The present invention relates to a method for forecasting health status of a distributed network by an artificial neural network comprising the phase of identifying one or more sites, one or more assets of the sides and the links between the identified assets in said distributed network, comprising the phase of evaluating the actual health status of each of the identified assets, the phase of evaluating the actual health status of each of said identified sites and the phase of forecasting, by the artificial neural network, the subsequent health status of each of the identified sites according to a forecasting function based on a set of values comprising the actual asset health status rank, the actual asset infection risk, the actual asset infection factor, the actual site health status rank and the actual site infection risk.

A site represents a physical location where a certain amount of network-reachable assets is located.
An asset is a physical (or virtual, as for example a Virtual Machine) network-enabled equipment that is physically connected inside the network of a site. An asset can be a computer, a tablet, a printer, or any other kind of device able to communicate in a TCP/IP or a like network.
Moreover, an asset can communicate or have the possibility to communicate with other assets. In this case, they have a common link which models the fact that an asset can communicate with another asset over the network with some protocol. Computer networks can have several components in between assets and different equipment types (routers, firewalls, application firewalls, etc.) exist that can inhibit all or some protocols between two assets. For this reason, a link needs to have a "from" and a "to" asset, and a protocol.
Due to the nature of networking software, one or more vulnerabilities can affect the one or more assets and, as such, are commonly subject to attacks that undermine their security.
In the cyber security world, it is common to evaluate the security posture of a given asset or system in a static way, by looking at its current health, vulnerabilities, and security measures put in place to prevent various kinds of disruption.
A complex way of evaluating the vulnerability of a system is to evaluate the entire system, as well as each asset, with a scoring system of the CVSS type consisting of three metric groups: Base, Temporal, and Environmental. The Base group represents the intrinsic qualities of a vulnerability that are constant over time and across user environments, the Temporal group reflects the characteristics of a vulnerability that change over time, and the Environmental group represents the characteristics of a vulnerability that are unique to a user's environment. Summing up, the Base metric produces a score, which can then be modified by scoring the Temporal and Environmental metrics.
Anyway, analyzing such aspects in isolation and with a static approach can give a false perception of reality and can bring to incorrect conclusion.
It would therefore be desirable to have a method capable for forecasting health status of a site in a distributed network. Furthermore, it would be desirable to have a method capable to better predict how risk can impact the health status of the system by analyzing holistically the evolution of the system over time. Finally, it would be desirable to have a method capable preventing anomalous health statuses connected to changes in assets vulnerability.
Likewise, it would be desirable to have an apparatus capable to better predict how risk can impact the health status of the system by analyzing holistically the evolution of the system over time.

Method for forecasting health status of distributed networks by artificial neural networks


Phytoremediation processes, methods, materials and compositions to remediate soil, sediment and groundwater that is contaminated by per- and polyfluoroalkyl substances (PFAS) via phytoextraction which includes the uptake and translocation of contaminants in the contaminated media by plant roots into the above ground portions of the plants. The plants can be selected from sixteen plants as well as other plants and the invention can include managing soil salinity levels of the plants, manipulating amounts of organic matter in the contaminated site media, managing pH levels of the contaminated sites, utilizing double cropping systems, utilizing double-canopy system, and managing harvest methodology of the plants.

PFAS are a large group of synthetic compounds that have been broadly used to make various products more resistant to stains, grease, and water since the 1940s and there is mounting evidence that exposure above specific levels to certain PFAS leads to adverse health effects. Examples of products with which PFAS have been used extensively include nonstick cookware, stain resistant textiles, and waterproof clothing. They have also been used in many food packaging and firefighting materials. Because they help reduce friction, they are also used in a variety of other industries, including aerospace, automotive, building and construction, and electronics. PFAS are known to break down slowly in the environment and are characterized as persistent. Due to their pervasive use and persistence, there is widespread human exposure to PFAS including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS).
There is a need for a viable and cost-effective phytoremediation cleanup methodology to address PFAS impacted soil, sediments, and groundwater. The methodology would be all the more desirable if it met core elements outlined in the American Society of Testing Materials (ASTM) E2893 Standard Guide for Greener Cleanups that include minimizing greenhouse gas emissions, air pollutants, use of materials, generation of waste, disturbance to land and ecosystems, and noise and light disturbance.
Current approaches to cleanup of impacted soil and sediment consists of expensive and energy consumptive excavation and removal.
In November 2016 the US EPA issued health advisories for PFOA and PFOS, based on the agency's assessment of the latest peer-reviewed science, to provide drinking water system operators, and state, tribal, and local officials who have the primary responsibility for overseeing these systems, with information on the health risks of these chemicals. With the issuance of these advisories greater focus has been brought to assessing the fate and potential remediation of PFAS in the environment. In February 2019, EPA issued a PFAS Action Plan to further understand and reduce PFAS risks to the public. The Action Plan describes EPA's approaches to addressing current PFAS contamination and specifically includes steps to propose designating PFOA and PFOS as "hazardous substances". In addition, the plan includes developing toxicity values for perfluorobutane sulfonic acid (PFBS) and developing guidance for cleanup actions where groundwater is contaminated with PFOA and PFOS.
Studies have indicated that PFAS accumulates in plants where it is found in the soil. However, these studies have not addressed processes, methods, materials and/or compositions to effectuate greater plant uptake for the purpose of phytoremediation.
Prospects of a phytoremediation approach for cleaning up PFAS-impacted soil and sediments were evaluated in a recent study from European researchers who found various plants species to be promising candidates for phytoremediation of PFAS (Gobelius, L., J. Lewis, and I. Ahrens, 2017. Plant Uptake of Per- and Polyfluoroalkyl Substances at a Contaminated Fire Training Facility to Evaluate the Phytoremediation Potential of Various Plant Species. Environ. Sci. Technol. 2017, 51, 12602-12610). This research consisted of a survey of plants present at a site known to be contaminated by PFAS.
Other related research has investigated the presence of PFAS in agricultural crops, largely to assess potential threats posed by PFAS in food supplies. These studies showed agricultural crop plants accumulating PFAS compounds in both root and above-ground tissue at low levels (Navarro et al 2017, Ghisi et al. 2018). The amount of accumulation depends on a variety of factors including plant species (Navarro et al. 2017, Ghisi et al. 2018), PFAS group and chain length (Blaine et al. 2014, Ghisi et al. 2018), water or soil concentration (Blaine et al. 2014, Ghisi et al. 2018), organic carbon content of the soil (Blaine et al. 2014), salinity and pH (Zhao et al. 2013). More recently, Zhang et al. (2019) reported on the uptake and accumulation of seven PFAS compounds by the wetland species Juncus effuses. They reported removal efficiencies from solution as high as 11.4% for spiked PFAS, but reported little translocation to above-ground components of the plant.
These previous studies differ from the invention presented herein because our invention focused on maximizing above-ground plant accumulation and was developed via a replicated statistically-based randomized block design study within an environmentally controlled greenhouse that produced and demonstrated repeatable results forming the basis of our phytoremediation processes, methods, materials and compositions which remediate soil, sediment, and groundwater contaminated by per- and polyfluoroalkyl substances (PFAS) via phytoextraction.

This patent is subject to a terminal disclaimer.

Perfluoroalkyl substances (PFAS) phytoremediation by manipulating soil properties and plant management


A system and method for converting code associated with synchronous method calls to code that can be employed to perform asynchronous method calls and for supporting such asynchronous method calls is provided. The system includes a pattern generator that can break code for a synchronous method call into one or more constituent parts including a begin asynchronous operation method, an end asynchronous operation method, an asynchronous call state object and an asynchronous call result object. The system includes a pattern data store that holds data associated with converting a synchronous method call to an asynchronous method call, which facilitates employing the system consistently across environments like file input/output, stream input/output, socket input/output, networking, remoting channels, proxies, web forms, web services and messaging message queues.

