The present invention provides combination therapy methods of treating proliferative diseases (such as cancer) comprising a first therapy comprising administering to an individual an effective amount of a taxane in a nanoparticle composition, and a second therapy which may include, for example, radiation, surgery, administration of chemotherapeutic agents, or combinations thereof. Also provided are methods of administering to an individual a drug taxane in a nanoparticle composition based on a metronomic dosing regime.

The failure of a significant number of tumors to respond to drug and/or radiation therapy is a serious problem in the treatment of cancer. In fact, this is one of the main reasons why many of the most prevalent forms of human cancer still resist effective chemotherapeutic intervention, despite certain advances in the field of chemotherapy.
Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery is a traditional approach in which all or part of a tumor is removed from the body. Surgery generally is only effective for treating the earlier stages of cancer. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, inaccessible to surgeons, nor in the treatment of disseminated neoplastic conditions such as leukemia. For more than 50% of cancer individuals, by the time they are diagnosed they are no longer candidates for effective surgical treatment. Surgical procedures may increase tumor metastases through blood circulation during surgery. Most of cancer individuals do not die from the cancer at the time of diagnosis or surgery, but rather die from the metastasis and the recurrence of the cancer.
Other therapies are also often ineffective. Radiation therapy is only effective for individuals who present with clinically localized disease at early and middle stages of cancer, and is not effective for the late stages of cancer with metastasis. Radiation is generally applied to a defined area of the subject's body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of radiation throughout the course of treatment. There are also some treatments that require exposure of the subject's entire body to the radiation, in a procedure called "total body irradiation", or "TBI." The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors.
Chemotherapy involves the disruption of cell replication or cell metabolism. Chemotherapy can be effective, but there are severe side effects, e.g., vomiting, low white blood cells (WBC), loss of hair, loss of weight and other toxic effects. Because of the extremely toxic side effects, many cancer individuals cannot successfully finish a complete chemotherapy regime. Chemotherapy-induced side effects significantly impact the quality of life of the individual and may dramatically influence individual compliance with treatment. Additionally, adverse side effects associated with chemotherapeutic agents are generally the major dose-limiting toxicity (DLT) in the administration of these drugs. For example, mucositis is one of the major dose limiting toxicity for several anticancer agents, including the antimetabolite cytotoxic agents 5-FU, methotrexate, and antitumor antibiotics, such as doxorubicin. Many of these chemotherapy-induced side effects if severe may lead to hospitalization, or require treatment with analgesics for the treatment of pain. Some cancer individuals die from the chemotherapy due to poor tolerance to the chemotherapy. The extreme side effects of anticancer drugs are caused by the poor target specificity of such drugs. The drugs circulate through most normal organs of individuals as well as intended target tumors. The poor target specificity that causes side effects also decreases the efficacy of chemotherapy because only a fraction of the drugs is correctly targeted. The efficacy of chemotherapy is further decreased by poor retention of the anti-cancer drugs within the target tumors.
Due to the severity and breadth of neoplasm, tumor and cancer, there is a great need for effective treatments of such diseases or disorders that overcome the shortcomings of surgery, chemotherapy, and radiation treatment.
Problems of Chemotherapeutic Agents
The drug resistance problem is a reason for the added importance of combination chemotherapy, as the therapy both has to avoid the emergence of resistant cells and to kill pre-existing cells which are already drug resistant.
Drug resistance is the name given to the circumstance when a disease does not respond to a treatment drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been responsive to the drug or drugs, or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously been responsive to. Multidrug resistance (MDR) is a specific type of drug resistance that is characterized by cross-resistance of a disease to more than one functionally and/or structurally unrelated drugs. Multidrug resistance in the field of cancer is discussed in greater detail in "Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs," by Kuzmich and Tew, particularly section VII "The Multidrug-Resistant Phenotype (MDR)," Medical Research Reviews, Vol. 11, No. 2, 185-217, (Section VII is at pp. 208-213) (1991); and in "Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy," by Georges, Sharom and Ling, Advances in Pharmacology, Vol. 21, 185-220 (1990).
One form of multi-drug resistance (MDR) is mediated by a membrane bound 170-180 kD energy-dependent efflux pump designated as P-glycoprotein (P-gp). P-glycoprotein has been shown to play a major role in the intrinsic and acquired resistance of a number of human tumors against hydrophobic, natural product drugs. Drugs that act as substrates for and are consequently detoxified by P-gp include the vinca alkaloids (vincristine and vinblastine), anthracyclines (Adriamycin), and epipodophyllotoxins (etoposide). While P-gp associated MDR is a major determinant in tumor cell resistance to chemotherapeutic agents, it is clear that the phenomenon of MDR is multifactorial and involves a number of different mechanisms.
A major complication of cancer chemotherapy and of antiviral chemotherapy is damage to bone marrow cells or suppression of their function. Specifically, chemotherapy damages or destroys hematopoietic precursor cells, primarily found in the bone marrow and spleen, impairing the production of new blood cells (granulocytes, lymphocytes, erythrocytes, monocytes, platelets, etc.). Treatment of cancer individuals with 5-fluorouracil, for example, reduces the number of leukocytes (lymphocytes and/or granulocytes); and can result in enhanced susceptibility of the individuals to infection. Many cancer individuals die of infection or other consequences of hematopoietic failure subsequent to chemotherapy. Chemotherapeutic agents can also result in subnormal formation of platelets which produces a propensity toward hemorrhage. Inhibition of erythrocyte production can result in anemia. For some cancer individuals, the risk of damage to the hematopoietic system or other important tissues frequently limits the opportunity for chemotherapy dose escalation of chemotherapy agents high enough to provide good antitumor or antiviral efficacy. Repeated or high dose cycles of chemotherapy may be responsible for severe stem cell depletion leading to serious long-term hematopoietic sequelea and marrow exhaustion.
Prevention of, or protection from, the side effects of chemotherapy would be a great benefit to cancer individuals. For life-threatening side effects, efforts have concentrated on altering the dose and schedules of the chemotherapeutic agent to reduce the side effects. Other options are becoming available, such as the use of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), epidermal growth factor (EGF), interleukin 11, erythropoietin, thrombopoietin, megakaryocyte development and growth factor, pixykines, stem cell factor, FLT-ligand, as well as interleukins 1, 3, 6, and 7, to increase the number of normal cells in various tissues before the start of chemotherapy (See Jimenez and Yunis, Cancer Research 52:413-415; 1992). The mechanisms of protection by these factors, while not fully understood, are most likely associated with an increase in the number of normal critical target cells before treatment with cytotoxic agents, and not with increased survival of cells following chemotherapy.
Chemotherapeutic Targeting For Tumor Treatment
Both the growth and metastasis of solid tumors are angiogenesis-dependent (Folkman, J. Cancer Res., 46, 467-73 (1986); Folkman, J. Nat. Cancer Inst., 82, 4-6 (1989); Folkman et al., "Tumor Angiogenesis," Chapter 10, pp. 206-32, in The Molecular Basis of Cancer, Mendelsohn et al., eds. (W. B. Saunders, 1995)). It has been shown, for example, that tumors which enlarge to greater than 2 mm in diameter must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. After these new blood vessels become embedded in the tumor, they provide nutrients and growth factors essential for tumor growth as well as a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, New Eng. J. Med., 324(1), 1-8 (1991)). When used as drugs in tumor-bearing animals, natural inhibitors of angiogenesis can prevent the growth of small tumors (O'Reilly et al., O'Reilly et al., Cell, 79, 315-28 (1994)). Indeed, in some protocols, the application of such inhibitors leads to tumor regression and dormancy even after cessation of treatment (O'Reilly et al., Cell, 88, 277-85 (1997)). Moreover, supplying inhibitors of angiogenesis to certain tumors can potentiate their response to other therapeutic regimes (e.g., chemotherapy) (see, e.g., Teischer et al., Int. J. Cancer, 57, 920-25 (1994)).
Protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp. 1, 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classified as receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, Ick, Zap70) kinases. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. For example, elevated epidermal growth factor receptor (EGFR) activity has been implicated in non-small cell lung, bladder and head and neck cancers, and increased c-erbB-2 activity in breast, ovarian, gastric and pancreatic cancers. Thus, inhibition of protein tyrosine kinases should be useful as a treatment for tumors such as those outlined above.
Growth factors are substances that induce cell proliferation, typically by binding to specific receptors on cell surfaces. Epidermal growth factor (EGF) induces proliferation of a variety of cells in vivo, and is required for the growth of most cultured cells. The EGF receptor is a 170-180 kD membrane-spanning glycoprotein, which is detectable on a wide variety of cell types. The extracellular N-terminal domain of the receptor is highly glycosylated and binds EGF antibodies that selectively bind to EGFR. Agents that competitively bind to EGFR have been used to treat certain types of cancer, since many tumors of mesodermal and ectodermal origin overexpress the EGF receptor. For example, the EGF receptor has been shown to be overexpressed in many gliomas, squamous cell carcinomas, breast carcinomas, melanomas, invasive bladder carcinomas and esophageal cancers. Attempts to exploit the EGFR system for anti-tumor therapy have generally involved the use of monoclonal antibodies against the EGFR. In addition, studies with primary human mammary tumors have shown a correlation between high EGFR expression and the presence of metastases, higher rates of proliferation, and shorter individual survival.
Herlyn et al., in U.S. Pat. No. 5,470,571, disclose the use of radiolabeled Mab 425 for treating gliomas that express EGFR. Herlyn et al. report that anti-EGFR antibodies may either stimulate or inhibit cancer cell growth and proliferation. Other monoclonal antibodies having specificity for EGFR, either alone or conjugated to a cytotoxic compound, have been reported as being effective for treating certain types of cancer. Bendig et al, in U.S. Pat. No. 5,558,864, disclose therapeutic anti-EGFR Mab's for competitively binding to EGFR. Heimbrook et al., in U.S. Pat. No. 5,690,928, disclose the use of EGF fused to a Pseudomonas species-derived endotoxin for the treatment of bladder cancer. Brown et al., in U.S. Pat. No. 5,859,018, disclose a method for treating diseases characterized by cellular hyperproliferation mediated by, inter alia, EGF.
Chemotherapeutic Modes of Administration
People diagnosed as having cancer are frequently treated with single or multiple chemotherapeutic agents to kill cancer cells at the primary tumor site or at distant sites to where cancer has metastasized. Chemotherapy treatment is typically given either in a single or in several large doses or over variable times of weeks to months. However, repeated or high dose cycles of chemotherapy may be responsible for increased toxicities and severe side effects.
New studies suggest that metronomic chemotherapy, the low-dose and frequent administration of cytotoxic agents without prolonged drug-free breaks, targets activated endothelial cells in the tumor vasculature. A number of preclinical studies have demonstrated superior anti-tumor efficacy, potent antiangiogenic effects, and reduced toxicity and side effects (e.g., myelosuppression) of metronomic regimes compared to maximum tolerated dose (MTD) counterparts (Bocci, et al., Cancer Res, 62:6938-6943, (2002); Bocci, et al., PNAS, vol, 100(22):12917-12922, (2003); and Bertolini, et al., Cancer Res, 63(15):4342-4346, (2003)). It remains unclear whether all chemotherapeutic drugs exert similar effects or whether some are better suited for such regimes than others. Nevertheless, metronomic chemotherapy appears to be effective in overcoming some of the major shortcomings associated with chemotherapy.
Chemotherapeutic Agents
Paclitaxel has been shown to have significant antineoplastic and anticancer effects in drug-refractory ovarian cancer and has shown excellent antitumor activity in a wide variety of tumor models, and also inhibits angiogenesis when used at very low doses (Grant et al., Int. J. Cancer, 2003). The poor aqueous solubility of paclitaxel, however, presents a problem for human administration. Indeed, the delivery of drugs that are inherently insoluble or poorly soluble in an aqueous medium can be seriously impaired if oral delivery is not effective. Accordingly, currently used paclitaxel formulations (e.g., Taxol®) require a Cremophor® to solubilize the drug. The presence of Cremophor® in this formulation has been linked to severe hypersensitivity reactions in animals (Lorenz et al., Agents Actions 7:63-67 (1987)) and humans (Weiss et al., J. Clin. Oncol. 8:1263-68 (1990)) and consequently requires premedication of individuals with corticosteroids (dexamethasone) and antihistamines. It was also reported that clinically relevant concentrations of the formulation vehicle Cremophor® EL in Taxol® nullify the antiangiogenic activity of paclitaxel, suggesting that this agent or other anticancer drugs formulated in Cremophor® EL may need to be used at much higher doses than anticipated to achieve effective metronomic chemotherapy (Ng et al., Cancer Res., 64:821-824 (2004)). As such, the advantage of the lack of undesirable side effects associated with low-dose paclitaxel regimes vs. conventional MTD chemotherapy may be compromised. See also U.S. Patent Pub. No. 2004/0143004; WO00/64437.
Abraxane™ is a Cremophor® EL-Free Nanoparticle Albumin-Bound Paclitaxel
Preclinical models have shown significant improvement in the safety and efficacy of Abraxane™ compared with Taxol® (Desai et al., EORTC-NCI-AACR, 2004) and in individuals with metastatic breast cancer (O'Shaughnessy et al., San Antonio Breast Cancer Symposium, Abstract #1122, December 2003). This is possibly due to the absence of surfactants (e.g., Cremophor® or Tween® 80, used in Taxol® and Taxotere®, respectively) in Abraxane™, and/or preferential utilization of an albumin-based transport mechanism utilizing gp60/caveolae on microvascular endothelial cells (Desai et al., EORTC-NCI-AACR, 2004). In addition, both Cremophor® and Tween® 80 have been shown to strongly inhibit the binding of paclitaxel to albumin, possibly affecting albumin based transport (Desai et al., EORTC-NCI-AACR, 2004).
IDN5109 (Ortataxel) is a new taxane, currently in phase II, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype (MDR/Pgp) and inhibition of P-glycoprotein (Pgp) (Minderman; Cancer Chemother. Pharmacol. 2004; 53:363-9). Due to its hydrophobicity, IDN5109 is currently formulated in the surfactant Tween® 80 (same vehicle as Taxotere®). Removal of surfactants from taxane formulations e.g., in the case of nanoparticle albumin-bound paclitaxel (Abraxane™) showed improvements in safety and efficacy over their surfactant containing counterparts (O'Shaughnessy et al., San Antonio Breast Cancer Symposium, Abstract #1122, December 2003). Tween® 80 also strongly inhibited the binding of the taxane, paclitaxel, to albumin, possibly compromising albumin based drug transport via the gp60 receptor on microvessel endothelial cells (Desai et al., EORTC-NCI-AACR, 2004).
The antitumor activity of colchicine, which is the major alkaloid of the autumn crocus, Colchicum autumnale, and the African climbing lily, Gloriosa superba, was first reported at the beginning of the 20th century. The elucidation of its structure was finally completed from X-ray studies and a number of total syntheses (see Shiau et al., J. Pharm. Sci. 1978, 67(3) 394-397). Colchicine is thought to be a mitotic poison, particularly in tyhmic, intestinal, and hermatopoietic cells, which acts as a spindle poison and blocks the kinesis. Its effect on the mitotic spindle is thought to represent a special case of its effects on various organized, labile, fibrillar systems concerned with structure and movement.
Thiocolchicine dimer IDN5404 was selected for its activity in human ovarian subline resistant to cisplatin and topotecan A2780-CIS and A2780-TOP. This effect was related to dual mechanisms of action, i.e., microtubule activity as in Vinca alkaloids and a topoisomerase I inhibitory effect different from camptothecin. (Raspaglio, Biochemical Pharmacology 69:113-121 (2005)).
It has been found that nanoparticle compositions of a taxane (such as albumin bound paclitaxel (Abraxane™)) have significantly lower toxicities than other taxanes like Taxol® and Taxotere® with significantly improved outcomes in both safety and efficacy.
Combination chemotherapy, e.g., combining one or more chemotherapeutic agents or other modes of treatment, e.g., combining for example, chemotherapy with radiation or surgery and chemotherapy, have been found to be more successful than single agent chemotherapeutics or individual modes of treatment respectively.
Other references include U.S. Pub. No. 2006/0013819; U.S. Pub. No. 2006/0003931; WO05/117986; WO05/117978; and WO05/000900.
More effective treatments for proliferative diseases, especially cancer, are needed.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

