/PI3K/Akt/mTOR Pathway).
The RTK/P13K/Akt pathway regulates various fundamental cellular processes such as proliferation, growth, apoptosis, and cytoskeletal rearrangement. The pathway involves receptor tyrosine kinases (RTKs), for example, epidermal growth factor receptor (EGFR), platelet derived growing factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), etc., as well as tumor suppressor protein phosphatase, for example, phosphatase and tension homolog (PTEN), and protein kinases PI3K, Akt, and mTOR. The Receptor Tyrosine Kinase pathway (RTK/PI3K/Akt/mTOR Pathway) is shown in FIG. 1.
EGFR gene amplification is the most frequent alteration (approximately 40%) in GBM. EGFR is a transmembrane glycoprotein member of the ErbB receptor family. In GBM, EGFR is dysregulated through overexpression, which arises because of EGFR gene amplification or activating mutations such as EGFRvIII that lead to ligand-independent signaling. EGFR aberrations have been correlated with a classical subtype of GBM (TCGA Research Network, Nature 455: 1061-68; Verhaak, Roel G. W. et al., Cancer Cell, 2010, 17: 98-110). Although it has been suggested that alterations of EGFR may be correlated with increased aggressiveness of GBM (Nakada, M. et al., Cancers, 2011, 3: 3242-3278), EGFR inhibitors (e.g., Gefinitib, Erlotinib) have not elicited clinical responses in patients with GBMs in clinical trials (Rich, J. N., et al., N. Engl. J. Med. 2004, 351, 1260-1261; Haas-Kogan, D. A. et al., J. Natl. Cancer Inst. 2005, 97, 880-887; van den Bent, M. J. et al., J. Clin. Oncol. 2009, 27, 1268-1274).
Overexpression of platelet-derived growth factor receptor (PDGFR), especially PDGFR-α and platelet-derived growth factor (PDGF) have been observed in astrocytic tumors of all grades, and their association with malignant progression has been suggested (Nakada, M. et al., Cancers, 2011, 3: 3242-3278). PDGFRA amplification (14%), as well as IDH1 mutation, are major features of the Proneural subtype of GBM according to the TCGA classification (TCGA Research Network, Nature 455: 1061-68; Verhaak, R. G. et al., Cancer Cell, 2010, 17: 98-110). Despite deep association of this molecule with GBM, anti-PDGFR therapy using Imatinib yielded only limited clinical responses (Reardon, D. A., et al., J. Clin. Oncol. 2005, 23, 9359-9368; Reardon, D. A., et al., Br. J. Cancer 2009, 101, 1995-2004).
The PI3Ks are widely expressed lipid kinases that promote diverse biological functions. The binding of PI3Ks and RTKs results in activation of Akt through phosphatidylinositol 3,4,5-triphosphate (PiP3) and 3-phosphoinositide dependent protein kinase-1 (PDK1), which affects multiple fundamental cellular processes including cell survival, proliferation, and motility. According to the integrated genomic classification of GBM, PI3K mutations (15%) are associated with the Proneural subtype (TCGA Research Network, Nature, 2008, 455: 1061-68; Verhaak, R. G. et al., Cancer Cell, 2010, 17: 98-110). Decreased PTEN activity can activate the RTKs/PI3K/Akt pathway since PTEN negatively regulates the pathway by antagonizing PI3K function. Homozygous deletion or mutation of PTEN is a common genetic feature in GBM (40%), resulting in constitutive activation of the RTKs/PI3K/Akt pathway. PTEN loss is associated with both classical and mesenchymal subtypes of GBM, according to the TCGA study (TCGA Research Network, Nature 455(23): 1061-68).
Akt is an STK (Serine/threonine specific protein kinase) that regulates cell growth, proliferation, and apoptosis. Akt activation has been reported in approximately 80% of human GBMs and correlates with the fact that RTKs/PI3K/Akt signaling is altered in 88% of GBM (TCGA Research Network, Nature 455(23): 1061-68). Oncogenic Akt mutations have not been detected in GBM. Akt inhibitor perifosine is undergoing clinical evaluation in malignant gliomas (Nakada, M. et al., Cancers, 2011, 3: 3242-3278).
2. p14ARF/MDM2/p53 Pathway