Conventional synchronous method calls, where the caller blocks until the completion of processing performed by the callee, may provide unsatisfactory results in some calling situations. By way of illustration, if the callee takes a long time to complete, the caller may be blocked for an unacceptable period of time waiting for the callee to return. Thus, resources (e.g., memory, processor cycles) associated with a blocked caller thread may be unavailable for other threads, reducing system performance. By way of further illustration, if the caller desires to make multiple calls to one or more callees, where, from the caller's point of view, such calls can be performed substantially in parallel, conventional synchronous method calling techniques may generate an unwanted, substantially serial performance.
Conventionally, synchronous calls can cause a thread to block. Threads are computationally and memory expensive. Therefore, having threads blocked can negatively impact system performance. It would be preferable to allow threads to enter a state (e.g., run to completion) where the resource can be freed, and thus reallocated, rather than being consumed by a blocked thread.
Due, at least in part, to undesired blocking, undesired resource consumption and undesired serial performance results from synchronous method calling a number of asynchronous method calling techniques have developed. Such asynchronous techniques are, in general, narrowly tailored to provide asynchronous calling capability for a specific programmatic situation. Such diverse, individually tailored asynchronous method calling techniques do not, in general, provide an efficient model to deal with asynchronous operations via a consistent programming model. Furthermore, objects employing such individually tailored asynchronous method calling techniques may require reprogramming to support asynchronous behavior. Such reprogramming may not be possible for existing objects, and thus it may be difficult, or impossible, to add asynchronous behavior to such existing objects.


A ceramic conductor is supported by an electrically insulative support member for attachment directly to a marine propulsion drive and for use as either an anode or electrode in a corrosion prevention system. The ceramic conductor is received within a depression formed in a surface of the electrically insulative support member and the exposed surface of the ceramic conductor can be offset from or coplanar with an exposed surface of the electrically insulative support member. The ceramic conductor can comprise oxides of iridium, tantalum and titanium that are formed as a coating on a titanium substrate.

1. Field of the Invention
The present invention is generally related to ceramic conductors and, more particularly, to a ceramic conductor used as an electrode in a marine cathodic protection system used to inhibit the formation of a galvanic circuit incorporating a marine drive housing and propeller.
2. Description of the Related Art
Those skilled in the art of marine propulsion systems are well aware that the use of dissimilar metals in an underwater environment can lead to the creation of a galvanic circuit with currents flowing between the dissimilar metals. As a result, the combination of a stainless steel propeller with an aluminum housing of a marine propulsion device can result in the disintegration of the aluminum housing, particularly when the marine propulsion device is used in a saltwater environment. This deleterious situation can also damage aluminum propellers when they are used in combination with steel propeller shafts and other materials having a lower electrical potential than the aluminum. This problem has been countered in the past through the use of sacrificial anodes and systems which affect the electric potential in the area around submerged materials to inhibit the galvanic circuit from forming.
U.S. Pat. No. 3,853,730, which issued to Anderson on Dec. 10, 1974, discloses a reference electrode. A marine cathodic protection device for aluminum hulls, sterndrives and outboard motors, adapted for hull installation on the bottom of a boat is described. Housings utilizing airfoil cross-section reduce drag and afford protection for the electrode surfaces.
U.S. Pat. No. 4,322,633, which issued to Staerzl on Mar. 30, 1982, discloses a marine cathodic protection system. The system maintains a submerged portion of a marine drive unit at a selected potential to reduce or eliminate corrosion thereto. An anode is energized to maintain the drive unit at a preselected constant potential in response to the sensed potential at a closely located reference electrode during normal operations. Excessive current to the anode is sensed to provide a maximum current limitation. An integrated circuit employs a highly regulated voltage source to establish precise control of the anode energization.
U.S. Pat. No. 4,357,226, which issued to Alder on Nov. 2, 1982, describes an anode of dimensionally stable oxide-ceramic individual elements. The anode consists of a plurality of individual oxide-ceramic elements of stable dimensions. The individual elements have linear cross-sectional dimensions of 2-12 centimeters on the current exit surface. These elements have a length which corresponds to 2-20 times the value of the mean linear cross-sectional dimension.
U.S. Pat. No. 4,391,567, which issued to Ciampolillo on Jul. 5, 1983, describes a corrosion preventing device for a marine propeller. It is intended for mounting in sea water on an electrically conductive propeller shaft supporting a marine propeller composed of a metal having a first galvanic potential. The propeller is fastened to the shaft by an electrically conductive propeller nut and is in electrical contact therewith. The device includes an annular washer having a generally circular periphery, composed of a metal having a second galvanic potential not greater than the first galvanic potential, with a central hole concentric with the circular axis thereof through which the shaft may fit to enable an electrical conductive mounting proximate to the propeller nut, for serving as an electrolytic cathode of the device.
U.S. Pat. No. 4,445,989, which issued to Kumar et al. on May 1, 1984, describes ceramic anodes for corrosion protection. An anode is described which is useful in corrosion protection comprising a metallic substrate having an applied layer thereon of a ferrite or a chromite, the layer having metallic electronic conductivity and a thickness of at least 10 mils.
U.S. Pat. No. 4,492,877, which issued to Staerzl on Jan. 8, 1985, discloses an electrode apparatus for cathodic protection. The apparatus is provided for mounting an anode and reference electrode of a cathodic protection system on an outboard drive unit. The apparatus includes an insulating housing on which the anode and reference electrode are mounted and a copper shield mounted below the anode and electrode to allow them to be mounted in close proximity to each other. The shield is electrically connected to the device to be protected and serves to match the electrical field potential at the reference electrode to that of a point on the outboard drive unit remote from the housing.
U.S. Pat. No. 4,528,460, which issued to Staerzl on Jul. 9, 1985, discloses a cathodic protection controller. The system for cathodically protecting an outboard drive unit from corrosion includes an anode and a reference electrode mounted on the drive unit. Current supply to the anode is controlled by a transistor, which in turn is controlled by an amplifier. The amplifier is biased to maintain a relatively constant potential on the drive unit when operated in either fresh or salt water.
U.S. Pat. No. 4,549,949, which issued to Guinn on Oct. 29, 1985, describes a marine propulsion device including cathodic protection. The lower unit of the device includes a housing having a lower portion submerged in water and defining an internal passage communicating with the water. Corrosion protection for both internal and external parts of the lower unit is provided by a sacrificial, galvanic-type anode mounted on the submerged portion of the housing and including a first or outer portion having a surface exposed to water external to the lower unit and a second or inner portion having a surface exposed to water present in the passageway.
U.S. Pat. No. 5,011,583, which issued to Tanbara on Apr. 30, 1991, describes a corrosion prevention system for a marine propulsion system. The system has a sacrificial anode for corrosion protection of the casing and includes structure whereby the propeller is electrically insulated from the casing and the sacrificial anode. The structure includes spacers made of insulating materials, spacers having insulating coatings, or insulating coatings on the surfaces of the propeller or the propeller shaft.
U.S. Pat. No. 5,298,794, which issued to Kuragaki on Mar. 29, 1994, describes an electrical anti-corrosion device for a marine propulsion device. It relates to an electrical anti-corrosion device for a marine propulsion arrangement. More particularly, the device relates to a cathodic protection arrangement which is suitable for use with an inboard/outboard propulsion unit. According to the invention, an anode and a reference electrode are housed within a housing unit which is mounted upon a propulsion unit mounting bracket. The two electrodes are arranged so that each is essentially equidistant from a point located approximately midway across the lateral width of an outboard drive unit.
U.S. Pat. No. 5,306,408, which issued to Treglio on Apr. 26, 1994, describes a method and apparatus for direct arc plasma deposition of ceramic coatings. High temperature resistant, electrically conductive ceramic compounds, such as titanium carbides and diborides, are coated onto an organic substrate. The substrate may be an organic resin matrix composite. The apparatus basically comprises a vacuum arc plasma generator, a high voltage insulated substrate holding table and a plasma channel. The plasma generator includes a vacuum chamber having a cylindrical cathode of the material to be deposited, surrounded by a ceramic insulator which is in turn surrounded by a metal trigger ring in contact with a trigger electrode.
U.S. Pat. No. 5,330,826, which issued to Taylor et al. on Jul. 19, 1994, describes a preparation of ceramic-metal coatings. A metal substrate (e.g. titanium having a calcium phosphate coating, particularly hydroxylapatite) and containing a metal such as cobalt, codeposited on the substrate by electrolyzing a cobalt salt, particularly cobalt sulfate, liquid electrolyte having a calcium phosphate material, particularly hydroxylapatite, suspended therein, employing a cobalt anode and the metal substrate as cathode is described. The particles of cobalt so codeposited with the particles of calcium phosphate material (e.g. hydroxylapatite) hold the latter particles strongly on the substrate metal. If desired, a second coating of the pure calcium, phosphate material (e.g. hydroxylapatite) optionally can be applied over the codeposited hydroxylapatite-cobalt coating. The calcium phosphate coated metal substrate of the invention, particularly the codeposited hydroxylapatite-cobalt coating, on a titanium or cobalt-chromium substrate, has particular value for application as medical implants (e.g. as hip prosthetics) and for high temperature high stressed applications.
U.S. Pat. No. 6,511,586, which issued to Nakashima et al. on Jan. 28, 2003, describes a marine organism prevention system for structures in seawater. An antifouling system for a structure exposed to seawater has an anode forming apparatus bonded to the seawater-exposed surface to be wetted with seawater of the structure via an insulating adhesive. The anode forming member is coated with an electrical catalyst film of an electrochemically active and stable electrical catalyst. A conductive member is disposed so as to be wetted with seawater. An external DC power supply has a positive terminal connected to the anode forming member and a negative terminal connected to the conductive member.
U.S. Pat. No. 7,044,075, which issued to Sica et al. on May 16, 2006, describes a marine vessel corrosion control system. The system contemplates redundant protection for a marine vessel against the effects of galvanic corrosion. The vessel is equipped with typical zinc anodes interconnected together and attached to metallic components to be protected from galvanic corrosion. A reference electrode immersed in the water provides signals to a control box representative of electrode voltage as compared to an internal stabilized voltage standard.
U.S. Pat. No. 7,064,459, which issued to Staerzl on Jun. 20, 2006, discloses a method of inhibiting corrosion of a component of a marine vessel. The method impresses an electronic current into the protected component and causes the protected component to act as a cathode in a galvanic circuit which comprises a conductor, such as a ground wire connected between the protected component and an electrical conductor which is external to the marine vessel on which the protective component is attached. The electrical conductor can be a ground wire of an electrical power cable connected between the marine vessel and the shore ground. The sea bed is caused to act as an anode in the galvanic circuit, with varying voltage potentials existing within the water between the sea bed and the protected component. The system can be a closed loop control circuit using a voltage sensed by an electrode, or an open looped circuit that provides current pulses based on empirical data.
The patents described above are hereby expressly incorporated by reference in the description of the present invention.
In corrosion protection systems that do not use a sacrificial anode, certain materials are preferred for use as an anode or electrode. These materials are selected to have a very low galvanic potential in order to prevent them from being sacrificed during normal use. In other words, unlike sacrificial anodes, the intent of this type of anode circuit is to be useful as a conductor in an electrical protective for a long period of time without requiring replacement. Typically, titanium or platinum is used as the anode in these types of systems. Since platinum is relatively expensive, a very small anode is typically used and it normally comprises a very thin layer of platinum deposited on a less expensive substrate. However, the surface of this anode must be submerged in the general vicinity of the marine drive that is being protected. As such, it is potentially subject to contact with various items, such as debris. As such, it is subject to damage. It would therefore be significantly beneficial if a non-sacrificial anode or electrode could be provided which is robust and not normally subject to damage if subjected to impact.