This patent is subject to a terminal disclaimer.

Combinations and modes of administration of therapeutic agents and combination therapy


Provided is a carbon dioxide electrolysis-carbon deposition/carbon fuel cell-integrated apparatus which enable interconversion between electric energy and chemical energy (electrodeposited carbon) through the use of an integrated electrochemical reaction system with a molten salt.

Japan, which has ratified the "Paris Agreement" as an international framework for global warming countermeasures after 2020, has set a goal of halving global greenhouse gas emissions by 2050 as compared with the current situation.
For the achievement of this goal, in order to reduce carbon dioxide emissions, which account for most of greenhouse gases, it is necessary to make the best use of renewable energy such as sunlight and wind power. The output of foregoing renewable energy, however, varies significantly with change in weather conditions, and the role of thermal power generation capable of following the load without depending on weather conditions is important for the stabilization of the electric power system. As a contradiction, however, if the ratio of thermal power generation is increased for following the load, carbon dioxide emissions will be also increased. Meanwhile, there is Carbon dioxide Capture and Storage (CCS) cited as one of effective measures for the direct reduction of carbon dioxide, and for example, techniques have been studied in which a high concentration of carbon dioxide separated and collected from exhaust gas of a thermal power plant is stored in the ground or the like.
On the other hand, studies have been also progressed to make efficient use of collected carbon dioxide in a positive manner, rather than simply storing the carbon dioxide in the ground, but for example, Enhanced Oil Recovery (EOR) causes an increase in the amount of oil used, and in addition, in the case of using the carbon dioxide as synthetic raw materials for methanol, dimethyl ether, various polymers, and the like, hydrocarbon raw materials are required in addition to carbon, and hydrogen is also required as a reducing agent. There are many cases of resulting in leading to increased carbon dioxide emissions, and no promising technique has been found.
Meanwhile, the applicant has found that the use of a "molten salt" which is a functional liquid allows "electrolytic deposition of carbon" with carbon dioxide as a raw material. For example, when carbon dioxide is supplied to a molten salt in which oxygen ions (oxide ions, O2−) are present, a carbon dioxide absorption reaction proceeds that produces carbonate ions (CO32−) in accordance with the formula (1).In molten salt: CO2+O2−→CO32−  (1)When this carbonate ion is reduced at a cathode, carbon is deposited on the cathode in accordance with the formula (2), and in this regard, various carbon electrodeposits from dense to porous electrodeposits can be obtained by controlling the electrolytic conditions.Cathodic reaction: CO32−+4e−→C+3O2  (2)With the use of an insoluble anode, some of the produced oxide ions are oxidized on the anode to generate oxygen in accordance with the formula (3).Anodic reaction: 2O2−→O2+4e−  (3)The oxide ions remaining in the molten salt without being oxidized on the anode can be used in the carbon dioxide absorption reaction of the formula (1), and the formulas (1) to (3) can be summed up to the following reaction from carbon dioxide to carbon and oxygen.Total reaction: CO2→C+O2  (4)
On the other hand, the deposited carbon is produced by supplying electric power, and if electric power can be extracted with the use of this carbon as a fuel, a new energy storage system can be created, as in the case of using hydrogen produced by electrolysis of water. Various forms of direct carbon fuel cells (DCFC) that use solid carbon as a fuel have been proposed since the end of the 19-th century, and in recent years, research on the cells has been activated particularly from the viewpoint of high efficiency use of coal.
In DCFC, for example, as in the following formulas (5) and (6), the reduction of oxygen proceeds at the positive electrode, whereas the reaction of generating carbon dioxide from carbon and oxide ions occurs at the negative electrode, and the sum of the formulas results in the reaction of producing carbon dioxide from carbon and oxygen as in the following formula (7).Positive electrode reaction: O2+4e−→2O2−  (5)Negative electrode reaction: C+2O2−→CO2+4e−  (6)Total reaction: C+O2→CO2  (7)
For the solid "carbon fuel" currently used in DCFC, fine coke particles have been often used until now, and there are also cases in which carbon black is used as in Lawrence Livermore National Laboratory or carbon produced by hydrocarbon decomposition is used as in Tokyo Institute of Technology, but carbon obtained from carbon dioxide by the above-mentioned molten salt electrolysis is also expected to be usable as such a carbon fuel.
As described above, the electrodeposition reaction of carbon from carbon dioxide and the oxidation reaction of carbon which proceeds in the direct carbon fuel cell (DCFC), which are totally opposite reactions, are considered capable of creating an apparatus that enables interconversion between electric energy and chemical energy (electrolytic product) through the same electrochemical system, such as a water electrolysis/fuel cell-integrated apparatus in which hydrogen obtained by electrolysis of water is used as a fuel for fuel cell.
Unlike the electrolysis of water (hydrogen generation reaction), however, the electrodeposition reaction of carbon from carbon dioxide deposits the residual electrolytic product on the electrode as a solid (carbon) rather than a gas (hydrogen) which is easily separated and collected, and thus, no attempt has been made to use the product (electrodeposited carbon) as a fuel for fuel cell.

