A soft toy that incorporates pacifiers into the shape of the toy. The toy includes a body made from a pair of planar sheets of a flexible material, the planar sheets having a perimeter that extends along an edge, and a soft, flexible filling. the filling being generally in the shape of the perimeter of the planar sheets. The sheets are connected to one another by way of a seam along a plane to form an enclosed space that covers the filling and results in the edges of the planar sheets are contained within the enclosed space. The connected sheets will create at least one area where a pair of sections of the seam converge towards one another at an angle of from 20 to 40 degrees, but preferably at an angle of about 25 to about 35 degrees. This connection will create an integral pacifier from the material of the toy. The pacifier portion will be nearly conical in shape.

(a) Field of the Invention
This invention generally relates to a flexible toy that provides components that allow the infant to chew on the device and also serves as a distraction device that pacifies the child. The device may include an internal musical component that cooperates with the sides of the toy so that the musical component can be easily activated by the child.
(b) Discussion of Known Art
It is well known that infant children can be amused by small stuffed animals or toys. The fabrication of these animals or toys has typically involved the assembly of various components that end up looking like the animal that is portrayed by the toy. For example, stuffed toy rabbits will include a head with large ears, a body and legs. The construction of such a toy will typically involve the use of several panels that are sown together to form the shape of the animal's body parts. A problem with this type of construction is that it can isolate the major parts of the body of the toy. This makes it difficult to effectively incorporate mechanisms such as electronic musical devices into the body of the toy. These musical devices must be inserted into the larger body portions of the toy, where sufficient room is found to accommodate the musical device. The placement of the musical device in these areas of the stuffed toy makes it difficult for an infant can squeeze the toy with sufficient force to allow the infant to trigger or activate the musical device.
Another problem associated with known stuffed toys is that they rely on the appearance of the toy as an attractant to get the child or infant to play with the toy. Thus, the accepted method for fabricating these toys involves creating a stuffed animal that looks like a real animal or a cartoon type character of such an animal. Infants, however, are not sufficiently familiar with animals or cartoon characters to appreciate the details of these types of toys. Therefore, the effectiveness of these toys as an attractant that distracts the child and thereby pacifying the child is limited in that they have been created from the perspective of a non-infant child or an adult that is familiar with these characters or animals.
Well known pacifier devices typically incorporate a rubber nipple portion that is instinctively chewed by the child. The shapes of these devices are designed to take advantage of this instinctive behavior by infants. Known stuffed animals, however, do not provide components that are designed to play on these instinctive impulses. For example, a stuffed rabbit may have floppy ears, but these ears do not incorporate the three dimensional features of the well-known pacifier.
Examples of stuffed toys and toys that use tethers and musical components can be found in U.S. Pat. No. 5,975,982 to Spector, issued Nov. 2, 1999, U.S. Pat. No. 5,480,340 to Bogar, issued Jan. 2, 1996, U.S. Pat. No. 5,478,268 to Au, issued Dec. 26, 1995, U.S. Pat. No. 4,756,109 to Marcus, issued Jul. 12, 1988, U.S. Pat. No. 4,722,713 to Williams et al., issued Feb. 2, 1988, U.S. Pat. No. 4,147,344 to Lee, issued Apr. 3, 1979, U.S. Pat. No. 3,699,704 to Hakim, issued Oct. 24, 1972, U.S. Pat. No. 3,927,482 to Marcus, issued Dec. 23, 1975. Examples of toys that include pacifiers are found in U.S. Pat. No. 5,665,113 to Decker et al. However, structure and geometry of these devices do not lend themselves to the use of the devices as pacifiers or teething devices. Furthermore, an infant's mind is constantly absorbing information on shapes and colors. Because the infant is learning to recognize shapes and colors, it would be advantageous to provide a device that can perform the functions of a pacifier and allow containment and activation of a musical component within the device. The activation of the musical component being in response to a tug or squeeze of the toy by the infant.
Still further, there remains a need for a device and method that can be used to help or teach infants in recognizing simple shapes, while also serving as a pacifier.
There remains a need for a device that includes bright colors and that can be serve as a pacifier as well as a tethered toy that can be carried by the child, tethered to the child's garment or body.
Therefore, a review of known devices reveals that there remains a need for a simple device that allows an infant to use the device as a teething device, a pacifier, a tethered toy, and an instructional device that can capture the attention of an infant.


This invention involves a child's car seat with a seat surface, a back rest, optionally with side arm supports and/or head supports or rests, and with side guides for the insertion of the belt of a car, and with at least one device for the automatic tightening of the car belt, and with a device for adjusting the inclination of the child's car seat relative to the vehicle's own seat. The device for the automatic tightening of the car belt is located in the area of a belt provided in the top area of the back rest guide and acts at the same time on the shoulder belt and the waist belt. There is further at least one device for fastening the car's shoulder belt immovably with respect to the child's car seat.

1. Field of the Invention
This invention relates to a child's car seat with a seat surface, back rest, optionally with arm rests on the side, and/or head rest, with lateral guides for inserting a car seat belt, and with at least one device for automatically tightening the car seat belt, and with a device for adjusting the inclination of the child's car seat relative to the vehicle's seat.
2. Description of the Prior Art
Depending on their age and size, children in children's car seats are belted in either with a belt of the seat itself or with a three-point car seat belt. If the children are fastened in with the seat's own belt, the car seat belt is often used to fasten the child's seat itself. Such a car seat belt is frequently connected or clamped to the child's seat at least one point so that the child's seat is anchored as well as possible despite the vehicle's own usual automatic rollup mechanism.
In any case it is important for all of the belts involved always to be pulled tight so that the buckled-in child is held securely in place in case the vehicle suddenly slows down, especially in case of an accident.
On the other hand, however, it is desirable also to offer a child a more sharply inclined relaxed position besides the vertical sitting position—especially for long vacation trips. However, this is impossible in case of an internal connection of the child seat in question with a tightly clamped vehicle belt.
A system of this type is disclosed by German Utility Patent G 91 15 290.0. Of course, in this case the rear of the seat back is has a convex arch longitudinally, so that when the inclination of the seat is adjusted, different areas of the back rest are against the car's seat, but not other areas. For example, if the lower back of the child's seat in the upright position rests against the car's seat, then in the sloping position it is the upper back, while the lower back area is displaced far forward, and can give the seat no support. If the car belt in this condition is not tightly fastened, for example because the child has played with the belt, then the seat can tip forward in case of a sudden slowdown and then completely loses contact with the vehicle's seat back. The result is completely uncontrolled motion, and the child's seat and the child sitting in it become like a plaything with high inertia and the life and limb of the child are in danger.
The problem inspiring the invention results from these drawbacks of the described state of the art, to develop a device that indeed allows adjustment of the child's seat with regard to its inclination, but nevertheless always provides optimal support of the child's seat on the vehicle's own seat.


A vehicle driving support system is provided with an environment detecting means for detecting objects existing around a vehicle and for producing output environment information, a command unit to specify a running mode of the vehicle, information processing means for generating driving operation reference information suitable for the specified running mode of the vehicle by processing the environment information specified in accordance with the running mode and a display unit to display the driving operation reference information. The information processing means monitors the inter-vehicle distance to a vehicle stopping in front of the vehicle and generates driving operation reference information to inform the driver of the starting of the precedent vehicle when the vehicle is in the congestion running mode. When the vehicle is in the narrow passing running mode, an object near the vehicle having a relative positional relationship to said vehicle is mounted and driving operation reference information is generated to inform the driver thereof. When the vehicle is in the parking running mode, driving operation reference information is generated to inform the driver of the distribution of the objects existing in a parking lot.

The present invention relates to a vehicle driving support system which provides a driver with reference information for driving a vehicle by detecting and processing environmental conditions around the vehicle.
There have been various automatic tracking control systems which detect the speed of a preceding vehicle and determine the distance between the subject and the preceding vehicle, that is the inter-vehicle distance, based on the detected speed, and which maintain the distance between the two vehicles in order to support long-distance driving with safety.
Such a system is already disclosed, for example, in Japanese Patent Application Laid-Open No. 3-295000 (1991).
There also have been alarm systems which detect the distance between a vehicle and a preceding vehicle and which produce an alarm to caution the driver against a rear-end collision. Such alarm systems are described in Japanese Patent Application Laid-open No. 4-201641 (1992) and No. 4-201643 (1992).
The systems mentioned above will be useful when vehicles are continuously running on ordinary roads or highways. From a running mode point of view, however, vehicles are driven more often in a congestion running mode on ordinary streets than in a high speed running mode on highways. When they are being driven on ordinary streets, they are generally forced to repeat stopping and slow running due to traffic signals and congestion. A driver, therefore, is kept busy when a vehicle is driven in the congestion running mode, and has to keep watching the driving state of the preceding vehicle, as well as watching the state of the street beyond the preceding vehicle. In such a situation, the mental and physical burdens imposed on the driver will be considerable.
Now, there are a lot of cases where a driver runs a vehicle in a narrow space, such as in a narrow passage in a downtown area, in a narrow parking lot or in a garage. In order to perform such driving reliably, a well experienced and skillful driving technique is indispensable. Especially, for beginners, drivers in name only, and physically handicapped persons, such driving conditions present a most difficult task. They have to bear both mental and physical stresses from such driving.
The control system and the alarm system in the systems described above have no support function for a driving operation in a congestion running mode or a narrow space running mode.

Vehicle driving support system which is responsive to environmental conditions


A method and device for externally checking cigarettes, whereby the cigarettes, housed inside respective seats on a conveyor, are fed by the conveyor in a transverse direction in relation to the seats and along a path, one portion of which is a scanning path past a CCD scanning array; each cigarette being rotated at least 360.degree. about its axis as it travels along the scanning path.