Cathodic protection system for a marine propulsion device with a ceramic conductor


An optical, multi-channel, Differential Phase Shift Keying (DPSK) receiver demodulates multiple Wavelength Division Multiplexed (WDM) channels using at least one interferometer. This distributes expense of the interferometer(s) over all channels of an optical signal, allowing for deployment of cost-effective, scalable, wideband, WDM DPSK systems. For example, for an 80 channel WDM link, the receiver uses a single interferometer instead of eighty interferometers and associated stabilization hardware, dramatically reducing size, weight, power, and cost. The receiver is architecturally compatible with existing interferometer technologies so previous development and qualification efforts can be leveraged. This allows for expedited technology insertion into existing optical communications networks, including terrestrial and space-based optical networks.

Recently, optical Differential Phase Shift Keying (DPSK) modulation has received considerable attention by the telecommunications industry primarily due to its increased sensitivity over commonly used On-Off-Keying (OOK) and its reduced peak power, which mitigates nonlinear effects in fiber-optic applications. This has led to demonstrated utility in long haul applications, with experiments confirming more than 3 Tb/s capacity using 80 Wavelength Division Multiplexed (WDM) DPSK channels. It is expected that the first wideband telecommunications fiber optic links using WDM DPSK will be deployed by 2006. DPSK is also an attractive modulation format for high-rate spectrally efficient Free Space Optical (FSO) links because the increase in sensitivity over OOK allows for a corresponding reduction in costly transmitter power.
DPSK conveys information by encoding a relative phase difference between two optical bits. Differential encoding simplifies the receiver by eliminating the need for a stable absolute phase reference that is required for coherent homodyne Phase Shift Keyed (PSK) modulation. Instead of mixing the received signal with a local oscillator phase reference to determine its phase, DPSK mixes the incoming signal with a delayed version of itself. Consequently the DPSK receiver is often referred to as a "self-homodyne" receiver.

Multi-channel differentially encoded phase shift keyed receivers


An electronic apparatus has a first housing, a second housing, and speakers. The first housing and second housing are so coupled as to be movable between a first position away from each other and a second position in which one of them is laid on the other. The speaker is provided in the first housing. A first opening is situated at a place covered over the second housing when it is in the second position and corresponding to the speaker. A second opening is located on the second housing at a place corresponding to the first opening when the second housing is in the second position. A third opening is provided in the second housing situated on the outer side at the second position and communicates with the second opening.

1. Field of the Invention
The present invention relates to an electronic apparatus, such as a portable computer, having a speaker in its body to allow the user to enjoy a TV sound and a played-back sound from a compact disk.
2. Description of the Related Art
An electronic apparatus, such as a portable computer, equipped with a speaker in its body has been popularized and it allows the user to enjoy a TV sound and a played-back sound from the data of a compact disk. The portable computer comprises a body having a keyboard and a display panel having an LCD unit. The speaker is built in a somewhat upper portion of the body. The body and LCD (Liquid Crystal Display) unit are coupled to each other by hinges to provide a foldable unit. The portable computer is convenient to carry, wholly thinner in thickness and lighter in weight. Various kinds of electronic components within the body are closely arranged and the speaker is arranged at a limited space.
For example, JPN PAT APPLN KOKAI PUBLICATION NO. 10-78831 discloses a portable computer in which a speaker is arranged in the inner side of a hinge section by which a display panel is foldably coupled to a body and a sound output hole is provided in a cover with which the speaker is covered.
JPN PAT APPLN KOKAI PUBLICATION No. 2001-100862 discloses a portable computer in which a continuous opening from the upper surface to a side surface of the body is provided in an offset position at the right and left end side portions of the upper surface of a body in the vicinity of a corresponding hinge and a speaker outputs sound from the upper and side portions of the opening.
Further, JPN PAT APPLN KOKAI PUBLICATION No. 2002-182784 discloses a portable computer in which a speaker is provided in an inner portion of a top cover which covers a hinge portion of a body. Many speaker holes are provided in a circular arc surface of the top cover. Sound is output past the speaker holes.
Even in any portable computer disclosed in these KOKAI PUBLICATIONs, the body and display panel are foldably coupled together by the hinges. The sound output section in any case is exposed with the display panel opened or closed relative to the body. The user can enjoy a TV sound, or a played-back sound from the sound data of the compact disk, on these portable computers.
According to JPN PAT APPLN KOKAI PUBLICATION No. 10-78831, a speaker is provided in the inner side of a hinge section. If, in this case, an area of a sound output section is made greater, then a hinge portion is greater. If the hinge portion becomes greater, then a cutout in the display panel becomes greater so as to prevent any hinge portion. As a result, the LCD unit is arranged away from the hinge portion.
According to JPN PAT APPLN KOKAI PUBLICATION No. 2001-100862, the speaker is so arranged as to generate sound from upper and side surface sides of the body. However, with the display panel closed, the top surface is covered with the display panel and sound is output from the side portion only and no adequate sound effect is ensured with the display panel closed.
According to JPN PAT APPLN KOKAI PUBLICATION No. 2002-182784, the speaker is provided in the inner portion of the top cover with which a hinge portion of the body is covered. As a result, the top cover is greater in size. Since the top cover is expose with the display panel closed in particular, the body and display panel become greater, thus presenting a problem.