Carbon dioxide electrolysis/carbon fuel cell-integrated apparatus


A method of operating a wagering game comprises detecting receipt of a primary wager for playing a primary wagering game, and activating a first bonus feature in response to one or more first eligibility criteria, the first bonus feature having a first bonus payback percentage. The method further comprises activating a second bonus feature in response to one or more second eligibility criteria, the one or more second eligibility criteria including activation of the first bonus feature. The second bonus feature has a second bonus payback percentage higher than the first bonus payback percentage. The method further comprises displaying a randomly selected outcome of the primary wagering game, and in response to at least one triggering event associated with the first and the second bonus features, conducting the first or second bonus feature if the first and second bonus feature is active.

Gaming machines, such as slot machines, video poker machines and the like, have been a cornerstone of the gaming industry for several years. Generally, the popularity of such machines with players is dependent on the likelihood (or perceived likelihood) of winning money at the machine and the intrinsic entertainment value of the machine relative to other available gaming options. Where the available gaming options include a number of competing machines and the expectation of winning at each machine is roughly the same (or believed to be the same), players are likely to be attracted to the most entertaining and exciting machines. Shrewd operators consequently strive to employ the most entertaining and exciting machines, features, and enhancements available because such machines attract frequent play and hence increase profitability to the operator. Therefore, there is a continuing need for gaming machine manufacturers to continuously develop new games and improved gaming enhancements that will attract frequent play through enhanced entertainment value to the player.
One concept that has been successfully employed to enhance the entertainment value of a game is the concept of a "secondary" or "bonus" game that may be played in conjunction with a "basic" game. The bonus game may comprise any type of game, either similar to or completely different from the basic game, which is entered upon the occurrence of a selected event or outcome in the basic game. Generally, bonus games provide a greater expectation of winning than the basic game and may also be accompanied with more attractive or unusual video displays and/or audio. Bonus games may additionally award players with "progressive jackpot" awards that are funded, at least in part, by a percentage of coin-in from the gaming machine or a plurality of participating gaming machines. Because the bonus game concept offers tremendous advantages in player appeal and excitement relative to other known games, and because such games are attractive to both players and operators, there is a continuing need to develop gaming systems with new types of bonus games to satisfy the demands of players and operators.
Traditionally, wagering games have employed relatively smaller numbers of bonus or supplemental features. Moreover, with activation of multiple bonus features, one problem that arises is that because of limited payback percentages provided my gaming machines, the frequency and size of bonus awards dispensed with such features is reduced. Another problem arises in that a player's perception of risk versus reward causes there to be a disincentive to the player to activate multiple features. This occurs because of the perception that each additional feature involves additional cost to the player, but the benefit is not perceived to be commensurate with such cost. In other words, activating larger number of features does not always result in the player receiving and participating in a proportionately increased number of bonus awards and features. Yet another problem arises in that additional costs of activating such bonus features are not always offset by increased payback percentages or expected values of awards paid out therefrom. The present invention is directed to solving these and other problems.

Gaming system having dynamic payback percentage as a function of enabled features


Methods, apparatus, systems and articles of manufacture are disclosed to manage cache memory in multi-cache environments. A disclosed apparatus includes a remote cache manager to identify a remote cache memory communicatively connected to a bus, a delegation manager to constrain the remote cache memory to share data with a host cache memory via the bus, and a lock manager to synchronize the host cache memory and the remote cache memory with a common lock state.

In recent years, coprocessor boards have been employed in computers (e.g., servers, personal computers, server farms, etc.) to expand one or more capabilities of such computers. The coprocessor boards may include any number of cores, memory and cache arranged on a bus-insertable add-in card. The coprocessor boards allow the computers to meet processing demands in a scalable manner as long as available bus interfaces reside on the host computer.

Methods and apparatus to manage cache memory in multi-cache environments


At least one exemplary embodiment is directed to a zoom lens system having a telephoto-type configuration at the telephoto end. When assuming that an Abbe number is vd, and a partial dispersion ratio is θgF, this zoom lens system includes a refractive optical element having positive refracting power made up of a solid material that can satisfy the following conditions:−2.100×10−3·vd+0.693<θgF0.555<θgF<0.9