The present invention relates to a method of externally checking cigarettes.
Cigarettes are normally checked externally by feeding them successively and transversely along a given check path past an optical device, normally consisting of a telecamera, the images produced by which are compared with a reference image with which the cigarettes are to conform within acceptable limits. If they do not, the optical device emits signals which normally provide for subsequently rejecting the faulty cigarettes.
On known cigarette manufacturing machines, the cigarettes are normally fed along the check path by means of rollers with peripheral seats, each housing a respective cigarette, which is normally retained inside the seat by means of suction.
A major drawback of the above method of feeding the cigarettes along the check path is that the portion of the cigarette contacting the seat on the roller is hidden from view, so that any surface defects on the portion go undetected.

External cigarette checking method and device


A method is provided to search for images. The method includes identifying an object in a two-dimensional reference image. The method includes determining a three-dimensional reference orientation axis of the object based on at least one attribute of the object. The method includes receiving an input that requests a change in a three-dimensional perspective of the object. The method further includes determining a new orientation axis based on the input and the reference orientation axis. The method includes executing a search query on a set of two-dimensional images, where the search query is based on the new orientation axis and at least one attribute of the object. The method also includes displaying image search results that are ranked based on correlations with the new orientation axis and the attribute of the object.

Display devices can display objects in a two-dimensional ("2D") manner or a three-dimensional ("3D") manner. If an object is displayed in a 2D manner (e.g., as in a flat photograph of a car), the computing system lacks information necessary to change the view of the object to a different angular perspective. However, objects that are displayed in a 3D manner can be viewed on a two-dimensional display device in a variety of different angular orientations or perspectives. For example, computer aided design ("CAD") programs allow the user to rotate a solid (or wire frame) representation of an object to view the object from different angular perspectives. The 3D model of the object includes additional information (e.g., X, Y and Z axis information) that allows the program to regenerate a new image of the object every time the user requests a change in perspective. However, in the case of objects viewed in a 2D manner, a rotational gesture (or other form of user input) will not result in a different viewing angle of the object. Therefore, the user is not able to provide input to change the rotational viewing perspective of the 2D images.

Method of searching images using rotational gesture input

International Business Machines Corporation


An air intake device of an internal combustion engine which is capable of enhancing the air intake efficiency and reducing the size is provided. The internal combustion engine includes a cylinder head, an intake manifold provided at a longitudinal side surface of the cylinder head, and a head cover provided on the cylinder head. The air intake device of the internal combustion engine includes an air cleaner including an upper casing and a lower casing detachably coupled to each other and incorporating a filter element, an atmospheric air introduction pipe for introducing air to the air cleaner, and an intake pipe extending from the air cleaner to the intake manifold.

Generally, this kind of air intake device comprises an air cleaner incorporating a filter element, an atmospheric air introduction pipe for introducing atmospheric air into the air cleaner, and an intake pipe for introducing the air cleaned by the air cleaner into the intake manifold in the internal combustion engine. To enhance the air intake efficiency of the internal combustion engine, the atmospheric air introduction pipe and the intake pipe need to have a sufficient length.
The Patent Document 1 as a prior art proposes to arrange an air cleaner on a head cover covering the upper surface of a cylinder head in an internal combustion engine. The air cleaner includes two divided parts and a filter element sandwiched therebetween.
In the structure proposed by the Patent Document 2 as another prior art, a surge tank in an intake manifold is provided on a head cover covering the upper surface of a cylinder head of an internal combustion engine so that an end of the surge tank projects from a longitudinal end of the head cover. An air cleaner is arranged at a lower surface of the surge tank at a portion which projects from the head cover.
The Patent Document 3 as another prior art proposes to arrange a casing, which includes two vertically divided parts, on a head cover covering the upper surface of a cylinder head of an internal combustion engine. In the casing, an air cleaner and an atmospheric air introduction pipe for introducing air to the air cleaner are incorporated, and an intake pipe for guiding air from the air cleaner to the intake manifold is provided.
However, to arrange an air cleaner on the upper side of a head cover covering the upper surface of a cylinder head like the Patent Document 1 causes the following problems.
Since the entirety of the air cleaner projects from the upper surface of the head cover, the total height of the internal combustion engine considerably increases.
Further, since the atmospheric air introduction pipe needs to have a sufficient length to enhance the air intake efficiency, the atmospheric air introduction pipe projects largely from the internal combustion engine in plan view. Therefore, space for accommodating such a projecting portion needs to be secured around the internal combustion engine.
Moreover, the intake pipe extending from the air cleaner to the intake manifold cannot have a length sufficient to enhance the air intake efficiency.
In the structure disclosed in the Patent Document 2 again, the atmospheric air introduction pipe for introducing air to the air cleaner projects from the internal combustion engine. Therefore, space for accommodating the atmospheric air introduction pipe needs to be secured around the internal combustion engine. Further, an intake passage having a length sufficient to enhance the air intake efficiency cannot be defined between the air cleaner and the surge tank in the intake manifold.
With the structure disclosed in the Patent Document 3, the entirety of the air cleaner projects from the upper surface of the head cover, similarly to the structure of the Patent Document 1. Therefore, the total height of the internal combustion engine considerably increases.
Patent Document 1: JP-A 2002-97920
Patent Document 2: JP-A 2003-239815
Patent Document 3: JP-A 2003-161216

Air intake device of internal combustion engine


A display device (1) includes (i) a display panel (12) including a polarizing plate (18) on a surface of the display panel (12) and (ii) a touch panel (20) including a birefringent base material (31) on which a Y electrode pattern (32) and an X electrode pattern (33) are provided. Polarized light which has exited from the polarizing plate (18) enters the birefringent base material (31). The display device (1) includes an antireflection layer (28) which reduces reflection of the polarized light. The antireflection layer (28) is provided on a first surface of the touch panel (20) which first surface is opposite to a second surface of the touch panel (20) which second surface faces the display panel (12).

As a touch panel conventionally known is an electrostatic capacitive touch panel which detects a contact position at which a detecting object, such as a finger or a pen for use in input, comes into contact with a display screen, by detecting a change in electrostatic capacitance caused by the contact.
In terms of cost, heat resistance, etc., a polyethylene terephthalate (PET) film etc. is conventionally and typically employed as a base material of a touch sensor of the touch panel (see, for example, Patent Literatures 1 and 2).
However, in a case where an observer who is wearing polarized glasses observes a liquid crystal display device on which front surface a touch panel that includes a birefringent base material such as the PET film is provided, the observer visually recognizes rainbow unevenness (see, for example, Patent Literatures 1 and 2).
Patent Literature 1 discloses eliminating rainbow unevenness which is visually recognized by a viewer with polarized glasses on when the viewer views a liquid crystal display device provided with an electrostatic capacitive touch sensor, by making an optical compensation with use of a ¼ wavelength plate that is provided between the electrostatic capacitive touch sensor and the liquid crystal display device, the rainbow unevenness being caused by beams of light passing through the polarized glasses to be combined with each other which beams of light have passed through the electrostatic capacitive touch sensor to make a phase difference.
Patent Literature 2 discloses eliminating rainbow unevenness which is visually recognized by a viewer with polarized glasses on when the viewer views a resistive film touch panel with which a liquid crystal display device is provided, by (i) providing a ¼ wavelength plate between the liquid crystal display device and (a) a first surface of an upper electrode plate which first surface is opposite to a second surface of the upper electrode plate on which second surface a transparent electrically-conductive film is provided or (b) a first surface of a lower electrode plate which first surface is opposite to a second surface of the lower electrode plate on which second surface a transparent electrically-conductive film is provided, and (ii) converting, into circularly-polarized light, linearly-polarized light emitted from the liquid crystal display device.
Patent Literature 2 further discloses absorbing, by use of a circular polarization plate in which a ¼ wavelength plate and a polarizing plate are combined, light which has externally entered and has been internally reflected.


In a semiconductor device, via holes are formed around a chip buried in a package, one end of a conductor filled in the via hole is covered with a pad portion exposed to the outside, and a wiring layer connected to the other end of the conductor is formed. The portion (pad portion) of the wiring layer which correspond to the conductor is exposed from a protective film, or an external connection terminal is bonded to the top of the pad portion. Electrode terminals of the chip are connected to the wiring layer, and the opposite surface of the chip is exposed to the outside.