The p53 gene encodes a protein that responds to diverse cellular stresses to regulate target genes that induce cell cycle arrest, cell death, cell differentiation, senescence, DNA repair, and neovascularization. Following DNA damage, p53 is activated and induces transcription of genes (such as p21Waf1/Cip1) that function as regulators of cell cycle progression at G1 phase. Mouse double minute 2 homolog (MDM2) oncogne inhibits p53 transcriptional activity by forming a tight complex with the p53 gene, and participates in the degradation of p53. The p14ARF gene codes a protein that directly binds to MDM2 and inhibits MDM2-mediated p53 degradation. In turn p14ARF expression is negatively regulated by p53. Thus, inactivation of p14ARF/MDM2/p53 is caused by altered expression of any of the p53, MDM2, or p14ARF genes. The p53 pathway plays a crucial role in the development of secondary GBMs. The p53 gene is the most commonly mutated p53 pathway gene in glioma; however, molecular abnormalities involving other genes in the pathway have also been described. (Nakada, M. et al., Cancers, 2011, 3: 3242-3278). The p14ARF/MDM2/p53 Pathway is shown in FIG. 2.
3. RB Pathway.
The RB (retinoblastoma tumor suppressor protein) pathway suppresses cell cycle entry and progression, as well as the p53 pathway. The 107-kDa RB1 protein encoded by RB1 (at 13q14) controls progression through G1 into the S-phase of the cell cycle (Serrano, M., et al., Nature, 1993, 366: 704-707). The CDKN2A protein (i.e. p16INK4a which is cyclin-dependent kinase inhibitor 2A) binds to cyclin-dependent kinases 4 (CDK4) and inhibits the CDK4/cyclin D1 complex, thus inhibiting cell cycle transition from G1 to S phase. Thus, alteration of RB1, CDK4, or CDKN2A can cause dysregulation of the G1-S phase transition. However, alteration of only the RB pathway is insufficient to induce tumor formation. EGFR amplification enhances the PI3K pro-growth pathway and is typically associated with CDKN2A deletions. CDKN2A loss is associated with the classical subtype of GBM, according to the TCGA study. (Nakada, M. et al., Cancers, 2011, 3: 3242-3278). The RB pathway is shown in FIG. 3.
4. Ras/MEK/MAPK Pathway.
RAS (Rat sarcoma) proteins act as on/off (RAS-GDP/RAS-GTP) switches controlled by RTKs and neurofibromatosis type 1 tumor suppressor gene (NF-1). Activated RAS (RAS-GTP) then activates serine/threonine kinase RAF. RAF activates mitogen-activated protein kinase kinase (MAPKK), also called MEK, which in turn activates MAPK. MAPK activation results in activation of various transcription factors, such as Elk1, c-myc, Ets, STAT1/3, and PPAR.
The NF-1 tumor suppressor gene encodes neurofibromin, which functions primarily as a RAS negative regulator and plays a role in adenylate cyclase- and Akt-mTOR-mediated pathways. There is increasing evidence that the NF-1 gene is involved in the tumorigenesis of not only NF-1-related, but also sporadically occurring, gliomas. In the TCGA pilot study, NF-1 mutation/homozygous deletions were identified in 18% of GBM. Mesenchymal GBMs, having frequent inactivation of the NF-1 (37%), p53 (32%), and PTEN genes, respond to aggressive chemo-radiation adjuvant therapies. (Nakada, M. et al., Cancers, 2011, 3: 3242-3278). The Ras/MAPK pathway is shown in FIG. 4. A global view of the signaling pathways mentioned above is shown in FIG. 4.
Other signaling pathways may play a role in GBM initiation, migration, and invasion.
Brain Stem Cells
Glial cells outnumber neurons by 10-fold in the human brain and are composed mainly of terminally differentiated cells and minor discrete precursor populations. (Ikanizadeh, S. et al., "Glial Progenitors as targets for transformation in glioma," Adv. Cancer Res. 121: 1-65 (2014)).
Two major germinal layers—the ventricular zone (VZ) and the subventricular zone (SVZ)—give rise to most neurons and glial cells in the forebrain. (Garcia-Verdugo, J M et al, "Architecture and Cell types of the adlt subventricular zone: in search of the stem cells," J. Neurobiol. 36: 234-48 (1998)). It was traditionally believed that the capacity of these germinal layers to generate neurons was restricted to the embryonic period; however, it is now known that new neurons continue to be added to certain regions of the adult vertebrate brain. In adult mammals, neuronal addition has been observed only in the olfactory bulb and the hippocampus. New neurons destined for the olfactory bulb are born in the SVZ of the lateral ventricles. A subpopulation of SVZ cells can proliferate in culture, giving rise to spherical clusters of cells (neurospheres), which have the capacity to generate neurons, astrocytes and oligodendrocytes. Based on their ability to self-renew and their potential to give rise to multiple cell types, these SVZ-derived cells are considered neural stem cells. Evidence also suggests that neural stem cells (NSCs) line the third and fourth ventricles (Ikanizadeh, S. et al., "Glial Progenitors as targets for transformation in glioma," Adv. Cancer Res. 121: 1-65 (2014), citing Weiss, S. et al, "Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis, "J. Neurosci. 16(23): 7599-7609 (1996); Xu, Y. et al., Neurogenesis in the ependymal layer of the adultrat 3rd ventricle," Exptl Neurol. 192(2): 251-64 (2005)).