1. Field of the Invention
The present invention relates to a zoom lens system and an image pickup apparatus having this system.
2. Description of the Related Art
In recent years, with image pickup elements (photoelectric transfer devices) employed for an image pickup apparatus such as a digital camera, high pixilation has advanced. In response to this, high resolution has been demanded for camera lenses (imaging optical systems) employed for an image pickup apparatus which can have a high pixel image pickup element. In order to realize a high resolution camera lens, it is useful for various aberrations relating to image capabilities at a single color (single wavelength) such as a spherical aberration, and a coma aberration to be reduced well, and in addition to this, it is useful for an image obtained when employing white illumination light to have a well-corrected chromatic aberration so as not to exhibit chromatic bleeding.
On the other hand, in order to enlarge a photographing area, there is demand for camera lenses to serve as a zoom lens which can have a high zoom ratio. Generally, further lengthening of the focal length at a zoom position at the telephoto end to obtain a high zoom ratio causes an increase in the chromatic aberration of magnification (lateral chromatic aberration) to occur at a zoom position on the wide-angle side, and also causes an increase in the chromatic aberration of magnification and axial chromatic aberration (longitudinal chromatic aberration) to occur at a zoom position on the telephoto side. Accordingly, in order to obtain imaging capabilities of high image quality, it has been important to appropriately perform not only primary spectrum correction but also secondary spectrum correction for chromatic aberration. Note that herein when referring to corrections or correcting an aberration, a reduction of the aberration or a correction of the aberration is intended.
In addition to this, recently, there is strong demand for reduction in size of the entire camera lens, due to the reduction in size of image pickup apparatuses.
Generally, with a photographic optical system, the more the entire lens length (distance from the first surface to the image surface, also referred to as "entire optical length") is reduced, the more chromatic aberrations such as axial chromatic aberration and chromatic aberration of magnification occur, and also optical capabilities deteriorate. In particular, with a telephoto-type optical system, the longer the focal length is, the more chromatic aberration expands, and also the more chromatic aberration due to reduction of the entire lens length increases.
As for a method for reducing such occurrences of chromatic aberrations, an achromatic method using an extraordinary partial dispersion material, or an achromatic method using a diffraction grating have been widely known.
With a telephoto-type optical system, a positive lens made up of a low dispersion material having extraordinary partial dispersion such as fluorite, and a negative lens made up of a high dispersion material are commonly employed for reducing chromatic aberrations as a forward lens unit in which the positions where a paraxial marginal ray and a paraxial chief ray pass through are relatively high as to the optical axis. Various types of such a telephoto-type optical system have been discussed (see Japanese Patent Publication No. 1985-49883 (corresponding to U.S. Pat. No. 4,241,983), Japanese Patent Publication No. 1985-55805 (corresponding to U.S. Pat. No. 4,348,084), and Japanese Patent Laid-Open No. 1999-119092 (corresponding to U.S. Pat. No. 6,115,188)).
Note that a paraxial marginal ray is a paraxial ray incident in parallel with the optical axis of an optical system with the height from the optical axis as 1 when normalizing the focal length of the entire optical system to 1. Also, a paraxial chief ray is a paraxial ray passing through the intersection between the incident pupil and optical axis of an optical system, of rays incident by −45 degrees as to the optical axis when normalizing the focal length of the entire optical system to 1. With the incident angle of the optical system, the clockwise rotation measured from the optical axis is assumed to be positive, and the counterclockwise rotation is assumed to be negative. Note that an object is assumed to be present on the left side of the optical system, and the ray incident to the optical system from the object side is assumed to proceed from the left to the right.
Also, a telephoto-type optical system has been known where a diffractive optical element is employed for correcting a chromatic aberration without employing an extraordinary partial dispersion material (see Japanese Patent Laid-Open No. 1994-324262 (corresponding to U.S. Pat. No. 5,790,321), Japanese Patent Laid-Open No. 1994-331887 (corresponding to U.S. Pat. No. 5,629,799), Japanese Patent Laid-Open No. 1997-211329 (corresponding to U.S. Pat. No. 5,872,658)).
Japanese Patent Laid-Open No. 1994-324262 (corresponding to U.S. Pat. No. 5,790,321) and Japanese Patent Laid-Open No. 1994-331887 (corresponding to U.S. Pat. No. 5,629,799) have discussed a telephoto-type optical system having an F number of F 2.8 or so of which a chromatic aberration is corrected relatively appropriately by combining a diffraction-type optical element and a refractive-type optical element.
In addition to these, as for a material, which can have a correction function of a chromatic aberration related to a diffractive optical element, a liquid material exhibiting properties of equivalently high dispersion and also equivalently extraordinary partial dispersion has been known, and an achromatic optical system employing this material has been known (see U.S. Pat. No. 4,913,535 and Japanese Patent Laid-Open No. 2002-156582 (corresponding to U.S. Pat. No. 6,496,310)).
Note that as for a telephoto-type zoom lens, a zoom lens, which can have a 4-unit configuration made up of lens units of positive, negative, positive, and positive refracting power in order from the object side to the image side in which a chromatic aberration is corrected with glass having extraordinary dispersion properties, has been known (see Japanese Patent Laid-Open No. 2001-194590 (corresponding to U.S. Pat. No. 6,404,561) and Japanese Patent Laid-Open No. 2002-62478 (corresponding to U.S. Pat. No. 6,594,087)).
Also, a zoom lens made up of lens units of positive, negative, positive, negative, and positive refracting power in order from the object side to the image side has been known (see Japanese Patent Laid-Open No. 1998-90601 (corresponding to U.S. Pat. No. 6,025,962)).
Glass having great extraordinary dispersion properties such as fluorite or Product Name S-FPL51 manufactured by Ohara Inc. is low in a material refractive index. Accordingly, it is useful for performing the desired secondary spectrum correction to equivalently enlarge the curvature of a lens surface to enforce the refracting power of the lens.
Consequently, a lens made up of such a material has a tendency of enlarging the lens thickness thereof. Also, with an optical system for aiming at suitable chromatic correction effects as apochromat, in order to realize the desired chromatic correction effects, it can be necessary in some circumstances to increase the number of lenses and cemented lens surfaces, and consequently, the entire optical length has been apt to increase to secure the lens thickness.
With the telephoto-type optical systems employing fluorite or other related or equivalent materials as known by one of ordinary skill in the relevant art discussed in Japanese Patent Publication No. 1985-49883 (corresponding to U.S. Pat. No. 4,241,983), Japanese Patent Publication No. 1985-55805 (corresponding to U.S. Pat. No. 4,348,084), and Japanese Patent Laid-Open No. 1999-119092 (corresponding to U.S. Pat. No. 6,115,188), a chromatic aberration is correctable in the case of the entire optical length being set relatively long. However, it can be difficult to correct occurrence of a chromatic aberration accompanied with reduction of the entire optical length. This is because this technique simply reduces chromatic aberrations generated by the forward lens unit itself using low dispersion and extraordinary partial dispersion included in the material such as fluorite. In order to correct chromatic aberrations increased along with reduction of the entire optical length, for example, with an optical system employing low-dispersion glass, which can have a great Abbe number such as fluorite, the chromatic aberration thereof is not changed unless the refracting power of the lens surface is greatly changed. This makes it difficult to satisfy correction of a chromatic aberration and correction of various aberrations such as a spherical aberration, coma aberration, and astigmatism, contemporaneously.
On the other hand, diffractive optical elements have a sufficient correction function of a chromatic aberration. However, the diffraction light of unnecessary diffraction order other than the diffraction light of design diffraction order actually employed becomes a colored flare light, which deteriorates image formation capabilities.
Also, the achromatic optical system employing a liquid material exhibiting relatively extraordinary partial dispersion properties has no function for agglutinating an optical lens, and also needs to have a configuration for sealing. Also, this system also has a problem where properties such as a refractive index and dispersion properties change along with change in temperature, and accordingly, we can say that environmental capabilities are far from being sufficiently satisfied.

Zoom lens system and image pickup apparatus including the same

Abstract: Thus, facilitating the configuration of a zoom lens system capable of appropriately correcting and/or reducing various aberrations, including a chromatic aberration straddling the entire zoom area.


In a transfer, a high thrust can be given to a front-wheel driving clutch by a high magnification function of a screw mechanism. Further, a necessary stroke for an operation of a high-low switching mechanism can be obtained by the screw mechanism. Accordingly, with the use of one motor, the screw mechanism, and a transmission mechanism, it is possible to perform a switching operation of the high-low switching mechanism and a torque adjustment of the front-wheel driving clutch by the same system. Hereby, it is possible to perform, with accuracy, the switching operation of the high-low switching mechanism and the torque adjustment of the front-wheel driving clutch, based on a motor rotation angle Am of one motor.

1. Field of the Invention
The present invention relates to a vehicle power transmission device including: a transfer provided with an input rotational member, a first output rotational member, a second output rotational member, a high-low switching mechanism, and a clutch; and a control device for controlling an operation of the transfer.
2. Description of Related Art
There has been well known a transfer including: a high-low switching mechanism for changing a speed of a rotation of an input rotational member and transmitting it to a first output rotational member; and a single-disc or a multi-disc clutch for adjusting a transmission torque to be transmitted from the first output rotational member to a second output rotational member. For example, U.S. Patent Application Publication No. 2007/0251345 describes a transfer including a high-low switching mechanism and a multi-disc clutch for adjusting a torque to be transmitted to a sub-driving wheel side. In the transfer described in U.S. Patent Application Publication No. 2007/0251345, a switching operation of the high-low switching mechanism and a torque adjustment of the clutch are performed by one motor. On that account, in the transfer described in U.S. Patent Application Publication No. 2007/0251345, a conversion mechanism for converting a rotation of the motor into a linear motion employs a drum cam system for the switching operation of the high-low switching mechanism, and a ball-cam+lever system for the torque adjustment of the clutch. Further, in the transfer described in U.S. Patent Application Publication No. 2007/0251345, the rotation of the motor is decelerated and transmitted to an actuator shaft, and based on a signal value of a rotation angle sensor on the actuator shaft, respective controls on the switching operation of the high-low switching mechanism and the torque adjustment of the clutch are executed.