(a) Field of the Invention
The present invention relates to a semiconductor device and a method of manufacturing the same. More specifically, the present invention relates to a semiconductor device having a package structure in which a semiconductor element (chip) is mounted within a wiring board for a reduction in thickness, and relates to a method of manufacturing the same.
(b) Description of the Related Art
Heretofore, semiconductor devices having various forms have been proposed in which a chip is mounted within a wiring board. As an example, there is a package structure (semiconductor device) intended to form a required circuit block by incorporating and stacking a plurality of chips, for example, typified by System Block Module manufactured by Toshiba Corporation Semiconductor Company. In this semiconductor device, connection between upper and lower layers is established around chips. Accordingly, on the upper and lower surfaces of each package, top-and-bottom connecting pads are placed around the chip. The top-and-bottom connecting pads are used for connecting packages (chips) stacked on and under the relevant package (chip). Most of the top-and-bottom connecting pads are connected also within the relevant package. In such a semiconductor device, plated through holes have been typically used as means for connecting the top-and-bottom connecting pads within the package.
Technologies relating to the above-described known technology include, for example, as described in Japanese unexamined Patent Publication (JPP) 2001-217337, a technology with which multilayer stacking can be realized by burying and mounting a semiconductor chip in a package, and providing external connection terminals on both surfaces of the package, or exposing, from a solder resist layer, terminal formation portions (pad portions) of a wiring pattern to which external connection terminals are to be connected.
As described above, in a known package structure (semiconductor device) adapted for the stacking of a plurality of chips using top-and-bottom connecting pads provided in a region around the chips, plated through holes have been used when the top-and-bottom connecting pads are connected within the package.
However, plated through holes are often formed by drilling. Consequently, the diameters of the through holes become relatively large (approximately 250 to 300 μm in the state of the art), and there has been a disadvantage in that a larger area is accordingly required. Further, there are constraints on design (i.e., the degree of freedom of wiring is low), such as the technical difficulty of placing top-and-bottom connecting pads on plated through holes. Accordingly, the relevant pads must be formed at other positions, and thus an area required around the chip increases. This has become an obstacle to miniaturization.
Essentially, one of major purposes in stacking chips is to enhance functionality by incorporating a larger number of functional elements (chips) into a smaller volume. However, the above-described problem becomes a serious obstacle to the accomplishment of this purpose. Namely, in a package (semiconductor device) containing a chip, a region around the chip is not a portion which exerts an essential function as the semiconductor device, but a portion used for simply connecting upper and lower stacked packages. Accordingly, in consideration of recent demands for smaller sizes, higher densities, and the like, of thin-type packages, it is more desirable that an area required around the chip is as small as possible.