Modeling of glioma in mice has shown that cells at various differentiation stages throughout glial and neuronal lineages have the potential to generate glioma. Recent advances highlight the cellular heterogeneity in gliomas, the influence of the tumor microenvironment, and that treatment-resistant tumor cells display a high degree of stemness.
Transcriptomal profiling of gliomas displaying a neuroepithelial origin, show that the mesenchymal phenotype is associated with stemness, invasiveness, and poor survival. Id. (citing H. S. Phillips, et al., "Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis," Cancer Cell. 9(3): 157-73 (2006); Sturm, D. et al, "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma," Cancer Cell 22(4): 425-37 (2012); Verhaak, R G W, et al., "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1, "Cancer Cell. 17(1): 98-110 (2010)).
Cancer stem cells (CSCs) or tumor-initiating cells (TIC) are a subpopulation of tumor cells with the ability to undergo self-renewal and recapitulate the entire tumor population Wang, L. et al., Interleukin-1β and transforming growth factor-β cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells," Stem al Res. & Therapy 3:5 (2012). Glioma stem cells (GSC) have been identified from human glioma tissues and glioma cells lines. Id. GSCs are characterized by the ability of self-renewal to generate three-dimensional aggregates of cells in suspension termed "neurospheres" when cultured in serum-free conditions supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Id. These glioma neurospheres reflect biological and pathological characteristics of primary gliomas, display resistance to chemo- and radio-therapies, and have enhanced oncogenic potential, generating tumors that reproduce the characteristics of the original tumors after intracranial transplantation. (Id., citing Ehrlicher, A. et al., Guiding neuronal growth with light," Proc. Natl Acad. Sci. U.S.A. 99: 16024-8 (2002); Difato, F. et al, "combined optical tweezers and laser dissector for controlled ablation of functional connections in neural networks," J. Biomed. Opt. 16: 051306 (2011); Dictus, C. et al, "Comparative analysis of in vitro conditions for rat adult neural progenitor cells," J. Neurosci Methods. 161: 250-58 (2007))
Animal Models of Glioma
The study of IDH-mutant gliomas has been obstructed by the lack of models of IDH-mutant glioma-producing mice. Brain-specific IDH1R132H knock-in mice are embryonically lethal. Izanizadeh, S. et al, citing Sasaki, M. et al, "D-2 hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function," Genes & Devel. 26(18): 2038-49 (2012)). Cell lines with IDH1R132H mutation can only be maintained transiently in vitro, since the mutation does not persist in non-immortalized cells. Primary IDH-mutant gliomas from patient tumors do not grow well in vitro (Id., citing Piaskowski, S. et al., "Glioma acells showing IDH1 mutation cannot be propagated in standard cell culture conditions," Br. J. Cancer 104(6): 968-70 (2011)). In contrast to normal cells, introduction of IDH mutations into glioma cells decreases the proliferation rate, which may ultimately cause a selection pressure against cultured glioma cells harboring IDH mutations (Id., citing Bralten, L B C, et al., "IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo," Annals Neurol. 69(3): 455-63 (2011)).
Spontaneous mouse models of GBM have been generated that are caused by mutation and therefore loss of three glioma relevant tumor suppressor genes: Pten, p53 and NFL These mice have tumors that exhibit histopathological and molecular similarity with human GBM and have provided a powerful platform for natural history studies, molecular studies and derivation of primary (Mut6) cells that can be maintained in low passage culture and reintroduced in allografts to produce GBM (Llaguno S A et al., "Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model", Cancer Cell. 2009 Jan. 6; 15(1): 45-56; Llaguno S A et al., "Neural and Cancer Stem Cells in Tumor Suppressor Mouse Models of Malignant Astrocytoma", Cold Spring Harb Symp Quant Biol. 2008; 73: 421-426).