A boiler-equipped absorption heat pump unit in which a regenerator, a boiler, and other high-temperature devices are separated from an evaporator, an absorber, and other low-temperature devices are separated by an insulated dividing wall. The dividing wall reduces heat loss by impeding the transfer of heat from the high-temperature devices to the low-temperature devices.

An absorption heat pump equipped with a boiler for reheating hot water is known from, for example, U.K. Patent No. 1519522.
As disclosed in U.K. Patent No. 1519522, the heat pump comprises: an evaporator for absorbing heat from an external source to evaporate a refrigerant; a compressor for pressurizing the refrigerant, the compressor being connected to the evaporator; a condenser for releasing the heat of the refrigerant to the exterior, the condenser being connected to the compressor; an expansion valve connected between the condenser and the evaporator; and a water supply tube for recovering the heat released to the exterior, the water supply tube being connected to the condenser.
A boiler for reheating hot water as necessary is provided to the water supply tube connected to the condenser. Hot water that has passed through the heat pump is heated by the boiler as necessary, and the heated hot water is used to heat a room or as a hot water source.
However, U.K. Patent 1519522 does not describe the relative positional relationship between devices when devices constituting a heat pump and devices including a boiler are placed inside a case. Additionally, the heat pump is a compression heat pump.
In view of the greater demand to conserve energy in heat pumps and the objective of reducing energy consumption, consideration is being given to the use of absorption heat pumps, in which the amount of energy consumed can be suppressed in comparison with compression heat pumps.

Absorption heat pump with a thermally insulating dividing wall


An optical code reading system and method are provided for reading optical codes imprinted or displayed on, or behind, reflective surfaces. The system includes an extended light source, including one of a backlight assembly and a frontlight assembly, emitting an extended-beam light for directly illuminating an optical code, at least one image sensor for sensing light reflected by the optical code and generating signals related to at least one image of the optical code, and at least one processor for processing at least a portion of the signals, generating a decodable image corresponding to the signals, and decoding at least a portion of the decodable image.

1. Field of the Invention
This invention relates to illuminating and reading optical codes using optical code reading devices. In particular, this invention relates to a system and method for illuminating and reading optical codes imprinted or displayed on reflective surfaces.
2. Description of the Prior Art
As industry has continued to refine and improve production techniques and procedures, corresponding requirements have been levied for placing identifying data related markings upon components of manufactured assemblies. These markings enable tracking of, for example, the historical stages of a product's manufacture. Further, these markings enable components of complex machinery, such as automobiles and the like, to be identified, for example, in the course of an investigation by quality control personnel or governmental authorities.
A variety of product marking approaches has been utilized in industry. For example, paper tags or labels carrying UPC codes are typically applied to components in the course of a product's assembly. This method provides identifying codes that are highly readable by prior art optical code readers. However, for many applications, such tags or labels may be lost, damaged or altered—rendering the coding useless. This shortcoming is well addressed by Direct Part Marking (DPM) and consequently DPM has gained widespread acceptance in industrial applications by providing durable markings, or code symbols, capable of being placed directly on a wide range of surfaces.
DPM is the technique of directly imprinting, etching or dot-peening (indentation marking) product and component surfaces with any of a number of symbologies—particularly high-density 2-D code symbologies, such as Data Matrix and QR Code, but even commonly used UPC codes are produced in this manner. However, as a result of being formed directly onto a wide variety of materials and textures, proper reading (and subsequently decoding) of DPM codes poses a challenge. Readability of DPM codes is typically a function of contrast between the code symbol and the background surface. The DPM method does not typically provide for the selection of background color or foreground color or reflectivity of the symbol markings, especially in the case of etching and dot-peening. Therefore, DPM markings often have low and inconsistent contrast, typically resulting in limited code readability.
Additionally, applications exist for displaying optical codes on screens, such as CRT or LCD displays, such as a cell phone display. For example, a consumer transaction may be performed using a cell phone where a consumer uses the cell phone to purchase a ticket, such as an event ticket or a lottery ticket, including making payment via the cell phone and receiving the purchased ticket as an electronic ticket through the cell phone in the form of a message bearing a barcode which is displayable by the cell phone. Upon redemption of the ticket, the electronic ticket's barcode displayed on the cell phone is scanned by the merchant redeeming the ticket.
Generally, prior art optical code scanners are designed for scanning paper-based optical codes. Optical codes, such as UPC symbols, printed on labels provide high contrast through selection of background and foreground colors—usually black geometrical shapes or foreground on a white background. Furthermore, paper's superb omni-directional scattering property covers up much of the traces of the structure in the light source.
However, many objects marked with a DPM code and display screens (e.g., mobile phone, CRT, LCD, plasma, etc., displays) displaying barcodes may have surfaces of entirely different characteristics. In some cases, a smooth surface may form a reflected image of the light source and cause the optical code symbol to appear washed-out or even indiscernible from its surroundings; in such circumstances, an extended light source, providing a large and uniform emission surface, would be desirable. Further, the precise angle of the originating light source, with respect to the DPM markings, needs to be controlled in order for variations in surface texture created by the marking method to reflect the light with different intensities. Surface background conditions that are reflective, or yield very little visible symbol contrast to the naked eye under general room lighting, can become highly visible when illuminated by a light source at a given angle from the surface. In such circumstances, directional (or direct-point) illumination is desirable.
One commercially available prior art DPM scanner (see Prior Art FIG. 1a) provides an extended light source and covers multiple angles. This prior art scanner is equipped with a lens 100 positioned in an optical path between an optical code (not shown) and an image sensor 105. The optical code is illuminated by a set of LEDs 101 situated behind a diffusing plate 102. The diffusing plate 102 transmits the light produced by the LEDs 101 as diffuse illumination instead of direct illumination. Additionally, a diffusing tube 103 prevents ambient light from illuminating the optical code, thus the only illumination applied to the optical code originates from the diffusing plate 102. Baffles 104, configured to prevent stray light from escaping the diffusing plate 102 directly into an aperture 120, are positioned around the aperture 120 leading to the lens 100.
However, this system has two limitations of particular interest with respect to the present invention. First, this system is relatively large, making the scanner cumbersome and generally unsuitable for integration with handheld computing devices. Second, the translucent diffusing plate used by this system has to be relatively thick to be effective for providing a large and uniform emission surface. The overly thick diffusing plate, however, is inefficient for transmitting light, and consequently requires more powerful illumination than would be necessary with by a light source.
In other instances, DPM images obtained using direct point light sources, or alternatively narrow beam light sources, produce better contrast, especially for DPM marks made using dot-peening methods—the method of repeatedly impacting the part surface with a sharp tool, thus, forming indentations on the surface. The indentations tend to reflect light at angles substantially similar to the incident angles of the illumination source. Another commercially available DPM scanner (shown in Prior Art FIG. 1b) combines the extended light source method described above and illustrated in FIG. 1a with a direct point light source method. The scanner depicted in FIG. 1b is equipped with a first and second set of LEDs 107. The first set of LEDs 107 is positioned close to the lens 106 for providing direct illumination of the optical code. The second set of LEDs 107 lying on the cover/diffusing plate 108 provide diffuse illumination to the optical code. This system allows multiple illumination sources to be utilized to provide the image sensor 109 with a decodable image of the optical code. However, this scanner is even larger than the extended light source DPM scanner described previously and illustrated in FIG. 1a.
Other commercially available systems include several banks of LEDs that are switched on at different times to illuminate the DPM markings from various directions using the same color. The image having the highest contrast is then selected for decoding. The contrast in the images obtained varies with each illumination direction; successful decoding depends on properly illuminating the DPM code or marking from at least one of the illumination directions.
Another system is available in which an extended light source is provided at a substantial angle to a reflective diffuser which reflects the light emitted by the extended light source for redirecting the light to an optical code being imaged. The angle of the extended light source and the reflective diffuser relative to one another and to a front face of the device creates the need for the device to have a substantial depth and to be relatively cumbersome.