Package structure having semiconductor device embedded within wiring board


The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

According to the World Health Organization (WHO), cancer ranged among the four major non-communicable deadly diseases worldwide in 2012. For the same year, colorectal cancer, breast cancer and respiratory tract cancers were listed within the top 10 causes of death in high income countries (who.int/mediacentre/factsheets/fs310/en/).
In 2012, 14.1 million new cancer cases, 32.6 million patients suffering from cancer (within 5 years of diagnosis) and 8.2 million cancer deaths were estimated worldwide (Ferlay et al., 2013; Bray et al., 2013).
Estimated incidences of different cancer types (adult population, both sexes) world-wide in 2012 were (Ferlay et al., 2013; Bray et al., 2013): For cancer of the brain and nervous system: 256213, for colorectal cancer: 1360602, for kidney cancer: 337860, for liver cancer: 782451, and for gastric cancer: 951594 cases.
Estimated incidences of different cancer types (adult population, both sexes) in the USA, EU-28, China and Japan in 2012 were (Ferlay et al., 2013; Bray et al., 2013): For cancer of the brain and nervous system: 135884, for colorectal cancer: 845797, for kidney cancer: 226733, for liver cancer: 513172, and for gastric cancer: 615641 cases.
Estimated mortalities of different cancer types (adult population, both sexes) world-wide in 2012 were (Ferlay et al., 2013; Bray et al., 2013): For cancer of the brain and nervous system: 189382, for colorectal cancer: 693933, for kidney cancer: 143406, for liver cancer: 745533, and for gastric cancer: 723073 cases.
Estimated mortalities of different cancer types (adult population, both sexes) in the USA, EU-28, China and Japan in 2012 were (Ferlay et al., 2013; Bray et al., 2013): For cancer of the brain and nervous system: 100865, for colorectal cancer: 396066, for kidney cancer: 83741, for liver cancer: 488485, and for gastric cancer: 447735 cases.
Within the groups of brain cancer, the current invention specifically focuses on glioblastoma (GBM). GBM is the most common central nervous system malignancy with an age-adjusted incidence rate of 3.19 per 100,000 inhabitants within the United States. GBM has a very poor prognosis with a 1-year survival rate of 35% and a 5-year survival rate lower than 5%. Male gender, older age and ethnicity appear to be risk factors for GBM (Thakkar et al., 2014).
Colorectal cancer—Depending on the colorectal cancer (CRC) stage, different standard therapies are available for colon and rectal cancer. Standard procedures include surgery, radiation therapy, chemotherapy and targeted therapy for CRC (Berman et al., 2015a; Berman et al., 2015b).
Removal of the tumor is essential for the treatment of CRC. Anatomic conditions differ for rectal carcinomas from another CRC as the rectum is located in the pelvis and the tumor can be difficult to access. Well-differentiated small rectal tumors (stage T1) require excision, but no further treatment with chemotherapy. Patients with rectal tumors of higher T stages receive neoadjuvant radio-chemotherapy with a fluoropyrimidine prior to total mesorectal excision (TME) and adjuvant chemotherapy. For chemotherapeutic treatment, the drugs capecitabine or 5-fluorouracil (5-FU) are used. For combinational chemotherapy, a cocktail containing 5-FU, leucovorin and oxaliplatin (FOLFOX) is recommended (Stintzing, 2014; Berman et al., 2015b).
Treatment of colon carcinomas involves radical hemicolectomy and lymph node resection. Early stages (UICC stage I) do not require additional treatment. Patients with tumors of UICC stage II receive 5-FU or capecitabine. Treatment for patients with UICC stage III includes the drug combinations FOLFOX and XELOX (capecitabine plus oxaliplatin) (Berman et al., 2015a; Stintzing, 2014).
Metastatic, unresectable CRC are treated with chemotherapeutical cocktails such as FOLFIRI (5-FU, leucovorin, irinotecan), FOLFOX, FOLFOXIRI (5-FU, irinotecan, oxaliplatin), FOLFOX/capecitabine, FOLFOX/oxaliplatin, FOLFIRI/capecitabine and irinotecan or UFT (5-FU, tegafur-uracil) (Stintzing, 2014).
In addition to chemotherapeutic drugs, several monoclonal antibodies targeting the epidermal growth factor receptor (EGFR, cetuximab, panitumumab) or the vascular endothelial growth factor-A (VEGF-A, bevacizumab) are administered to patients with high stage disease. For second-line and later treatment the inhibitor for VEGF aflibercept, the tyrosine kinase inhibitor regorafenib and the thymidylate-synthetase inhibitor TAS-102 and the dUTPase inhibitor TAS-114 can be used (Stintzing, 2014; Wilson et al., 2014).
Latest clinical trials analyze active immunotherapy as a treatment option against CRC. Those strategies include the vaccination with peptides from tumor-associated antigens (TAAs), whole tumor cells, dendritic cell (DC) vaccines and viral vectors (Koido et al., 2013).
Peptide vaccines have so far been directed against carcinoembryonic antigen (CEA), mucin 1, EGFR, squamous cell carcinoma antigen recognized by T cells 3 (SART3), beta-human chorionic gonadotropin (beta-hCG), Wilms' Tumor antigen 1 (WT1), Survivin-2B, MAGE3, p53, ring finger protein 43 and translocase of the outer mitochondrial membrane 34 (TOMM34), or mutated KRAS. In several phase I and II clinical trials patients showed antigen-specific CTL responses or antibody production. In contrast to immunological responses, many patients did not benefit from peptide vaccines on the clinical level (Koido et al., 2013; Miyagi et al., 2001; Moulton et al., 2002; Okuno et al., 2011).
Dendritic cell vaccines comprise DCs pulsed with either TAA-derived peptides, tumor cell lysates, apoptotic tumor cells, or tumor RNA or DC-tumor cell fusion products. While many patients in phase I/II trials showed specific immunological responses, only the minority had a clinical benefit (Koido et al., 2013).
Whole tumor cell vaccines consist of autologous tumor cells modified to secrete GM-CSF, modified by irradiation or virus-infected, irradiated cells. Most patients showed no clinical benefit in several phase II/III trials (Koido et al., 2013).
Vaccinia virus or replication-defective avian poxvirus encoding CEA as well as B7.1, ICAM-1 and LFA-3 have been used as vehicles in viral vector vaccines in phase I clinical trials. A different study used non-replicating canary pox virus encoding CEA and B7.1. Besides the induction of CEA-specific T cell responses 40% of patients showed objective clinical responses (Horig et al., 2000; Kaufman et al., 2008).
Gastric cancer—The wall of the stomach is made up of 3 layers of tissue: the mucosal (innermost) layer, the muscularis (middle) layer, and the serosal (outermost) layer. Gastric cancer (GC) begins in the cells lining the mucosal layer and spreads through the outer layers as it grows. Four types of standard treatment are used. Treatment for gastric cancer may involve endoscopic or surgical resection, chemotherapy, radiation therapy or chemoradiation. Surgery is the primary treatment and the only curative treatment for gastric cancer. Since the early stages of gastric cancer are mostly asymptomatic, the disease is usually diagnosed in an advanced stage. For metastatic gastric cancer, no globally accepted standard chemotherapy combination regimen has yet been established. However, the combination of 5-FU and a platinum analog is still the most widely accepted reference regimen worldwide, although 5-FU can be replaced by capecitabine or irinotecan and cisplatin can be replaced by oxaliplatin. Additionally, triple-combination therapies comprising cisplatin, 5-FU and docetaxel or, in the case of HER-2 over-expressing tumors, cisplatin, 5-FU and trastuzumab can be applied (Leitlinie Magenkarzinom, 2012).
The efficacy of current therapeutic regimens for advanced GC is poor, resulting in low 5-year survival rates. Immunotherapy might be an alternative approach to ameliorate the survival of GC patients. Adoptive transfer of tumor-associated lymphocytes and cytokine induced killer cells, peptide-based vaccines targeting HER2/neu, MAGE-3 or vascular endothelial growth factor receptor 1 and 2 and dendritic cell-based vaccines targeting HER2/neu showed promising results in clinical GC trials. Immune checkpoint inhibition and engineered T cells might represent additional therapeutic options, which is currently evaluated in pre-clinical and clinical studies (Matsueda and Graham, 2014).
Glioblastoma—The therapeutic options for glioblastoma (WHO grade IV) are very limited. According to the guidelines released by the German Society for Neurology the standard therapy in young patients includes resection or biopsy of the tumor, focal radiation therapy and chemotherapy with temozolomide. Alternative chemotherapeutic regimens consist of CCNU/lomustine or a combination of procarbazine with CCNU and vincristine (PCV). In elderly patients' resection or biopsy of the tumor are not recommended. These patients receive chemo- or radiation therapy, depending on the methylation state of the O6-methylguanine-DNA-methyltransferase-(MGMT)-promotor. Negative methylation state is an indication for focal radiation therapy, whereas positive methylation state is an indication for temozolomide treatment with or without focal radiation therapy. Relapse therapy comprises again resection as well as chemo- and radiation therapy. In the USA, Canada and Switzerland treatment with bevacizumab (anti-VEGF-antibody) is also approved for relapse therapy (Leitlinien für Diagnostik and Therapie in der Neurologie, 2014).
Different immunotherapeutic approaches are investigated for the treatment of GB, including immune-checkpoint inhibition, vaccination and adoptive transfer of engineered T cells.
Antibodies directed against inhibitory T cell receptors or their ligands were shown to efficiently enhance T cell-mediated anti-tumor immune responses in different cancer types, including melanoma and bladder cancer. The effects of T cell activating antibodies like ipilimumab and nivolumab are therefore assessed in clinical GB trials, but preliminary data indicate autoimmune-related adverse events.
Different vaccination strategies for GB patients are currently investigated, including peptide-based vaccines, heat-shock protein vaccines, autologous tumor cell vaccines, dendritic cell-based vaccines and viral protein-based vaccines. In these approaches peptides derived from GB-associated proteins like epidermal growth factor receptor variant III (EGFRvIll) or heat shock proteins or dendritic cells pulsed with autologous tumor cell lysate or cytomegalo virus components are applied to induce an anti-tumor immune response in GB patients. Several of these studies reveal good safety and tolerability profiles as well as promising efficacy data.
Adoptive transfer of genetically modified T cells is an additional immunotherapeutic approach for the treatment of GB. Different clinical trials currently evaluate the safety and efficacy of chimeric antigen receptor bearing T cells directed against HER2, IL-13 receptor alpha 2 and EGFRvIll (Ampie et al., 2015).
Liver cancer—Disease management depends on the tumor stage at the time of diagnosis and the overall condition of the liver. If possible, parts of the liver (partial hepatectomy) or the whole organ (liver resection) is removed by surgery. Especially patients with small or completely resectable tumors are qualified to receive a liver transplant.
If surgery is not a treatment option, different other therapies are available at hand. For tumor ablation, a probe is injected into the liver and the tumor is destroyed by radio or microwaves or cryotherapy. In embolization procedures, the blood supply of the tumor is blocked by mechanical or chemical means. High energy radio waves can be used to destroy the tumor in radiation therapy.
Chemotherapy against HCC includes combinations of doxorubicin, 5-fluorouracil and cisplatin for systemic therapy and doxorubicin, floxuridine and mitomycin C for hepatic artery infusions. However, most HCC show a high resistance to chemotherapeutics (Enguita-German and Fortes, 2014).
Therapeutic options in advanced non-resectable HCC are limited to Sorafenib, a multi-tyrosine kinase inhibitor (Chang et al., 2007; Wilhelm et al., 2004). Sorafenib is the only systemic drug confirmed to increase survival by about 3 months and currently represents the only experimental treatment option for such patients (Chapiro et al., 2014; Llovet et al., 2008).
Lately, a limited number of immunotherapy trials for HCC have been conducted. Cytokines have been used to activate subsets of immune cells and/or increase the tumor immunogenicity (Reinisch et al., 2002; Sangro et al., 2004). Other trials have focused on the infusion of Tumor-infiltrating lymphocytes or activated peripheral blood lymphocytes (Shi et al., 2004; Takayama et al., 1991; Takayama et al., 2000).
So far, a small number of therapeutic vaccination trials have been executed. Butterfield et al. conducted two trials using peptides derived from alpha-fetoprotein (AFP) as a vaccine or DCs loaded with AFP peptides ex vivo (Butterfield et al., 2003; Butterfield et al., 2006). In two different studies, autologous dendritic cells (DCs) were pulsed ex vivo with autologous tumor lysate (Lee et al., 2005) or lysate of the hepatoblastoma cell line HepG2 (Palmer et al., 2009). So far, vaccination trials have only shown limited improvements in clinical outcomes.
Renal cell carcinoma—Initial treatment is most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment (Rini et al., 2008). For first-line treatment of patients with poor prognostic score a guidance elaborated by several cancer organizations and societies recommend the receptor tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, the monoclonal antibody bevacizumab combined with interferon-α (IFN-α) and the mTOR inhibitor temsirolimus. Based on guidelines elaborated by the US NCCN as well as the European EAU and ESMO, the TKIs sorafenib, pazopanib or recently axitinib are recommended as second-line therapy in RCC patients who have failed prior therapy with cytokines (IFN-α, IL-2). The NCCN guidelines advise also sunitinib in this setting (high-level evidence according to NCCN Category I).
Everolimus and axitinib are recommended as second-line therapy of those patients who have not benefited from a VEGF-targeted therapy with TKIs according to the established guidelines.
The known immunogenity of RCC has represented the basis supporting the use of immunotherapy and cancer vaccines in advanced RCC. The interesting correlation between lymphocytes PD-1 expression and RCC advanced stage, grade and prognosis, as well as the selective PD-L1 expression by RCC tumor cells and its potential association with worse clinical outcomes, have led to the development of new anti PD-1/PD-L1 agents, alone or in combination with anti-angiogenic drugs or other immunotherapeutic approaches, for the treatment of RCC (Massari et al., 2015). In advanced RCC, a phase III cancer vaccine trial called TRIST study evaluates whether TroVax (a vaccine using a tumor-associated antigen 5T4, with a pox virus vector), added to first-line standard of care therapy, prolongs survival of patients with locally advanced or mRCC. Median survival had not been reached in either group with 399 patients (54%) remaining on study however analysis of the data confirms prior clinical results, demonstrating that TroVax is both immunologically active and that there is a correlation between the strength of the 5T4-specific antibody response and improved survival. Further there are several studies searching for peptide vaccines using epitopes being over-expressed in RCC.
Various approaches of tumor vaccines have been under investigation. Studies using whole-tumor approaches, including tumor cell lysates, fusions of dendritic cells with tumor cells, or whole-tumor RNA were done in RCC patients, and remissions of tumor lesions were reported in some of these trials (Avigan et al., 2004; Holtl et al., 2002; Marten et al., 2002; Su et al., 2003; Wittig et al., 2001).
Considering the severe side-effects and expense associated with treating cancer, there is a need to identify factors that can be used in the treatment of cancer in general and colorectal cancer, glioblastoma, gastric cancer, hepatocellular carcinoma, and renal cell carcinoma. There is also a need to identify factors representing biomarkers for cancer in general and colorectal cancer, glioblastoma, gastric cancer, hepatocellular carcinoma, and renal cell carcinoma in particular, leading to better diagnosis of cancer, assessment of prognosis, and prediction of treatment success.
Immunotherapy of cancer represents an option of specific targeting of cancer cells while minimizing side effects. Cancer immunotherapy makes use of the existence of tumor associated antigens.
The current classification of tumor associated antigens (TAAs) comprises the following major groups:
a) Cancer-testis antigens: The first TAAs ever identified that can be recognized by T cells belong to this class, which was originally called cancer-testis (CT) antigens because of the expression of its members in histologically different human tumors and, among normal tissues, only in spermatocytes/spermatogonia of testis and, occasionally, in placenta. Since the cells of testis do not express class I and II HLA molecules, these antigens cannot be recognized by T cells in normal tissues and can therefore be considered as immunologically tumor-specific. Well-known examples for CT antigens are the MAGE family members and NY-ESO-1.b) Differentiation antigens: These TAAs are shared between tumors and the normal tissue from which the tumor arose. Most of the known differentiation antigens are found in melanomas and normal melanocytes. Many of these melanocyte lineage-related proteins are involved in biosynthesis of melanin and are therefore not tumor specific but nevertheless are widely used for cancer immunotherapy. Examples include, but are not limited to, tyrosinase and Melan-A/MART-1 for melanoma or PSA for prostate cancer.c) Over-expressed TAAs: Genes encoding widely expressed TAAs have been detected in histologically different types of tumors as well as in many normal tissues, generally with lower expression levels. It is possible that many of the epitopes processed and potentially presented by normal tissues are below the threshold level for T-cell recognition, while their over-expression in tumor cells can trigger an anticancer response by breaking previously established tolerance. Prominent examples for this class of TAAs are Her-2/neu, survivin, telomerase, or WT1.d) Tumor-specific antigens: These unique TAAs arise from mutations of normal genes (such as β-catenin, CDK4, etc.). Some of these molecular changes are associated with neoplastic transformation and/or progression. Tumor-specific antigens are generally able to induce strong immune responses without bearing the risk for autoimmune reactions against normal tissues. On the other hand, these TAAs are in most cases only relevant to the exact tumor on which they were identified and are usually not shared between many individual tumors. Tumor-specificity (or -association) of a peptide may also arise if the peptide originates from a tumor- (-associated) exon in case of proteins with tumor-specific (-associated) isoforms.e) TAAs arising from abnormal post-translational modifications: Such TAAs may arise from proteins which are neither specific nor overexpressed in tumors but nevertheless become tumor associated by posttranslational processes primarily active in tumors. Examples for this class arise from altered glycosylation patterns leading to novel epitopes in tumors as for MUC1 or events like protein splicing during degradation which may or may not be tumor specific.f) Oncoviral proteins: These TAAs are viral proteins that may play a critical role in the oncogenic process and, because they are foreign (not of human origin), they can evoke a T-cell response. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical carcinoma.
T-cell based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins, which are presented by molecules of the major histocompatibility complex (MHC). The antigens that are recognized by the tumor specific T lymphocytes, that is, the epitopes thereof, can be molecules derived from all protein classes, such as enzymes, receptors, transcription factors, etc. which are expressed and, as compared to unaltered cells of the same origin, usually up-regulated in cells of the respective tumor.
There are two classes of MHC-molecules, MHC class I and MHC class II. MHC class I molecules are composed of an alpha heavy chain and beta-2-microglobulin, MHC class II molecules of an alpha and a beta chain. Their three-dimensional conformation results in a binding groove, which is used for non-covalent interaction with peptides.
MHC class I molecules can be found on most nucleated cells. They present peptides that result from proteolytic cleavage of predominantly endogenous proteins, defective ribosomal products (DRIPs) and larger peptides. However, peptides derived from endosomal compartments or exogenous sources are also frequently found on MHC class I molecules. This non-classical way of class I presentation is referred to as cross-presentation in the literature (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules can be found predominantly on professional antigen presenting cells (APCs), and primarily present peptides of exogenous or transmembrane proteins that are taken up by APCs e.g. during endocytosis, and are subsequently processed.
Complexes of peptide and MHC class I are recognized by CD8-positive T cells bearing the appropriate T-cell receptor (TCR), whereas complexes of peptide and MHC class II molecules are recognized by CD4-positive-helper-T cells bearing the appropriate TCR. It is well known that the TCR, the peptide and the MHC are thereby present in a stoichiometric amount of 1:1:1.
CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8-positive cytotoxic T cells. The identification of CD4-positive T-cell epitopes derived from tumor associated antigens (TAA) is of immense importance for the development of pharmaceutical products for triggering anti-tumor immune responses (Gnjatic et al., 2003). At the tumor site, T helper cells, support a cytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006) and attract effector cells, e.g. CTLs, natural killer (NK) cells, macrophages, and granulocytes (Hwang et al., 2007).
In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system, especially professional antigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells. In cancer patients, cells of the tumor have been found to express MHC class II molecules (Dengjel et al., 2006).
Longer (elongated) peptides of the invention can act as MHC class II active epitopes.
T-helper cells, activated by MHC class II epitopes, play an important role in orchestrating the effector function of CTLs in anti-tumor immunity. T-helper cell epitopes that trigger a T-helper cell response of the TH1 type support effector functions of CD8-positive killer T cells, which include cytotoxic functions directed against tumor cells displaying tumor-associated peptide/MHC complexes on their cell surfaces. In this way tumor-associated T-helper cell peptide epitopes, alone or in combination with other tumor-associated peptides, can serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses.
It was shown in mammalian animal models, e.g., mice, that even in the absence of CD8-positive T lymphocytes, CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon-gamma (IFNγ) (Beatty and Paterson, 2001; Mumberg et al., 1999). There is evidence for CD4 T cells as direct anti-tumor effectors (Braumuller et al., 2013; Tran et al., 2014).
Since the constitutive expression of HLA class II molecules is usually limited to immune cells, the possibility of isolating class II peptides directly from primary tumors was previously not considered possible. However, Dengjel et al. were successful in identifying a number of MHC Class II epitopes directly from tumors (WO 2007/028574, EP 1 760 088 B1).
Since both types of response, CD8 and CD4 dependent, contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor-associated antigens recognized by either CD8+ T cells (ligand: MHC class I molecule+peptide epitope) or by CD4-positive T-helper cells (ligand: MHC class II molecule+peptide epitope) is important in the development of tumor vaccines.
For an MHC class I peptide to trigger (elicit) a cellular immune response, it also must bind to an MHC-molecule. This process is dependent on the allele of the MHC-molecule and specific polymorphisms of the amino acid sequence of the peptide. MHC-class-1-binding peptides are usually 8-12 amino acid residues in length and usually contain two conserved residues ("anchors") in their sequence that interact with the corresponding binding groove of the MHC-molecule. In this way, each MHC allele has a "binding motif" determining which peptides can bind specifically to the binding groove.
In the MHC class I dependent immune reaction, peptides not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR).
For proteins to be recognized by T-lymphocytes as tumor-specific or -associated antigens, and to be used in a therapy, particular prerequisites must be fulfilled. The antigen should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues. In a preferred embodiment, the peptide should be over-presented by tumor cells as compared to normal healthy tissues. It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell). Tumor-specific and tumor-associated antigens are often derived from proteins directly involved in transformation of a normal cell to a tumor cell due to their function, e.g. in cell cycle control or suppression of apoptosis. Additionally, downstream targets of the proteins directly causative for a transformation may be up-regulated and thus may be indirectly tumor-associated. Such indirect tumor-associated antigens may also be targets of a vaccination approach (Singh-Jasuja et al., 2004). It is essential that epitopes are present in the amino acid sequence of the antigen, in order to ensure that such a peptide ("immunogenic peptide"), being derived from a tumor associated antigen, leads to an in vitro or in vivo T-cell-response.
Basically, any peptide able to bind an MHC molecule may function as a T-cell epitope. A prerequisite for the induction of an in vitro or in vivo T-cell-response is the presence of a T cell having a corresponding TCR and the absence of immunological tolerance for this particular epitope.
Therefore, TAAs are a starting point for the development of a T cell based therapy including but not limited to tumor vaccines. The methods for identifying and characterizing the TAAs are usually based on the use of T-cells that can be isolated from patients or healthy subjects, or they are based on the generation of differential transcription profiles or differential peptide expression patterns between tumors and normal tissues. However, the identification of genes over-expressed in tumor tissues or human tumor cell lines, or selectively expressed in such tissues or cell lines, does not provide precise information as to the use of the antigens being transcribed from these genes in an immune therapy. This is because only an individual subpopulation of epitopes of these antigens are suitable for such an application since a T cell with a corresponding TCR has to be present and the immunological tolerance for this particular epitope needs to be absent or minimal. In a very preferred embodiment of the invention it is therefore important to select only those over- or selectively presented peptides against which a functional and/or a proliferating T cell can be found. Such a functional T cell is defined as a T cell, which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector functions ("effector T cell").
In case of targeting peptide-MHC by specific TCRs (e.g. soluble TCRs) and antibodies or other binding molecules (scaffolds) according to the invention, the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor.