A shock absorbing type steering device decreases variations in press fitting loads corresponding to a friction force between two columns. A shock can be appropriately absorbed by relative movements of the two columns in an axial direction. At least one of a first column and a second column press fitted into an opening at one end of the first column is formed with swaged parts on a peripheral wall thereof at a plurality of positions having intervals in a circumferential direction of the column, respectively at a plurality of positions having intervals in an axial direction of the column. Positions of tip ends of the swaged parts are different between a group of swaged parts near the opening at the end of the first column and other groups remote from the opening.

1. Field of the Invention
The present invention relates to a shock absorbing type steering device to be employed for absorbing a shock which will attack a driver in the event of collision of vehicles, and a method of producing the same.
2. Description of the Related Art
There has been heretofore used a shock absorbing type steering device having a first column in a cylindrical shape and a second column in a cylindrical shape which is press fitted into an opening at one end of the first column, and adapted to absorb a shock in the event of collision of a driver with a steering wheel mounted on a steering shaft which is covered with the two columns, by relative movements of the two columns in an axial direction.
In the shock absorbing type steering device as described above, the shock will be absorbed by friction force acting between the two columns when the first column and the second column move in an axial direction relative to each other. Therefore, in case where such shock absorbing type steering devices are manufactured in mass production, variations in loads of press fitting the second column to the first column corresponding to the friction force between the two columns must be minimized, so that the shock can be appropriately absorbed. Such variations in the press fitting loads can be minimized by decreasing dimensional tolerance of an inner diameter of the first column or an outer diameter of the second column. However, in order to decrease such dimensional tolerance, it is necessary to accurately work with an inner periphery of the first column or an outer periphery of the second column, and working cost will be increased.
Under the circumstances, it is considered that the first column is provided with swaged parts which are arranged in a row in a circumferential direction of the column on a peripheral wall thereof, respectively at two positions spaced in an axial direction of the column, and thereafter, the second column is press fitted into an opening at one end of the first column so as to press the two columns to each other by way of the swaged parts (Patent document No. 1). Because it is easier to accurately swage so that the dimensional tolerance of swaging depth may be decreased, as compared with a case of accurately working with the inner periphery of the first column or the outer periphery of the second column, variations in the press fitting loads can be minimized at a low cost.
[Patent Document No. 1]
Japanese Patent Publication No. JP-A-10-203381
However, in the conventional structure in which the swaged parts have been formed as described above, it has been impossible to sufficiently decrease those variations in the press fitting loads. Specifically, in the conventional structure, there have been formed swaged parts 101a, 101b which are arranged in a row in a circumferential direction of the column, on a peripheral wall of a first column 101 made of steel, respectively at two positions spaced in an axial direction of the column, as shown in FIG. 6, and thereafter, a second column 102 made of steel has been press fitted into an opening 101A at one end of the first column 101. In this case, a diameter D of a circle defined by tip ends of the swaged parts 101a positioned close to the opening 101A has been made equal to a diameter D of a circle defined by tip ends of the swaged parts 101b positioned remote from the opening 101A.
FIG. 7 is a graph showing relation between strokes and press fitting loads of the second column 102 with respect to the first column 101 on occasion of press fitting in the conventional case, as results obtained in five samples. In this case, the swaged parts 101a, 101b were formed at eight positions in a circumferential direction, respectively at two positions spaced in an axial direction of the column. An inner diameter D1 of the first column 101 was 34.06 mm, an outer diameter D2 of the second column 102 was 33.115 mm, the diameter D of the circles defined by the tip ends of the swaged parts 101a, 101b was 31.82 mm, a thickness of each of the columns 101, 102 was 2.0 mm, an axial length L of each of the swaged parts 101a, 101b was 13.8 mm, a distance L1 from the opening 101A to the swaged parts 101a close to the opening was 2.6 mm, and a distance L2 from the opening 101A to the swaged parts 101b remote from the opening was 49.6 mm. The press fitting loads in the five samples have slightly increased when the swaged parts 101a at the position close to the opening 101A of the first column have been pressed onto the outer periphery of the second column 102, and have largely increased when the swaged parts 101b at the position remote from the opening 101A have been pressed onto the outer periphery of the second column 102. It has been recognized that when the swaged parts 101b at the position remote from the opening 101A have been pressed onto the outer periphery of the second column 102, variations in the press fitting loads have amounted to 300N at most. An object of the present invention is to provide a shock absorbing type steering device in which such variations in press fitting loads can be decreased, and a method of producing the same.

Shock absorbing type steering device for vehicles and method of producing the same


Apparatus for melting and heating shortening includes a housing having a top, a bottom and sidewalls; a heating grid mounted in the housing and spaced above the bottom thereof for melting shortening and allowing melted shortening to pass therethrough toward the bottom of the housing. A door is mounted to the housing for introducing a block of shortening onto the heating grid. A bottom heater is mounted adjacent the housing bottom for maintaining the melted shortening at a desired temperature. A control circuit maintains control of the operation of both the heating grid and the bottom heater in a predetermined fashion for initially melting a block of shortening introduced onto the heating grid while substantially preventing smoking of the same, and for maintaining melted shortening at the desired temperature.

The invention is directed generally to the heating apparatus arts and more particularly to a novel and improved shortening and heating apparatus for use in melting large cubes of shortening and thereafter holding a supply of melted shortening at a relatively stable temperature, to be dispensed in desired quantities for use.
In large scale food service operations as, for example, of the so-called "fast food" variety and the like, large quantities of shortening are used in the course of the day. At normal room temperature, shortening is generally in solid form. However, it is desirable to have the shortening in liquid form for cooking. Accordingly, when such large quantities of shortening are required, it is also desirable to have a supply of heated shortening in liquid form to be dispensed for use as necessary.
Heretofore, systems for heating and melting shortening often cause excessive smoking of the shortening, particularly during the melting thereof. It is desirable to avoid such smoking. It is also been found desirable to prevent the heating elements from operating when no shortening, or insufficient shortening is present, whether in solid form or liquid form. We have further found that it is desirable to discontinue melting operations, or to take other means to prevent the melting of further shortening in the event the apparatus reaches a predetermined fill level.


Novel semaphorin Z; a gene thereof; a partial peptide of the semaphorin Z; an antibody; a DNA or an RNA complementary to the semaphorin Z gene; a method for screening a semaphorin Z inhibitor by using the semaphorin Z; the semaphorin Z inhibitor obtained by the screening; and a CNS neuron regeneration promoter comprising the inhibitor.