Benzamide or benzamine compounds useful as anticancer agents for the treatment of human cancers

The Board of Regents of The University of Texas System


This indexing system (10) for use with a binder (12) includes a plurality of section divider sheets (14) each having an outstanding tab (16) with index indicia thereon and a foldout index sheet assembly (18). The assembly (18) is formed from a unitary foldable sheet which includes a carrier portion (20) and a foldout index portion (22) provided with index indicia corresponding to the indicia on the tabs.

This invention relates generally to index sheets for binders and more particularly to an index sheet which can be moved into a visible position for review.
There are several ways of indexing binders, the most common probably being the provision of index information directly on tabs attached to section divider sheets. Another indexing system, which is more convenient, provides the divider tabs with indexing indicia such as sequential numerals or letters and an index sheet which provides corresponding indicia and related index information aligned with the divider tabs. The latter system works well but suffers from the disadvantage that when the binder is open at a particular section the index sheet is hidden. Systems have been devised to provide index sheets which can be moved into a viewing position.
The closest known reference is commonly-owned U.S. Pat. No. 5,299,879, which discloses an indexing system for use with a binder having a plurality of section divider sheets each having an outstanding tab with index indicia thereon and a foldout index sheet assembly. The assembly disclosed in U.S. Pat. No. 5,299,879 includes a carrier sheet and a foldable index sheet provided with index indicia corresponding to the indicia on the tabs and attachable to the carrier sheet. This system permits the use of a foldable index sheet adhesively attached to a carrier sheet of the same size to facilitate use in conjunction with a copying machine of standard size.
The present system overcomes this limitation and other disadvantages in a manner not revealed in the known prior art.

American Trading and Production Corporation


A folding space shelf has a lower backplane and an upper backplane that are connected by one or more hinges, and a pair of top crossbeams and a pair of upper stringers. Each top crossbeam has a first end hinged to an upper portion of the upper backplane and a second end rotatably connected to one of the pair of upper stringers. It further contains a pair of bottom crossbeams and a pair of bottom stringers. Each bottom crossbeam has a first end hinged to a lower portion of the lower backplane and a second end rotatably connected to one of the pair of bottom stringers. The folding space shelf also contains a pair of middle stringers, each having a first end connected to one of the pair of upper stringers and a second end hinged to one of the pair of the bottom stringers.

In recent years, to satisfy various civil, military and scientific research needs, a space unfolding mechanism gradually becomes a research hotspot of all countries due to its advantages of small mass, folding performance, low manufacture cost and good carrying economy. A space unfolding shelf is in a folded state before carrying or launching process, can be unfolded from a folded state with a small volume and locked by a locking mechanism during work so as to obtain a larger working space, and has wide application prospects in the aerospace field.
Most of the existing space shelves are integral rigid structures, cannot be folded for storage, needs to occupy large space in the carrying process and in a non-working state such as idle state, and is not convenient for storage and transportation. In addition, it is increasingly difficult for the integral rigid shelves to satisfy the needs of the future development of deep space exploration due to its defects of large mass, high manufacture cost and high launching cost.

SHENYANG INSTITUTE OF AUTOMATION, CHINESE ACADEMY OF SCIENCES


A medical diagnostic imaging system comprises a user interface comprising at least one physical control. The system also comprises a camera positioned to view the physical control. The system further comprises a processor connected to the camera and configured to detect a manipulation involving the physical control and associate the manipulation with a desired user input for controlling the imaging system.

The subject matter disclosed herein relates to medical diagnostic imaging systems, such as an ultrasound imaging system, and more particularly to a user input system for such imaging systems.
Cleaning and sterilizing the user interface of a medical diagnostic imaging system, such as an ultrasound system, can be a challenge. The chemicals used to clean and sterilize can hinder the operation of and even damage electronic components and controls. Different approaches have been employed in attempt to solve this problem. For example, tempered glass touch sensitive interfaces have been employed. However, this attempted solution suffers from the disadvantage that an operator, such as an ultrasound sonographer, may find it difficult to control the ultrasound system with one hand while viewing the image on the display as they are scanning the subject with a probe held in the other hand. This is because the operator must often and repeatedly look away from the display to the control panel to change the settings of the system. Having controls that the operator can identify by touch without looking at them may allow the operator to better focus on the images or behavior of the system while simultaneously modifying various settings because there is less need to look at the controls.
Therefore, a system and method of controlling a medical diagnostic imaging system that can be easily sterilized without fear of damage to electrical components and easily operated by an operator without repeatedly looking at the controls is desired.