Peptides and combination thereof for use in the immunotherapy against cancers


Polymerase chain reaction primers and methods directed to detecting the EGFR mutant C→T at the position corresponding to base 2369 of EGFR cDNA. The invention provides a PCR primer that hybridizes under suitable PCR conditions to a polynucleotide sequence 5′ in each respective strand to a mutation of an EGFR gene that encodes a substitution of threonine by methionine at position 790 of the EGFR polypeptide. The invention also provides a PCR primer hybridizes to a sequence that includes a mutant T at the position corresponding to base 2369 of EGFR cDNA but not to a second EGFR polynucleotide containing a wild type C. The invention provides several methods and kits for detecting a mutant epidermal growth factor receptor (EGFR) gene in a sample comprising probing the sample with a means for selectively detecting a nucleotide sequence comprising a mutant T at the position corresponding to base 2369 of EGFR cDNA, and identifying that the base at said position is T. These methods and kits are also useful to predict resistance to the therapeutic effects of gefitinib or erlotinib in a subject suffering from or suspected of having a cancer.

The epidermal growth factor receptor (EGFR) has been identified as a relevant target for treatment of solid tumors, as it is involved in regulating cellular functions important in the proliferation and survival of cancer cells. EGFR is commonly expressed in a range of tumors, and high expression is often related to poor prognosis. A new class of targeted therapies directed at inhibiting the EGFR, tyrosine kinase inhibitors, have appeared. Two known examples are gefitinib (Iressa) or erlotinib (Tarceva). Despite initial responses of some patients to these therapies, patients eventually progress by unknown mechanisms of "acquired" resistance.
EGFR has been thought to play an important role in lung cancer. However only a small portion non-small cell lung cancers (NSCLCs) respond to Iressa or Tarceva (see FIG. 1 for structures). Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib or erlotinib usually harbor somatic gain-of-function mutations in exons encoding the tyrosine kinase domain of EGFR. Such mutations are found in about 10% of NSCLCs from the United States [1,2,3], with higher incidences observed in east Asia [2,4,5,6]. Some 90% of NSCLC-associated mutations occur as either multi-nucleotide in-frame deletions in exon 19, involving elimination of four amino acids, Leu-Arg-Glu-Ala, or as a single nucleotide substitution at nucleotide 2573 (T→G) in exon 21, resulting in substitution of arginine for leucine at position 858 (L858R). Both of these mutations are associated with sensitivity to the small-molecule kinase inhibitors gefitinib or erlotinib [1,2,3]. Unfortunately, nearly all patients who experience marked improvement on these drugs eventually develop progression of disease. While KRAS (v-Ki-ras2, Kirsten rat sarcoma viral oncogene homolog, a RAS family member) mutations have been associated with some cases of primary resistance to gefitinib or erlotinib [7], mechanisms underlying "acquired" or "secondary" resistance are unknown.
Therefore there is a need in the art for the determining the underlying causes of such resistance so that a diagnostic test can be developed and a more effective treatment provided. Moreover, there is a need in the art for new compounds that are able to treat patients that show cancer progression or relapse despite initial response to current EGFR inhibitors.