System and method for illuminating and reading optical codes imprinted or displayed on reflective surfaces


A system for reducing a transition short circuit current in an inverter circuit includes a first inverter and a variable resistor set. The first inverter includes a first output node, a first PMOS device, and a first NMOS device. The variable resistor set biases the first inverter such that the first PMOS device is switched at a first time and the first NMOS device is switched at a second time, thereby substantially reducing the transition short circuit current. A method for reducing the transition short circuit current and a buffer circuit also are described.

The present invention relates generally to inverter circuits and, more particularly, to a system and method for substantially reducing the current flow during a transition period.
Buffer circuits are used to temporarily hold data while the data is being transferred or processed e.g., within a computer. Buffer circuits often include an inverter circuit that inverts an input data bit or input signal.
FIG. 1A is a schematic diagram of a conventional inverter 100. The inverter 100 includes an input node 102, where an input signal INa is applied and an output node 104, where an output signal OUTa can be taken. The inverter 100 also includes two MOS transistors 110, 112 and an output capacitor 108. The transistors are equal value transistors having opposite polarities in that transistor 110 is a PMOS transistor and transistor 112 is an NMOS transistor. A positive input signal INa is inverted to produce a negative output signal OUTa. Conversely, a negative input signal INa is inverted to produce a positive output signal OUTa. When the output signal OUTa is a low state, transistor 112 is conducting. Conversely, when the output signal OUTa is a high state, transistor 110 is conducting.
FIG. 1B is a timing diagram 150 for the operation of the conventional inverter 100. The inverter 100 does not switch instantaneously but rather gradually switches (or changes state) from high to low output signal OUTa in response to similarly gradually changing input signal INa. As shown in FIG. 1B, the input signal INa is shown as it transitions from a low state at time T1 to a high state at time T5. The output signal OUTa is shown transitioning from a high state at time T2 to a low state at time T4, in response to the transitioning state of the input signal INa.
As discussed above, when the output signal OUTa is a low state, transistor 112 is conducting and when the output signal OUTa is a high state, transistor 110 is conducting. Therefore, during the transition period between time T2 and time T4, peaking at about time T3, both transistor 110 and transistor 112 are conducting simultaneously. Because both transistor 110 and transistor 112 are conducting simultaneously a "transition short circuit current," Is, flows from VDD, through transistor 110 and transistor 112 to ground. By way of example, the magnitude of the transition short circuit current, Is, can be about 220 mA at the peak at about time T3.
A transition short circuit current flow, Is, of 220 mA is greater than is necessary for the inverter 100 to invert the input signal INa. As a result, this excess current flow is wasted power. In view of the foregoing, there is a need for a technique that reduces the transition short circuit current flow and thereby reduces the amount of wasted power.

System and method for reducing short circuit current in a buffer


Methods and systems for managing requests for access to devices managed by a hypervisor in virtualized computing environment. A hypervisor receives a request for access to a device from a guest. The hypervisor provides an address hint associated with the device to the guest and an association between the address hint and the device is stored in a reference table. Upon receipt of a subsequent request from the guest including the address hint, the hypervisor performs a look-up in the reference table based on the address hint to identify the device and establishes access to the device by the guest.

In computer science, a virtual machine (VM) is a portion of software that, when executed on appropriate hardware, creates an environment allowing the virtualization of an actual physical computer system. Each VM may function as a self-contained platform, running its own operating system (OS) and software applications (processes). Typically, a virtual machine monitor (VMM) or hypervisor manages allocation and virtualization of computer resources, such as physical and virtual devices.
Frequently, a guest running on a virtual machine requires access to a device managed by the hypervisor. To gain the desired access, the guest specifies to the hypervisor which virtual or physical device or device function it wishes to access (i.e., the desired device) by providing a request for access to the device including address information associated with the desired device. Upon receipt of the device access request, the hypervisor decodes the device address information provided in the request in order to identify the desired device.
One conventional method for assigning and managing the device addresses associated with the multiple devices managed by a hypervisor involves a static assignment by the hypervisor of a fixed address to a particular device. However, this approach is inflexible, particularly when adding or removing devices from the system. Furthermore, this approach requires the hypervisor to maintain state information associated with the device in order to properly manage the access requests received from the guest. Maintenance of the device state information places an additional burden on the hypervisor, such as, for example, requiring the transfer of the maintained state information during the migration of a virtual machine (and guest) from one hypervisor to another.
Another conventional approach to device address assignment is for the guest to dynamically assign an address to the desired device. According to this approach, the guest sets the device address by an instruction that is trapped by the hypervisor. Then, a follow-up instruction from the guest includes the device address, which is used by the hypervisor to identify the desired device. Although this approach provides the guest with flexibility, by giving the guest the ability to designate a device address, the hypervisor is forced to manage device addresses having a variety of data structures (e.g., device addresses having a wide range of different data structure forms and formats). Due to the lack of uniformity in dynamic guest-assigned device addresses, device look-up and identification is an inefficient and time-consuming process.

Managing device access using an address hint


Dynamic and asymmetric sub-channel allocation in a wireless communications system—particularly an orthogonal frequency division multiple access (OFDMA) system—is disclosed. The methods and constructs of the present disclosure identify a plurality of cells, each divided into an equal number of sectors. A transmission channel associated with each cell is divided into a plurality of sub-channel groups. For each sector, a set of adjoining inter and intra coverage area sectors is identified, and associated together as a pool set. For each such pool set, a resource pool is formed from the plurality of sub-channel groups. A single sub-channel group from a resource pool is allocated to each sector in a corresponding pool set. Additional sub-channel group in that resource pool are thereafter allocated to sectors from the pool set on an as-needed, as-available basis.

Increasing demand for more powerful and convenient data communication has resulted in the proliferation of a number of wideband and high-throughput wireless technologies. In the field of wireless communications, a number of industry standards and operational protocols have been developed to address different wireless end-user applications.
Many of the current and emerging high throughput wireless technologies utilize a modulation scheme, such as orthogonal frequency division multiplexing (OFDM)—to organize or allocate data transmissions across their transmission bandwidths. OFDM divides a transmission channel into many narrowband sub-channels. Each sub-channel carries, for example, a quadrature amplitude modulated (QAM) signal. In a number of OFDM systems, only a single user may transmit on all of the sub-carriers at any given time. Such a system may employ time division or frequency division arbitration techniques to support multiple users.
Orthogonal frequency division multiple access (OFDMA), also referred to as multi-user OFDM, is an extension of OFDM that is gaining interest as a modulation and multiple access method for next-generation wireless networks. OFDMA divides a frequency band equally into multiple orthogonal sub-carriers—each grouping of which may be referred to as sub-channel. A given user is typically assigned one or more sub-channels, such that the user's original high-speed data can be transmitted on multiple sub-carriers—in parallel—using relatively low rates. This provides OFDM with inherit advantages for suppressing inter-symbol interference (ISI) incurred by frequency-selective fading. The OFDMA sub-channels may thus be assigned to multiple users for simultaneous multiple access, or multiple sub-channels may be assigned to a single user for higher speed data transmission.
There are a number of emerging high throughput wireless standards and operational protocols in which OFDMA may be supported or utilized—including IEEE 802.16, WiBRO (Wireless Broadband), and a number of advanced 3G (third generation) and 4G (fourth generation) systems. In some conventional systems, operational simplicity may be provided by assigning neighboring cells in a wireless network different transmission frequency spectrums (i.e., channels), such that no two neighboring cells share the same channel spectrum. In the interest of providing more efficient spectrum utilization, however, some OFDMA systems may divide a single channel frequency spectrum into a number of sub-channel groups. Each cell within the network coverage area may then be subdivided into a corresponding number of sectors. Sub-channel groups may then be allocated and associated with corresponding sectors in such a manner that adjacent cells may share the same channel frequency spectrum, while no two adjoining sectors—either intra-cell or inter-cell—share the same sub-channel. This is sometimes referred to in such contexts as a "frequency-reuse-of-1" scheme. To the extent that conventional systems provide a "frequency-reuse-of-1" topology or protocol, such systems usually utilize a sub-channel allocation that is symmetric and static in nature.
Unfortunately, actual real-time communication traffic in an operational end-user wireless system is usually unevenly distributed among sectors (i.e., asymmetric). Traffic requirements can vary dramatically, as large numbers of end-users transition into and out of a given cell and its neighbor cells. Conventional schemes (e.g., IEEE 802.16) do not appear to address asymmetric or dynamic allocation of sub-channel resources among adjoining (or adjacent) sectors and cells, and thus commonly have difficulty in adequately or efficiently meeting fluctuating end-user demands for high data rate. For example, a static allocation scheme may under-allocate bandwidth in a heavily populated sector or cell, while wasting bandwidth by over-allocation in a sparsely populated sector or cell. For example, a static allocation scheme may under-allocate bandwidth in a heavily populated sector or cell, while wasting bandwidth by over-allocation in a sparsely populated sector or cell.
As a result, there is a need for a system that provides both dynamic and asymmetric sub-channel allocation groups for neighbor sectors and cells in a wireless system. In particular, there is a need for a system that avoids undue inter-cell and intra-cell interference while maintaining frequency-reuse properties, thereby providing efficient and dependable wireless communications in an easy and cost-effective manner.