It is widely known that a central nervous system (CNS)-neuron in higher organisms such as human is not capable of regeneration once injured. Therefore, one who has received an injury on his (her) spinal cord due to, for example, a traffic accident is compelled to spend the rest of his (her) life in a hemiplegic state. On the contrary, it is known that a peripheral nervous system (PNS)-neuron retains a vigorous regeneration ability even in those higher organisms, and therefore, neurons in a limb, when disconnected, can gradually regenerate with a concomitant recovery of their function.
In early nineteen-eighties, a group of Aguayo et al. found that when PNS-neuron is experimentally grafted into an injured CNS-neuron in a higher organism, axon growth of CNS-neuron is induced. This observation demonstrates that CNS-neuron in higher organisms which had been generally considered not to have a regeneration ability can regenerate if a suitable environment is provided (Nature, 284, 264-265 (1980), Science, 214, 931-933 (1981)). That report suggests a possibility that in CNS of higher organisms, there may exist a factor, namable "CNS-neuron regeneration inhibitor", which inhibits the regeneration of CNS-neuron, and that a release from such inhibition may allow the regeneration of CNS-neurons. This suggestion paved the way for a CNS-neuron regeneration therapy.
In 1988, a group of Schwab et al. demonstrated that there existed such CNS-neuron regeneration inhibitor among proteins derived from CNS myelin. They also succeeded in purifying, though partially, a protein having said CNS-neuron regeneration inhibition activity, and named this protein fraction NI35/250 (Annu. Rev. Neurosci., 16, 565-595 (1993)), although no one has succeeded in its isolation, identification and gene cloning yet. In addition, they immunized animals with the partial purified NI35/250, and succeeded in obtaining an antibody (IN-1) having a neutralizing activity. This antibody is capable of recognizing a band for NI35/250 in Western blotting, and capable of staining, in an immunostaining, the region where NI35/250 is supposed to be distributed. Furthermore, they demonstrated that administration of this antibody to an animal experimentally received an injury on its spinal cord has promoted regeneration of axons in spinal cord, though partially, within 2-3 weeks, and restored its function within 2-3 months (Nature, 343, 269-272 (1990), Nature, 378, 498-501 (1995)). These findings are of great value, because they experimentally demonstrated that there existed a CNS-neuron regeneration inhibitor as suggested by Aguayo et al. (supra) and that CNS-neuron can be regenerated by inhibiting the activity of said inhibitor. The above noted antibody is, however, directed not to human but to rat NI35/250, and exhibits a low stability and specificity. In addition, although regeneration of CNS-neuron was observed as described above by administering said antibody, its effect was so partial and incomplete that not all of the motor functions could be restored. It is, therefore, believed essential in solving these problems to identify the gene coding for NI35/250 or corresponding CNS-neuron regeneration inhibitor, and, based on knowledges of molecular biology, neuroscience and the like, develop an inhibitor effectively inhibiting the CNS-neuron regeneration inhibition activity, or develop a method for inhibiting the expression of the gene for said regeneration inhibitor.
Apart from the above, the nervous system, whether it is central or peripheral, requires formation of a complicated neural network among neurons or between neurons and peripheral receivers or effectors during development, that is, in the stage of embryo or fetus, in order to precisely carry out its principal functions, i.e., to transfer and process the information. To establish the neural network, an ingenious mechanism is necessary, which precisely guides a growing neurite to the target site locating remote therefrom.
It has been hitherto believed that a factor which positively control the neurite outgrowth such as neurite growth promoter and neurite growth attractant may play a major role in the formation of the neural network. However, it is now being demonstrated by recent studies on the mechanism of the network formation that the opposite factor, that is, a negative factor having an outgrowth inhibition activity is important for an accurate guidance (Cell, 78, 353-356 (1994)).
A representative factor having such an outgrowth inhibition activity is a protein called "Semaphorin". Semaphorin firstly discovered is Fasciclin IV found in grasshopper. Collapsin (latterly named Collapsin I) was subsequently discovered in chick (Cell, 75, 217-227 (1993); Neuron, 9, 831-845 (1992)). To date, more than 10 genes belonging to the Semaphorin family have been reported in a wide range of species covering insects such as drosophila and beetle, human, and viruses (Cell, 81, 471-474 (1995)). These Semaphorins characteristically contains in their amino acid sequences a certain structure called semaphorin domain consisting of about 500 amino acids (Neuron, 14, 941-948 (1995); Cell, 75, 1389-1399 (1993)). However, the homologies of the primary amino acid sequences in Semaphorin domains among these Semaphorin genes are 80-20%, and not necessarily high.
Of these Semaphorins, functions have been verified for only a few, including, for example, Fasciclin IV of grasshopper, Semaphorins I and II of drosophila, Collapsin of chick, and Semaphorin III which corresponds to Collapsin in mammals. All of these Semaphorins are known to inhibit neurite outgrowth and synapsis formation. In particular, Semaphorin III has been reported to have an activity collapsing in a short time the growth cone of cultured neuron (growth-cone collapse activity) in vitro (Neuron, 14, 941-948 (1995); Neuron, 14, 949-959 (1995); Cell, 81, 631-639 (1995); Cell, 75, 1389-1399 (1993); Cell, 75, 217-227 (1993); Neuron, 9, 831-845 (1992)).
Although it is now being demonstrated, as described above, that Semaphorin has a growth-cone collapse activity and a neurite outgrowth inhibition activity during development, and plays a role in giving an accurate guidance to neuron, it is not evident at present whether or not Semaphorin exerts some function not only during development but also in the adult, and less evident whether or not Semaphorin plays a role as a CNS-neuron regeneration inhibitor. Of course, since Semaphorin has been shown to be a negative guidance factor inhibiting neurite outgrowth, it would not be unreasonable to consider said Semaphorin as a candidate for a CNS-neuron regeneration inhibitor (Nature, 378, 439-440 (1995)). However, it has been shown by in vitro experiments that Semaphorin III (Sema III), only one Semaphorin of higher organisms of which function has been analyzed, exerts its neurite-outgrowth inhibition activity on a sensory neuron and sympathetic neuron both of which are peripheral, but not on a retinal neuron which is central (Cell, 75, 217-227 (1993)). In addition, Northern analysis on the distribution of Sema III expression in the adult conducted by the present inventors has revealed that it is expressed mainly in peripheral tissues (see Reference example 2 below). It is therefore hardly believed that Sema III having such features has a function as a "CNS-neuron regeneration inhibitor".


Disclosed are various examples for threat detection and security for edge devices in communication with Internet-of-Things (IoT) devices. In one example, a profile is associated with a virtual machine of a gateway device. The profile includes an expected behavior for the virtual machine. The virtual machine is executed by a hypervisor of the gateway device. An actual behavior for the virtual machine is determined. A remedial action is performed. The remedial action is based on an anomaly between the expected behavior and the actual behavior.

An enterprise can utilize a management service capable of protecting email, corporate documents, and other enterprise data from theft, data loss, and unauthorized access. The management service can provide various applications for the enterprise and end users associated with the enterprise. The enterprise can also provide applications for the end users through the management service. Errors that occur in an application can be debugged in order to ensure effectiveness of the applications and productivity of users.
In some cases, applications are not sufficiently tested in development cycles to provide completely error-free code. In addition, actual product usage can subject applications to additional scenarios that are not anticipated by the management service or the enterprise. Log files for the application can be useful for identifying error conditions and other issues with the operation of the application by end users. The log files can capture personally identifiable information and other parameters that end users of the application, or the enterprise, desires to maintain secured. Providing effective security solutions for log files can be costly in time and effort in an enterprise environment. Securely providing log files for debugging can include numerous back-and-forth communications with end users. Further, current solutions do not provide a way for end users or enterprises to ensure that the information in the log files is aggregated in a protected manner.


A bubble blower and penholder arrangement is disclosed to include a penholder holding a writing element, and a bubble blower mounted in the penholder for pressing by hand to extend the writing element out of the penholder for writing. The bubble blower includes a fluid container, which has a bottom extension tube inserted into the penholder and stopped at the top end of the writing element, and an applicator detachably fastened to the fluid container for picking up the bubble fluid for blowing bubbles.