Methods and compositions for detecting a drug resistant EGFR mutant


A two-way switching circuit for connecting a supply power to a load comprises two electronic switches connected to each other. Each of the two electronic switches includes two electronic switch units connected to each other. Each of the two electronic switches has a control circuit including a common actuator selectively connected to both of the electronic switch units thereof for alternately turning on the respective electronic switch units. A first of the electronic switch unit of each of the two electronic switches is connected to each other and a second of the electronic switch units of each of the electronic switches is connected to each other, whereby switching circuit is thus adapted to connect a power supply to a load when both of the first electronic switch units or both of the second electronic switches are on.

1. Field of the Invention
The present invention concerns two-way switching circuits of the kind used to control a load alternately from one of two separate control location which may be far apart.
2. Description of the Prior Art
At present such two-way switching circuits use exclusively mechanical switches, with their inherent disadvantages, in particular arcing which is liable to lead to serious deterioration of the electrical contacts and generate noise.
The present invention is based on an observation that it is possible to construct such two-way switching circuits using electronic switches.


A plasma processing method, which enables the etching controllability for a high-dielectric-constant insulating film to be improved. A substrate having a high-dielectric-constant gate insulating film and a hard mask formed thereon is subjected to etching processing using a plasma of a processing gas containing a noble gas and a reducing gas.

1. Field of the Invention
The present invention relates to a plasma processing method, a storage medium, and a plasma processing apparatus, and in particular relates to a plasma processing method that carries out etching processing on a high-dielectric-constant insulating film formed on a substrate.
2. Description of the Related Art
As semiconductor devices manufactured from semiconductor wafers as substrates are made smaller in size and with an increased degree of integration, there are increased demands to make gate insulating films of transistors and dielectric portions of capacitors (i.e. insulating films) of the semiconductor devices thinner. An insulating film satisfying these demands for thinness is only a few atoms thick, and in this case, with the conventional insulating film material SiO2, current leakage through the insulating film due to a quantum tunneling effect increases. It is thus difficult to use SiO2 as the material of such a thin insulating film.
In response to this problem, high-dielectric-constant insulating film materials according to which there is no current leakage even if a large current is passed have been developed. Such high-dielectric-constant insulating film materials are metal-based materials; specifically, an oxide of hafnium (Hf) or zirconium (Zr), or such an oxide with silicon (Si) additionally contained therein, or an oxide of aluminum (Al), or the like, can be used. However, there is a problem with these high-dielectric-constant insulating film materials that, in the case that etching is carried out using a plasma of a fluorine gas-based mixed gas as conventionally used in the etching of SiO2, the etching rate is slow.
A metal-based insulating film can be etched with a high etching rate using chemical etching comprised of a combination of corrosion with a corrosive gas and high temperature processing, but there are many problems, for example to carry out such chemical etching, a corrosion processing chamber and a high temperature processing chamber are both required, and hence a new system construction is required, and the cost of the system increases.
In recent years, there has thus been developed a plasma processing method in which a high-dielectric-constant gate insulating film is etched using a conventional etching apparatus with a plasma of a mixed gas comprised of argon (Ar), helium (He), or a mixed gas of argon and helium, with methane (CH4) added thereto (a noble gas-based mixed gas) (see Japanese Laid-open Patent Publication (Kokai) No. 2005-39015).
However, with a low sputter etching apparatus, even if a plasma of such a noble gas-based mixed gas is used, the etching rate is still slow, i.e. the required etching rate cannot be realized. Moreover, with a high sputter etching apparatus, the etching rate is sufficiently high, and hence the required etching rate can be realized, but silicon nitride (SiN), which is the material of a hard mask, is also etched with a high etching rate, and hence it is difficult to secure a good (high) etching selectivity ratio for the high-dielectric-constant insulating film versus the hard mask. That is, there is a problem that the etching controllability for the high-dielectric-constant insulating film is still low.


A tray for supporting linear lamps in large cartons may be made to nest in one orientation and on rotation by 180 degrees may stack to form a latched array of lamp cradles. The cradle walls are formed along their lengths with alternating lengths and gaps. The alternating wall sections of the cradle walls are asymmetric right to left along the cradle axis. The walls forming the rows of cradles are arranged to be paired with a non-nesting wall on rotation by 180 degrees. In this way, at least one point along the length of each wall is supported in the non-nesting orientation. By forming latching features at the support points, the trays can be locked together as a rigid array of lamp cradles.

1. Field of the Invention
The invention relates to packaging for electric lamps and particularly to tubular electric lamps. More particularly the invention is concerned with a packing tray for tubular lamps.
2. Description of the Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
Fluorescent lamps are commonly stacked and then shipped in an outer case. The lamps are divided and cushioned one from another so they do not crash into each other during shipping. On arrival the outer carton is frequently placed on an open shelf and used as a dispenser. As lamps are selected they are removed from the outer carton. As more lamps are removed the separating materials, which in the past have been pulpwood tray dividers, soft packing materials such as singleface wrappers, and other cushioning materials, either pull out with the lamps or become disorganized and free to move making it difficult to reload the case for display, storage or recycling purposes. There is then a need for a packing structure that continues to function despite the number of lamps removed from the outer carton. At the same time, the packing material must be able to be nested in condensed forms to efficiently ship and store them before and after they are used to ship the fluorescent lamp products. It is expensive to ship, hold and recycle bulky packing materials. There is then a need for a packing structure that is easily condensed for original shipping and storing, and also for return.


A wire housing unit has a shell body including a rear wall and two substantially parallel side walls extending orthogonally from the rear wall, a top plate removably attached to the top or bottom portion of the shell body closing the top or bottom, a bottom plate removably attached to the bottom or top portion of the shell body closing the bottom or top, a nailing fin disposed on the outside surface of one of the vertical side walls the fin substantially parallel with the rear wall of the shell body, and a modular contact junction block having a contact plug receptacle and terminals connecting house wires to a plugin outlet or switch assembly. The junction block is removably mounted to the inside surface of the top or bottom plates and in a position to accept contact plug-in of the outlet or switch assembly.

1. Field of the Invention
The present invention is in the field of construction, more particularly electrical wiring, and pertains particularly to methods and apparatus for installing electrical junction boxes and electric utility components.
2. Discussion of the State of the Art
In home construction and repair or maintenance, electrical wiring is installed to enable connection and control of electric utilities such as outlets or switches, for example. Typical new home construction requires installation of electrical wiring boxes at junction points anchored to studs or frame members of the structure before walls are finished. Such prefabricated boxes are designed to be nailed in a correct orientation at a junction point and have break-out tabs in the material that allow for insertion of electrical wires into the interior of the box.
Some units may have a termination block or panel installed in a fixed position within the box, the block or panel having facilities to attach electrical wires that have been stripped at the ends. The wires inserted through the box wall and into the interior are fastened to the termination panel at designated wire connection points. An electrical wall outlet or wall switch or a combination thereof may be installed over the face of the electrical box after the hosting wall is finished. The exposed and trimmed wire ends of the electric utilities (outlet, switch) are connected to the termination block or panel at designated wire connection points. The outlet or switch plate is then fastened to the face of the electrical box.
There are several problems with current utility box installation that may occur during the installation process. For example, correct orientation of the box is required to accommodate the direction of wiring at the junction point. Boxes have only one open face into the interior where contact is made. Therefore, the wiring process may be challenged by lack of adequate room or space to work in making connections and disposing excess wire in any available volume left within the box. Moreover, wiring from the utility outlet must also be confined within a small space making it hard to ensure reliable connections.
Therefore, what is clearly needed is a modular electrical wiring unit that mitigates the problems stated above.


A transceiver device capable of calibration, and a calibration method used by the transceiver device. The transceiver device includes a reference transceiver, a plurality of remaining transceivers, and a plurality of transmission calibration paths connecting the remaining transceivers to the reference transceiver for transmission calibration of the remaining transceivers. An envelope detector included in the reference transceiver is shared with the remaining transceivers. When implementing a multiple input multiple output (MIMO) transceiver in a single chip, the chip size and manufacturing cost of the MIMO transceiver device can be substantially reduced.