Versatile system for adaptive subchannel allocation in wireless communications


A ballast and its operating method for a dielectrically impeded discharge lamp. The ballast contains a transformer having a third winding which can be short-circuited via a switch. By so doing, the injection of the voltage pulse into the lamp circuit may be controlled by an external trigger signal.

Such discharge lamps are known per se. They must be operated using an electronic ballast which can apply iterative high-voltage pulses to the discharge lamp. However, the invention is also based on ballasts for other types of lamps which can be operated using iteratively produced voltage pulses, and particularly on those lamps or lamps with such circuitry that there is a capacitive characteristic as in the case of dielectrically impeded discharges.
It is also known per se to use inductances in ballasts for producing high-voltage pulses, and to produce the desired voltage pulses using various converter principles, for example so-called forward converters or flyback converters. The inductance may in this case be a simple inductor or else a so-called autotransformer having taps for a supply circuit and for a lamp circuit containing the lamp or, as is preferred here, may be an isolating transformer. The supply circuit produces a flow of current through the inductance and can be connected in this case using a switch, referred to here as a first switch (generally a primary circuit switch).

Electronic ballast for a lamp to be operated using iterative voltage pulses

Patent-Treuhand-Gesellschaft fur Elektrisch Gluhlampen mbH


The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and treatment of cancer.

The Ras gene is found activated in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein, since Ras must be localized in the plasma membrane and must bind with GTP in order to transform cells (Gibbs, J. et al., Microbiol. Rev. 53:171-286 (1989)). Forms of Ras in cancer cells have mutations that distinguish the protein from Ras in normal cells.
At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a xe2x80x9cCAAXxe2x80x9d or xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
Farnesylation of Ras by the isoprenoid farnesyl pyrophosphate (FPP) occurs in vivo on Cys to form a thioether linkage (Hancock et al., Cell 57:1167 (1989); Casey et al., Proc. Natl. Acad. Sci. USA 86:8323 (1989)). In addition, Ha-Ras and N-Ras are palmitoylated via formation of a thioester on a Cys residue near a C-terminal Cys farnesyl acceptor (Gutierrez et al., EMBO J. 8:1093-1098 (1989)); Hancock et al., Cell 57: 1167-1177 (1989)). Ki-Ras lacks the palmitate acceptor Cys. The last 3 amino acids at the Ras C-terminal end are removed proteolytically, and methyl esterification occurs at the new C-terminus (Hancock et al., ibid). Fungal mating factor and mammalian nuclear lamins undergo identical modification steps (Anderegg et al., J.Biol. Chem. 263:18236 (1988); Farnsworth et al., J. Biol. Chem. 264:20422 (1989)).
Inhibition of Ras farnesylation in vivo has been demonstrated with lovastatin (Merck and Co., Rahway, N.J.) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids and the farnesyl pyrophosphate precursor. It has been shown that a farnesyl-protein transferase using farnesyl pyrophosphate as a precursor is responsible for Ras farnesylation. (Reiss et al., Cell, 62: 81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249: 1133-1139 (1990); Manne et al., Proc Natl. Acad. Sci USA, 87: 7541-7545 (1990)).
Inhibition of farnesyl-protein transferase and, thereby, of farnesylation of the Ras protein, blocks the ability of Ras to transform normal cells to cancer cells. The compounds of the invention inhibit Ras farnesylation and, thereby, generate soluble Ras which, as indicated infra, can act as a dominant negative inhibitor of Ras function. While soluble Ras in cancer cells can become a dominant negative inhibitor, soluble Ras in normal cells would not be an inhibitor.
A cytosol-localized (no Cys-Aaa1-Aaa2-Xaa box membrane domain present) and activated (impaired GTPase activity, staying bound to GTP) form of Ras acts as a dominant negative Ras inhibitor of membrane-bound Ras function (Gibbs et al., Proc. Natl. Acad. Sci. USA 86:6630-6634(1989)). Cytosol localized forms of Ras with normal GTPase activity do not act as inhibitors. Gibbs et al., ibid, showed this effect in Xenopus oocytes and in mammalian cells.
Administration of compounds of the invention to block Ras farnesylation not only decreases the amount of Ras in the membrane but also generates a cytosolic pool of Ras. In tumor cells having activated Ras, the cytosolic pool acts as another antagonist of membrane-bound Ras function. In normal cells having normal Ras, the cytosolic pool of Ras does not act as an antagonist. In the absence of complete inhibition of farnesylation, other farnesylated proteins are able to continue with their functions.
Farnesyl-protein transferase activity may be reduced or completely inhibited by adjusting the compound dose. Reduction of farnesyl-protein transferase enzyme activity by adjusting the compound dose would be useful for avoiding possible undesirable side effects resulting from interference with other metabolic processes which utilize the enzyme.
These compounds and their analogs are inhibitors of farnesyl-protein transferase. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of Ras, and other cellular proteins, with a farnesyl group. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in vivo and inhibits Ras function. Inhibition of farnesyl-protein transferase is more specific and is attended by fewer side effects than is the case for a general inhibitor of isoprene biosynthesis.
Previously, it has been demonstrated that tetrapeptides containing cysteine as an amino terminal residue with the CAAX sequence inhibit Ras farnesylation (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). It was, however, disclosed that tetrapeptides which further contained a cyclic amino acid residue, such as proline, had greatly reduced inhibitory activity when compared to tetrapeptides not containing a cyclic amino acid (Reiss et al., (1991). Tetrapeptide inhibitors may inhibit while serving as alternate substrates for the Ras farnesyl-transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas).
It is, therefore, an object of this invention to develop non-peptide compounds which will inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention, and methods for producing the compounds of this invention.
The present invention includes partially reduced tetrapeptide analogs containing a cyclic amino acid which inhibit farnesyl-protein transferase (FPTase) and the farnesylation of the oncogene protein Ras, chemotherapeutic compositions containing the compounds of this invention, and methods for producing the compounds of this invention. It has been surprisingly found that these analogs containing a cyclic amino acid show FPTase inhibitory activity which is comparable to partially reduced tetrapeptide analogs which do not contain a cyclic amino acid. The invention also includes ester and lactone analogs which are prodrugs which deliver the active acid forms of the compounds to the intracellular compartment.
The compounds of this invention are illustrated by the formulae I and II:
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula I:
wherein:
R1 and R2 are independently selected from H, C1-4 alkyl, C1-4 aralkyl, xe2x80x94S(O)mxe2x80x94R6 and
R3 and R4 are independently selected from: H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7, or
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
R5 is hydrogen;
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
t is 1 to 4;
X is O or H2;
Y is substituted or unsubstituted nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle, and wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
In a second embodiment of this invention are prodrugs of the inhibitors of farnesyl-protein transferase, those prodrugs which are illustrated by the formula I:
wherein:
R1 and R2 are independently selected from H, C1-4 alkyl, C1-4 aralkyl, xe2x80x94S(O)mxe2x80x94R6 and
R3 and R4 are independently selected from: H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
R5 is C1-8 alkyl, C3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
t is 1 to 4;
X is O or H2;
Y is substituted or unsubstituted nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle, and wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
In a third embodiment of this invention are prodrugs of the inhibitors of farnesyl-protein transferase, those prodrugs which are illustrated by the formula II:
wherein:
R1 and R2 are independently selected from H, C1-4 alkyl, C1-4 aralkyl, xe2x80x94S(O)mxe2x80x94R6 and
R3 is H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
5) xe2x80x94NR6R7
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
xe2x80x83wherein
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
t is 1 to 4;
X is O or H2;
Y is substituted or unsubstituted nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle, and wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
In a preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula I:
wherein:
R1 and R2 are independently selected from H and C1-4 alkyl;
R3 and R4 are independently selected from: H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
R5 is hydrogen;
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
xe2x80x83wherein
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
t is 1 to 4;
X is H2;
Y is substituted or unsubstituted ring system selected from the following
xe2x80x83and wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
In another preferred embodiment of this invention are prodrugs of the inhibitors of farnesyl-protein transferase, those prodrugs which are illustrated by the formula I:
wherein:
R1 and R2 are independently selected from H and C1-4 alkyl;
R3 and R4 are independently selected from: H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
R5 is C1-8 alkyl, C3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
xe2x80x83wherein
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
t is 1 to 4;
X is H2;
Y is substituted or unsubstituted ring system selected from the following
xe2x80x83wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
In another preferred embodiment of this invention are prodrugs of the inhibitors of farnesyl-protein transferase, those prodrugs which are illustrated by the formula II:
wherein:
R1 and R2 are independently selected from H, C1-4 alkyl, C1-4 aralkyl, xe2x80x94S(O)mxe2x80x94R6 and
R3 and R4 are independently selected from: H; C1-8 alkyl, alkenyl, alkynyl, or
xe2x80x83unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)tOR6,
c) (CH2)tNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6, S(O)R6, SO2R6,
R5 is C1-8 alkyl, C3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
R6, R7 and R8 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
xe2x80x83wherein
R6 and R7 may be joined in a ring, and
R7 and R8 may be joined in a ring;
R9 is C1-4 alkyl or aralkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;
t is 1 to 4;
X is H2;
Y is substituted or unsubstituted ring system selected from the following
xe2x80x83wherein the substituent is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
or the pharmaceutically acceptable salts or disulfides thereof.
Specific compounds of this invention are as follows:
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-methionine methyl ester (Compound 1)
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-methionine (Compound 2)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 3)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 4)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine methyl ester (Compound 5)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine (Compound 6)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine methyl ester (Compound 7)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine (Compound 8)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 9)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone (Compound 10)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine methyl ester (Compound 11)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine (Compound 12)
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-homoserine lactone (Compound 13)
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-homoserine (Compound 14)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-homoserine lactone (Compound 15)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-homoserine (Compound 16)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-homoserine lactone (Compound 17)
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-homoserine (Compound 18)
N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-prolyl-homserine lactone (Compound 19)
N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-prolyl-homserine (Compound 20)
N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-2(S)-pipecolyl-homserine lactone (Compound 21)
N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-2(S)-pipecolyl-homserine (Compound 22)
N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 23)
N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 24)
N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 25) and
N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone (Compound 26)
or the pharmaceutically acceptable salts or disulfides thereof.
The preferred compounds of this invention include the following inhibitor and the corresponding lactone/ester prodrug pairs:
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-homoserine (Compound 14) and
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-homoserine lactone (Compound 13)
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-methionine (Compound 2) and
N-[Nxe2x80x2-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxyl]-methionine methyl ester (Compound 1)
N-[2(8)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine methyl ester (Compound 5) and
N-[2(8)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine (Compound 6)
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. The present invention further includes all disulfides of the claimed compounds, derived from two of the same compounds. When any variable (e.g. aryl, heterocycle, R1, R2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo.
As used herein, xe2x80x9carylxe2x80x9d is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m=0, 1 or 2), and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the phrase xe2x80x9cnitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C6 aromatic ringxe2x80x9d which defines moiety xe2x80x9cYxe2x80x9d of the instant invention includes but is not limited to the following ring systems:
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., xe2x80x9cThe Peptidesxe2x80x9d, Vol. 1, Academic Press 1965, or Bodanszky et al., xe2x80x9cPeptide Synthesisxe2x80x9d, Interscience Publishers, 1966, or McOmie (ed.) xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, 1973, or Barany et al., xe2x80x9cThe Peptides: Analysis, Synthesis, Biologyxe2x80x9d 2, Chapter 1, Academic Press, 1980, or Stewart et al., xe2x80x9cSolid Phase Peptide Synthesisxe2x80x9d, Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.
Abbreviations used in the description of the chemistry and in the Examples that follow are:
Ac2O Acetic anhydride;
Boc t-Butoxycarbonyl;
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;
DMAP 4-Dimethylaminopyridine;
DME 1,2-Dimethoxyethane;
DMF Dimethylformamide;
EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride;
HOBT 1-Hydroxybenzotriazole hydrate;
Et3N Triethylamine;
EtOAc Ethyl acetate.
FAB Fast atom bombardment;
HOOBT 3-Hydroxy-1,2,2-benzotriazin-4(3H)-one;
HPLC High-performance liquid chromatography;
MCPBA m-Chloroperoxybenzoic acid;
MsCl Methanesulfonyl chloride;
NaHMDS Sodium bis(trimethylsilyl)amide
Py Pyridine;
TFA Trifluoroacetic acid;
TBF Tetrahydrofuran;
The compounds of this invention are prepared by employing reactions A-C as shown in the Reaction Scheme, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are:
Reaction A. Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Reaction B. Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
Reaction C. Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.
where RA and RB are R3, R4 or part of the structure of Y as previously defined, including their protected forms compatible with the reaction conditions shown, for example, the triphenylmethyl (trityl) protected side chain of cysteine.
The compounds of this invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. These compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient""s intramuscular blood-stream by local bolus injection.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient""s symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day.

Inhibitors of farnesyl-protein transferase


A device (110) receives consecutive negative acknowledgments (NACKs) (540), measures a downlink channel quality (530) associated with the device (110), and triggers autonomous retransmission (430) when power is limited in the device (110), when the device (110) is using a minimum usable enhanced dedicated channel (E-DCH) transport format combination (ETFC), and when one of a number of consecutive NACKs (540) is greater than a predefined number or the measured downlink channel quality (530) is less than a predefined threshold.