1. Technical Field
The present invention relates to a transceiver device having a direct conversion structure and a calibration method used by the transceiver device.
2. Related Art
In the related art, wireless local area networks (WLANs) are an emerging application of wireless systems. Institute of Electrical and Electronics Engineers (IEEE) 802.11 is a WLAN standard. The 802.11b standard was the first to be commercialized, and the 802.11a standard was developed to address the new needs of the WLAN market. The 802.11a standard uses a frequency of 5 GHz and adopts orthogonal frequency division multiplexing (OFDM) as its modulation scheme. OFDM distributes data among a large number of carriers a predetermined distance apart from one another in a given frequency range. The predetermined distance provides "orthogonality," which prevents a demodulator from referring to frequencies other than its own frequency.
Related art direct conversion transceivers are a type of transceiver used in wireless systems such as the WLAN. The use of related art direct conversion transceivers is becoming widespread, since they can be implemented in a single-chip structure at a low cost by using a complementary metal oxide semiconductor (CMOS) technology. In addition, related art direct conversion transceiver problems, such as in-phase and quadrature (IQ) mismatch, local oscillator (LO) leakage, and DC offset, can be minimized in a calibration process by using a digital signal processor (DSP) or a microprocessor.
To achieve highly efficient data transmission, a related art transceiver device using a multiple input multiple output (MIMO) method that adopts a plurality of such direct conversion transceivers is being actively developed.
FIG. 1 is a schematic block diagram of a related art MIMO transceiver device 100 that includes first through nth transceivers 110 through 150 having identical structures. The structure of the first transceiver 110 is described below as an example.
The first transceiver 110 includes an up-mixer 111, an envelope detector 112, a down-mixer 113, and a plurality of switches 114 through 116. The up-mixer 111 converts an input baseband signal into an RF signal and outputs the RF signal. The down-mixer 113 converts an input RF signal into a baseband signal and outputs the baseband signal. The envelope detector 112 detects and outputs the envelope of an input signal. The first through third switches 114 through 116 are for forming a plurality of calibration paths. Generally, the envelope detector 112 can be easily implemented using a diode.
Due to their structural characteristics, related art direct conversion transceivers suffer from IQ mismatch, LO leakage, DC offset, and so on. Ideally, the phase difference between an in-phase signal path and a quadrature signal path of a direct conversion transceiver must be 90 degrees, and the gain between the in-phase signal and the quadrature signal must be 0 dB. IQ mismatch occurs when these conditions for the phase difference between the in-phase signal path and the quadrature signal path and the gain are not met. More specifically, I refers to in-phase and Q refers to quadrature. IQ mismatch is caused mainly by imperfect performance of the up-mixer 111 and the down-mixer 113. Also, a major cause of LO leakage is imperfect performance of a local oscillator. Since elements of a direct conversion transceiver on a transmission or receiving path cannot perform ideally, DC offset is present in a baseband signal.
Calibration is required to minimize such related art problems as IQ mismatch. Usually, calibration is performed during the initialization of a transceiver device. A related art calibration process is described below with reference to the MIMO transceiver device 100 of FIG. 1.
Generally, calibration is divided into transmission calibration and receiving calibration. In the transmission calibration, after the first switch 116 and the second switch 114 are turned on and the third switch 115 is turned off, a test signal is transmitted to the up-mixer 111 through a baseband transmission port 117. The up-mixer 111 modulates the test signal to, for example, an RF signal having a high frequency of 5 GHz and outputs the RF signal. The RF signal is demodulated back to the baseband signal by the envelope detector 112 and output through a baseband receiving port 120. The baseband signal output from the baseband receiving port 120 is input to a DSP or a central processing unit (CPU). Based on the baseband signal, the DSP or the CPU carries out calibration of the transceiver device according to a predetermined calibration algorithm.
In the receiving calibration, after the second switch 114 and the third switch 115 are turned on and the first switch 116 is turned off, a test signal is transmitted to the up-mixer 111 through the baseband transmission port 117. The up-mixer 111 modulates the test signal to an RF signal having a high frequency and outputs the RF signal. The RF signal is down-converted back to the baseband signal by the down-mixer 113 and output through the baseband receiving port 120. As in the transmission calibration, the baseband signal output from the baseband receiving port 120 is input to the DSP or the CPU. Based on the baseband signal, the DSP or the CPU carries out calibration according to a predetermined calibration algorithm.
According to the related art, the up-mixer 111 on a transmission path is used in the receiving calibration. Thus, the transmission calibration must precede the receiving calibration. The same calibration process is performed on the second through nth transceivers 130 through 150.
For the calibration of the related art MIMO transceiver device 100, each of the first through nth transceivers 110 through 150 must include an envelope detector. Hence, when the transceiver device 100 is implemented in a single-chip structure, efficiency in the use of space cannot be achieved. In addition, in case of an asymmetric MIMO transceiver device which does not use one of a plurality of transmission paths, a transmission calibration must be performed, even on the non-used transmission path for a receiving calibration, thereby prolonging the overall calibration time.

Transceiver device capable of calibration and calibration method used by the same


A ring oscillator with differential delay stages employs an automatic gain control circuit producing a gain adjust signal that is responsive to a frequency control voltage applied to the ring oscillator. The effect of the frequency control voltage on the output voltage of the ring oscillator is counterbalanced by the gain adjust signal which prevents the output voltages of the delay stages from varying excessively over frequency. Further, the output stage of the ring oscillator includes shut off circuitry that allows the ring oscillator to be shut off in a non-oscillating mode in which it draws little current.

1. Field of the Invention
The invention pertains to oscillator circuits, and more specifically to a multi-stage differential ring oscillator with automatic gain controller and low frequency shut off.
2. Description of Related Art
Oscillators are used in a variety of integrated circuits to generate clocking signals. One type of well known oscillator design is a multi-stage differential ring oscillator. Such an oscillator is generally constructed of a plurality of delay cells, delay cell gain adjust circuitry, and an output stage.
There are a number of concerns for power sensitive designs for ring oscillators. These concerns include dynamic power consumption, static power consumption, and a range of operability. Affecting dynamic power consumption and range of operability is the gain control circuitry. Generally, delay cells have outputs whose amplitudes vary with operating frequency. Gain adjust circuitry is provided to the delay cells to counteract that variance. Over the operating range of the oscillator, the gain adjust circuitry ensures the output levels will not vary by an excessive amount. This permits both the wide range of operation and prevents high dynamic power consumption in a situation where the delay cells might drive their outputs to excessive levels.
Prior ring oscillator designs often employed fairly complex automatic gain control circuitry that tracked the output levels of either an actual delay cell or a "dummy" delay cell to provide gain control to keep the output level constant. This feedback approach, however, typically required an extra differential amplifier and other additional circuitry.
Static power consumption can be affected when the oscillator is turned off. Some designs permit excessive current drain due to low frequency oscillations, even when the oscillator is off.

Ring oscillator having automatic gain and low frequency shut off circuits


The present invention relates to methods for the preparation of an aerosol. More specifically the present invention provides methods for the preparation of an aerosol of immunoglobulin single variable domains wherein the amount of aggregate formation is significantly reduced. The invention further provides aerosols prepared by the methods of the invention, as well as compositions for use in the methods of the invention. The invention further relates to methods for the preparations of such compositions, to containers, kits and aerosol delivery systems comprising such compositions and to uses of the same.

Immunoglobulin single variable domains (as further described herein) are characterized by formation of the antigen binding site by a single variable domain, which does not require interaction with a further domain (e.g. in the form of VH/VL interaction) for antigen recognition. Immunoglobulin single variable domains against a wide range of different targets have been described (WO 04/062551, WO 05/044858, WO 06/040153, WO 06/122825, WO 07/104529, WO 08/020079, WO 08/074839, WO 08/071447, WO 08/074840, WO 08/074867, WO 08/077945, WO 08/101985, WO 08/142164, WO 09/068625, WO 08/142165, WO 09/068627) that could be candidates for drug development. Immunoglobulin single variable domains against the p19 subunit of IL-23 that block the interaction of IL-23 with its receptor have been described e.g. in WO 09/068627. Immunoglobulin single variable domains against the F protein of human Respiratory Syncytial Virus (hRSV) that can neutralize hRSV have been described e.g. in WO 09/147248.
Most immunoglobulin single variable domains in pre-clinical or clinical development have been administered parenterally (i.e. by intravenous or subcutaneous administration) and stable formulations for these administration methods have been described (see e.g. PCT application No. PCT/EP2010/062972 (filed 3 Sep. 2010) based on US provisional application No. U.S. 61/275,816 (filed 3 Sep. 2009) and PCT application No. PCT/EP2010/062975 (filed 3 Sep. 2010) based on US provisional application No. U.S. 61/284,502 filed by Ablynx N. V. on 18 Dec. 2009). These delivery methods, however, have a rather low patient acceptance and a need exists for alternative, more convenient (needle-free) modes of administration which can easily be performed by the patients themselves.
One possible alternative method is the delivery of the immunoglobulin single variable domain through the lungs. Pulmonary drug delivery can be achieved by inhalation, orally and/or nasally. Examples of pharmaceutical devices for pulmonary delivery include metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers. Traditionally, nebulizers have been classified into two main types: air-jet (pneumatic) and ultrasonic devices. Recently, a third type, vibrating-mesh nebulizers has been commercialized (Newman and Gee-Turner, 2005, J. Appl. Ther. Res. 5: 29-33).
The nebulizer is a logical first choice for development of a pharmaceutical protein-based drug for pulmonary delivery as most proteins are purified and stored as aqueous concentrate. However, the stability of aqueous solutions on the shelf may not translate to stability during nebulization and the protein may be denatured by several mechanisms including drying, shear and surface effects (Charm and Wong, 1970, Biotechnol. Bioeng 12: 1103-1109; Andrews, 1991, Biochem. Soc. Trans, 272S 19). It was shown, for example, that nebulization induced the loss of enzymatic activity of lactate dehydrogenase (LDH) and resulted in aggregation, which mainly consisted of dimer formation, and degradation of recombinant human granulocyte stimulating factor (G-CSF) (Niven and Brain, 1994, Int. J. Pharm., 104: 73-85).
WO 04/041867 describes methods and compositions for the pulmonary delivery of immunoglobulin single variables domain. In WO 09/074634, methods of direct pulmonary delivery of domain antibodies, and particular domain antibody compositions suitable for direct pulmonary delivery, are described. More specifically, compositions are described which comprise a domain antibody polypeptide and a buffer containing 2% to about 10% PEG1000 and 1.2% sucrose (w/v). These domain antibody compositions appear to have a viscosity that allows the production of sufficient droplets with the correct size for administration to a subject by direct local pulmonary delivery. None of the above documents describe or discuss the reduction of aggregate formation and/or the improvement of the stability during pulmonary delivery of immunoglobulin single variable domains. There remains a need for additional methods and compositions for the delivery of intact and functional immunoglobulin single variable domains by the pulmonary route.