Enhanced uplink (EUL) is proposed in the Third Generation Partnership Project (3GPP) Release 6 to improve uplink performance of Wideband Code Division Multiple Access (WCDMA) systems. Two transmission time intervals (TTIs) are proposed for enhanced uplink, a ten (10) milliseconds TTI and a two (2) milliseconds TTI. The ten milliseconds TTI provides similar cell coverage as previous Universal Mobile Telecommunications System (UMTS) releases, but its cell throughput is too small. The two milliseconds TTI provides better cell throughput than the ten milliseconds TTI, but its cell coverage is insufficient.
One technique that improves enhanced uplink coverage is hybrid automatic repeat request (HARQ) retransmission. According to current 3GPP specifications, enhanced uplink HARQ retransmission can occur only after expiration of a round trip time (RTT). Since the RTT for the two milliseconds TTI is sixteen (16) milliseconds and three (3) retransmissions may be required to guarantee reliable reception of a packet, a retransmission delay of forty-eight (48) milliseconds could be introduced by enhanced uplink HARQ. Such a delay may not be acceptable for some delay sensitive services (e.g., voice over Internet protocol (VoIP) services, etc.).
Autonomous retransmission has been proposed as an effective way to reduce such HARQ retransmission delay. A core concept of autonomous retransmission is that user equipment (UE) sends a number of retransmissions consecutively, without waiting for receipt of a negative acknowledgment (NACK) before starting the next retransmission. However, if three retransmissions are required, autonomous retransmission may only reduce the retransmission delay to six (6) milliseconds. Some autonomous retransmission techniques describe how a receiver knows that a bundle of transmissions are designated for a single packet, how the receiver decodes the packets transmitted with autonomous retransmission correctly, how to apply autonomous retransmission in high-speed downlink packet access (HSDPA), how to use autonomous retransmission for extended coverage, how to apply autonomous retransmission to notify a non-serving Node B, etc.
Although autonomous retransmission is an effective way to improve uplink coverage, it still suffers from several drawbacks. For example, if autonomous retransmission is applied with an excessively large number of transmission attempts or at an inappropriate time, autonomous retransmission will generate unnecessary interference in a system. On the other hand, autonomous retransmission with less (or an inadequate number of) transmission attempts can not take full advantage of the benefits of the technique.

Uplink coverage via autonomous retransmission


The method of the invention provides novel compounds, termed acid-labile isotope-coded extractants (ALICE), for quantitative mass spectrometric analysis of protein mixtures. The compounds contain a thiol-reactive group that is used to capture cysteine-containing peptides from all peptide mixtures, an acid-labile linker, and a non-biological polymer. One of the two acid-labile linkers is isotopically labeled and therefore enables the direct quantitation of peptides/proteins through mass spectrometric analysis. Because no functional proteins are required to capture peptides, a higher percentage of organic solvent can be used to solubilize the peptides, particularly hydrophobic peptides, through the binding, washing and eluting steps, thus permitting much better recover of peptides. Moreover, since the peptides are covalently linked to the non-biological polymer (ALICE), more stringent washing is allowed in order to completely remove non-specifically bound species. Finally, peptides captured by ALICE are readily eluted from the polymer support under mild acidic condition with high yield and permit the direct down stream mass spectrometric analysis without any further sample manipulation. In combination with our novel dual column two dimensional liquid chromatography-mass spectrometry (2D-LC-MS/MS) design, the ALICE procedure proves to a general approach for quantitative mass spectrometric analysis of protein mixtures with better dynamic range and sensitivity.

The present invention relates to the field of high-throughput quantitative protein analysis and, more specifically, to novel reagents for use in such analysis.
Most approaches to quantitative protein analysis are accomplished by combining protein separation, most commonly by high-resolution two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), with mass spectrometry (MS)-based sequence or tandem mass spectrometry (MS/MS)-based sequence identification of selected, separated protein species.
S. P. Gygi, et al., Nature Biotech, 17:994–999 (October 1999) describes an approach to quantitative protein analysis based on a class of reagents termed isotope-coded affinity tags (ICAT), which consist of three functional elements: a specific chemical reactivity, an isotopically coded linker, and an affinity tag. The reagents described by Gygi utilize biotin as the affinity tag and rely upon biotin-avidin affinity binding to isolate the cysteine-containing peptides from the complex peptide mixture.
Although the ICAT approach has many advantages over the traditional 2D-PAGE/MS approaches, it does possess some intrinsic limitations. For example, ICAT adds a relatively large chemical moiety onto the cysteine-containing peptides and this functionality is very labile under collision induced dissociation (CID) condition and thus complicates the downstream data analysis. Non-specific binding is also a concern since the enrichment relies on non-covalent affinity binding between a protein (avidin) and the biotinylated peptides. Finally, the captured peptides are not readily eluted from the avidin beads with high recovery using MS-compatible conditions. Thus, there is a need in the art for additional reagents and methods for improving performance in quantitative mass spectrometric analysis of protein mixtures.

Acid-labile isotope-coded extractant (ALICE) and its use in quantitative mass spectrometric analysis of protein mixtures


A system and method of playing an extension game to a lottery game is disclosed. A lottery game player enters a base game and receives a base game entry, and may elect to play a second lottery game in addition to the base game, and if so, selects or has selected for them game indicia therefor. A winning entry for the base game is selected, whereupon the winning game indicia for the second game is selected to be the game indicia selected for the second game on the winning base game entry. Lottery players who won the base game receive a prize, and those lottery players who did not win the base game but that have the winning game indicia for the second game, as well as those lottery players that won the base game and have the have the winning game indicia for the second game, receive a prize.

1. Field of the Invention
The invention relates in general to lottery games. More particularly, the invention relates to a lottery game in which winning numbers are determined by an accompanying game.
2. Description of the Related Art
Traditionally a lottery chooses its winner by means that is not affected by action of lottery players. For example, in a raffle game, a winner is chosen by selecting a winning number from a set of numbers, and the selection is not affected by each player's action. Some lotteries have taken a different approach, in which the winning number is indirectly affected by players. An example of this approach is "Darkhorse Wagering" disclosed in U.S. Pat. No. 6,098,797. Darkhorse Wagering permits a player to make selections that affect the outcome of the game, and the least popular player selection is chosen to be the winner. In Darkhorse Wagering the winner is always the least popular player selection, which means that majority of players will not win most of time, and they may lose interest in the game in the long run. Therefore, it is to an extension lottery game in which players who make popular choices may occasionally win that the present invention is primary directed.

Extension to a lottery game for which winning indicia are set by selections made by winners of a base lottery game


The invention relates to an information display device which attaches to a tubular conduit. The tubular conduit has a longitudinal axis for transporting liquids. A display member having lateral and vertical edges and a display area for displaying information is attached to said tubular conduit by a tubular portion having a longitudinal vertical axis substantially parallel with the vertical edge of the display member. The attachment mechanism has an opening in the exterior wall along said longitudinal axis for inserting the tubular conduit therein. The display area is used for recording information. An extension member extends beyond the display area wrapping around the attachment tubular conduit for securing said information display device to said tubular conduit.

The present invention relates in general to information display devices and, in particular to display devices to display information related to the medical treatment of patients with medications administered by intravenous means, commonly described as IV.
In this treatment, the liquid medication is contained in a pliable plastic bag which is typically hung in an elevated position and a supply tube carries the solution by gravitation or pump from the bag to the needle inserted in the patient's vein.
When such treatment is being administered, it is important that all of the care-givers who may be responsible for an IV administration are able to determine quickly and accurately the status of the treatment. Various stages of the treatment must be performed at specified intervals in order to prevent adverse reactions by the patient. For example, a typical IV procedure or Tubing Policy might include the following schedule items:
Change the parts of the system as follows:
a. IV solution--at least every 24 hours PA1 b. IV site rotation--every 72 hours PA1 c. Dressing--every 72 hours PA1 d. Primary Administration Sets--every 72 hours PA1 e. Secondary Administration Sets--every 24 hours
A record of these changes must be available at the treatment site at all times for the benefit of all care-givers on all working shifts.
This information is, of course, always available in the patients medical chart. However, this chart is usually maintained at a central nurse's station and not in the patient's room. In the prior art, information regarding the treatment schedule has been entered on a label attached to the medication container which supplies the IV fluid. The label may then be transferred to the patient's chart. However, when the container is changed a new label must be attached and the last activity in the treatment regimen is available only in the chart.
This invention overcomes these disadvantages by providing a treatment information display device which can be attached directly to the IV tubing without the use of additional tools and without interfering with the flow of the medication and provides a labeling area with space for treatment information to be recorded. This device may be quickly replaced with a new device without disturbing the IV and, while in place, displays the latest activity in the treatment schedule. More than one display device may be placed on an IV tubular conduit at one time if additional information is required. In addition, the label may be provided with an elongated adhesive-backed portion which can be wrapped around the IV tubing to help secure the device in place.