Methods and compositions for the preparation of aerosols


There is provided a heat sink in which the thermal resistance from a portion where the heat sink directly or indirectly makes contact with a heat-generating device to a portion where the heat sink makes contact with a coolant is set to be a value that is different from the thermal resistance at a different position in the flowing direction of the coolant, so that it is made possible to suppress the temperature difference between the upstream end and the downstream end of the heat-generating device.

In recent years, the heat-generation densities of heat-generating devices such as a CPU (central processing unit), an LSI (large-scale integration), and a power semiconductor device have increased, and hence the temperatures thereof are liable to rise; thus, in some times, a liquid-type cooling apparatus whose cooling performance is higher than that of a conventional air-type cooling apparatus is utilized. In a liquid-type cooling apparatus in which a fin region provided with cooling fins is formed in an extended manner along the flowing direction of a coolant, the temperature of the coolant in the downstream region of the coolant is higher than that of the coolant in the upstream region, due to heat transferred from a heat-generating device disposed in the upstream region.
Accordingly, the temperature of a heat-generating device thermally connected with the coolant in the downstream region is higher than that of a heat-generating device thermally connected with the coolant in the upstream region; thus, a temperature difference occurs between the heat-generating devices. The occurrence of a temperature difference between heat-generating devices poses a problem that there occur variations in the lifetimes of the heat-generating devices or variations in the characteristics of the heat-generating devices; therefore, it is desired to contrive a method for preventing the occurrence of a temperature difference between the heat-generating device in the upstream region and the heat-generating device in the downstream region even when there occurs a temperature difference between the coolant in the upstream region and the coolant in the downstream region.
To date, there has been proposed a technology in which heat-generating devices are arranged in such away as to be in parallel with each other with respect to the flowing direction of a coolant so that the temperature difference between the heat-generating devices is cancelled (e.g., refer to Patent Document 1). In a liquid-type cooling apparatus in which a fin region is formed in an extended manner along the flowing direction of a coolant, the closer to the heat-generating surface a region is, the higher the temperature of the cross section perpendicular to the flowing direction of the coolant is, and the farther from the heat-generating surface the region is, the lower the temperature of the cross section perpendicular to the flowing direction of the coolant is. The heat radiation amount is proportional to the temperature difference between the heat-generating device and the coolant; thus, when a non-uniform temperature distribution occurs in the coolant and hence the temperature of the coolant in the region close to the heat-generating surface becomes high, the cooling performance is deteriorated.
In order to suppress the cooling performance from decreasing, it is required that the temperature distribution of a coolant is made uniform in a cross section perpendicular to the flowing direction of the coolant; in order to make the temperature distribution of the coolant uniform in the cross section perpendicular to the flowing direction of the coolant, the method of stirring the coolant sufficiently is effective. Therefore, to date, there have been proposed a liquid-type cooling apparatus (e.g., refer to Patent Document 2) in which fins are arranged on two surfaces that face each other in a coolant path so that the coolant is stirred and a liquid-type cooling apparatus (e.g., refer to Patent Document 3) in which depressions and protrusions for guiding a coolant are provided in the surfaces of comb-like heat radiation fins so that the coolant is stirred.

Liquid-type cooling apparatus and manufacturing method for heat radiation fin in liquid-type cooling apparatus


A computer system is provided. The computer system includes a memory, a network interface, and a processor coupled to the memory and the network interface. The processor is configured to receive a response to a request to verify whether an ostensible client of a service is actually a client or a bot, the response including an indicator of whether the ostensible client is a client or a bot; receive information descriptive of interoperations between the ostensible client and the service that are indicative of whether the ostensible client is a client or a bot; and train a plurality of machine learning classifiers using the information and the indicator to generate a next generation of the plurality of machine learning classifiers.

Anomaly detection processes identify samples within a population that possess attributes that depart significantly from the norm. Anomaly detection processes can employ any of a variety of specialized heuristic, statistical, or machine learning approaches to identify aberrant samples. Each of these approaches has benefits and disadvantages. For instance, heuristic approaches are often easy to implement and computationally efficient but can be inaccurate or imprecise. Statistical approaches can be precise, accurate, and computationally efficient but require an understanding of the underlying distribution a priori to be effective. Machine learning approaches can also be precise, accurate, and computationally efficient (once trained) but require computationally complex training on large sets of data. Anomaly detection processes can be useful in a variety of applications, such as fraud, fault, and intrusion detection, among others.


A method of concentrating energy to produce large velocity, high pressure and/or high temperature conditions, including the steps of forming a resonant cavity inside a container; filling the resonant cavity with a liquid having a compressibility that is smaller than that of water at room temperature; coupling energy into the resonant cavity at a frequency which drives the resonant cavity at or near a resonant mode thereby creating one or more velocity nodes in the resonant cavity; and capturing a quantity of material or mixture of material in the resonant cavity at one of the velocity nodes.

This invention generally relates to a technique which is used to produce cavitation and/or sonoluminescence in liquids.
It is well known that high velocity motion in a liquid can cause cavitation, or bubbles in the liquid. Many diverse mechanisms, e.g. propellers in water or ultrasonic sound waves, have been observed to cause such cavitation. Ultrasonic sound waves can produce not only cavitation but also a phenomenon known as sonoluminescence, which is the emission of light from the gas in cavitation bubbles.
In 1990, a paper was published by F. Gaitan and L. Crum, (see "Sonoluminescence from Single Bubbles" T. Acoust. Soc. AM. Suppl. 1, 87, 3141 (1990)) in which they reported that it is possible to capture a single small bubble of gas in the interior of a volume of water in which there existed a standing sound wave. This volume of water was excited at its fundamental vibrational mode. The bubble trapped in the center of the volume of liquid was shown to emit light. This phenomena goes by the name of "Single Bubble Sonoluminescence." Since that time, much experimental and theoretical work has been done on single bubble sonoluminescence, and there is now an extensive literature on the subject.
The following are representative of the papers that have been written and they contain extensive references to other earlier published work:
"Synchronous Picosecond Sonoluminescence," Ph.D, Dissertation of Bradley Paul Barber, UCLA Physics Department, Los Angeles, Calif. (1992)
"Sensitivity of Sonoluminescence to Experimental Parameters," B. P. Barber, C. C. Wu, R. Lofstedt, P. H. Roberts, and S. J. Putterman, Physical Review Letters, Volume 72, Number 9, Feb. 28, 1994, pages 1380-1383
"A Model of Sonoluminescence," C. C. Wu and P. H. Roberts, Proceedings of the Royal Society of London, A (1994) 445, pages 323-349
"Sonoluminescence," L. A. Crum and R. A. Roy, Science, Volume 266, Oct. 14, 1994, pages 233-234
"Effect of Noble Gas Doping in Single-Bubble Sonoluminescence," R. Hiller, K. Weninger, S. J. Putterman and B. P. Barber, Science, Volume 266, Oct. 14, 1994, pages 248-250
The above-referenced articles and the references cited therein all describe similar technologies. In general, the technology typically involves using a resonant container filled with water as the central component. Then, using a well known acoustical technique, a transducer is attached or glued to the surface of the container to drive the container at its resonant frequency. Various techniques are disclosed for injecting a gas bubble into the water including using a stirring rod, shooting a stream of air into the water using a hypodermic needle, and passing a current through a wire that is immersed in the water.
Researchers have tried to increase the temperatures and pressures that are obtainable with the trapped bubbles that exhibit sonoluminescence. The focus in some of these efforts has been on reducing the amount of dissolved gases in the liquid. For example, the above article entitled "Effect of Noble Gas Doping in Single-Bubble Sonoluminescence" by Hiller et al., who have looked in achieving sonoluminescence in nonaqueous fluids such as alcohol and silicon oil, states the following:
In nonaqueous fluids, we have been able to trap (nonlight emitting) air bubbles with sound, but at high drive levels, these systems have resisted our attempts to observe the transition to SL [sonoluminescence-ed.]. We propose that this difficulty is related to the unusually low solubility of gases in water (6), or equivalently to the fact that air is far more soluble in nonaqueous fluids such as alcohol and silicon oil.
Similarly, in another reference, namely the above-identified Ph.D. Dissertation entitled "Synchronous Picosecond Sonoluminescence", B. P. Barber notes that in order to obtain sonoluminescence in water it was first necessary to completely de-gas the water.
Some authors have also recognized that single-bubble sonoluminescence might be applicable to inertial confinement fusion. For example, in the above-referenced article entitled "Sensitivity of Sonoluminescence to Experimental Parameters", the authors write:
Assuming that these estimates would apply for a gas bubble which contains a mixture of deuterium and tritium, and that they remain physically valid at such minute length and time scales, the repetitive SL implosions generate about 1 n/s in such a mixture. Changes in the equation of state that these temperatures would bring about have also been ignored in making these estimates.
The neutron emission, N. was obtained from the standard formula [15] . . . . This computation yields about 40 n/s, but the results are very sensitive to the launch conditions, in part because a depends strongly on the conditions in a Van der Waals gas [16]."
This article calculates the fusion rate on the basis of an equilibrium temperature. As can be seen from the above quotation, this calculation yields a value for the neutron flux many orders of magnitude below any useful value for the generation of heat.

Method and apparatus for generating large velocity, high pressure, and high temperature conditions