1. Field of the Invention
The present invention relates bubble blowers and, more specifically, to the arrangement of a bubble blower and the penholder of a pen, in which the bubble blower can be pressed to drive the writing element of the pen out of the penholder for writing.
2. Description of the Related Art
A conventional bubble-blowing apparatus generally comprises a fluid container holding a bubble fluid, and an applicator for picking up the bubble fluid from the fluid container for blowing bubbles. There are also known pen-base bubble blowers. A pen-base bubble blower is generally comprised of a penholder holding a writing element for writing, and an applicator. The penholder has a top open chamber adapted to hold a bubble fluid. The applicator can be fastened to the penholder to close the top open chamber. Due to limited space, the top open chamber holds a limited amount of bubble fluid. According to this design, the applicator cannot be designed as pres means for pressing by the user to control the movement of the writing element of the pen between the writing position and the non-operative position.
The present invention has been accomplished under the circumstances in view. It is the main object of the present invention to provide A bubble blower and penholder arrangement comprising a penholder holding a writing element, and a bubble blower mounted in said penholder for pressing by hand to extend said writing element out of said penholder for writing, said bubble blower comprising a fluid container holding a bubble fluid, and an applicator insertable into said fluid container to pick up said bubble fluid for blowing bubbles, said fluid container having a top bottleneck through which said applicator is inserted into the inside of said fluid container to pick up said bubble fluid, and a bottom extension tube inserted into said penholder and stopped at a top end of said writing element in said penholder.

5th Floor, No. 4, Lane 7, Pao Kao Road, Hsintien


A frame assembly for a lower blanking tool of a carton die cutting machine. The frame assembly includes a rigid outer frame, an inner grid comprised of a plurality of lengthwise and crosswise extending bars, and a plurality of clamp devices attaching the bars to the outer frame. Each clamp device includes an upright plate member in which is formed a substantially U-shaped upper cavity. A wedge is disposed within the cavity for sliding movement between clamped and released positions to rigidly hold the ends of the bars of the inner grid to the outer frame. In an alternate embodiment, the clamp has an upper and lower cavity together with upper and lower wedges which are simultaneously moved between clamped and released positions.

The present invention relates to die cutting machines for making carton blanks, and more particularly to a frame assembly for a lower blanking tool that supports carton scrap during a blanking operation in a die cutting machine.
In the manufacture of cartons, small sheets of paper material having specific profiles are cut out of larger sheets of paper material. These smaller sheets are known as carton blanks which, in turn, are formed into cartons and/or boxes. The blanks are formed during a process known as a blanking operation in a die cutting machine.
In a die cutting machine, the blanks are cut, but not removed from a large sheet of paper material. After the blanks have been cut, the sheet is moved downstream in the die cutting machine to a blanking station where the sheet is positioned over a frame assembly for support. The frame assembly includes an outer frame and an inner grid having large openings which correspond in size, in shape and in position to the profile of the carton blank previously cut. Below the frame is a mechanism for stacking the carton blanks.
At the blanking station, an upper tool is used in combination with the lower tool or frame assembly to knock the carton blanks from the sheet of paper material while holding the scrap material that surrounds the blanks. The upper tool has a support board that moves vertically up and down in the die cutting machine, and the support board typically has a plurality of stand-offs depending therefrom that hold pushers spaced beneath the board which in turn are used to push the carton blanks from the sheet through the lower tool or frame assembly. A plurality of presser assemblies are also mounted in the support board and depend therefrom to hold the scrap material against the lower tool or frame assembly during the blanking operation so that the blanks may be pushed from the sheet. A presser assembly typically includes a presser rail which is biased downwardly away from the support board by a spring so that the rail is positioned slightly below the pushers. As the upper tool is lowered, the presser rail engages the sheet of paper material first such that a scrap portion of the large sheet of material is secured between the presser rail and the frame. The upper tool then continues to be lowered such that the sheet of material engages the inner grid within the frame while at substantially the same time the pushers engage the carton blanks and knock the blanks out of the sheet of material and through the inner grid. The carton blanks then fall into a stacking mechanism below the frame where the blanks are stacked for further processing.
The lower tool used in the blanking operation is typically comprised of a steel outer frame that supports an inner grid. The inner grid is typically comprised of a plurality of lengthwise and crosswise extending bars. In order to secure the inner grid in place on the outer frame, the end of each bar is typically screwed onto attachment pieces which in turn are mounted on the lengthwise and crosswise rails of the outer frame. Since the frame and grid support a sheet of paper material during the blanking operation, the grid must be configured to match or conform to the die cut in the sheet of paper material. In addition, the grid must be reconfigured whenever a different carton blank needs to be produced. Thus, unscrewing the inner grid from the outer frame oftentimes becomes very cumbersome and time consuming. Thus, it is desirable to provide a quicker manner of attaching and removing the inner grid from the outer frame.
Other types of attachment pieces include wedges which are used to clamp the ends of the bars in place. Although these wedges provide a type of quick-connect and quick-disconnect for the bars of the grid, they also have the disadvantage of oftentimes moving the bars slightly during assembly. Movement of the bars, even slight movements thereof, result in the grid being misaligned with the die cut in the sheet of paper material which in turn may result in an imprecise blanking operation.
It is an object of the present invention to provide an improved frame assembly for a lower blanking tool of a carton die cutting machine.
It is another object of the present invention to provide a frame assembly for a lower blanking tool that includes an inner grid that may be easily attached and removed from its supporting outer frame, can be precisely positioned during assembly, and yet maintains its rigidity during normal blanking operations.
It is yet another object of the invention to provide a frame assembly for a lower blanking tool which is easy to assemble, compatible with standard blanking operation machinery, and relatively inexpensive.
In order to accomplish the above objects, the present invention provides a frame assembly for a lower blanking tool of a carton die cutting machine. The frame assembly includes a rigid outer frame, and an inner grid comprised of a plurality of lengthwise and crosswise extending bars for supporting a sheet of die cut paper material during a blanking operation. The frame assembly also includes a plurality of clamps attaching the ends of the bars of the inner grid to the outer frame. Each clamp comprises an upright plate member defining a substantially flat vertically extending inner face, a substantially flat opposite vertically extending outer face, and a horizontally extending upper face. A substantially U-shaped upper cavity is formed in the inner face of the plate member and opens at its upper end to the upper face. The upper cavity defines an upper abutment surface, an opposite downwardly sloped surface disposed at an acute angle with respect to the upper abutment surface, and an upper support surface. An upper wedge member is disposed within the upper cavity for sliding movement along the downwardly sloped surface between clamped and released positions. The upper wedge is also substantially U-shaped and defines a clamping surface disposed parallel to and spaced from the upper abutment surface, an opposite downwardly angled surface disposed to engage against and slide along the downwardly sloped surface of the U-shaped upper cavity, and a base surface disposed substantially parallel to and spaced from the upper support surface of the cavity when the wedge member is in its clamped position. A screw extends through the upper wedge member into the upper support surface and is used to move the upper wedge between its clamped and released positions so as to hold or clamp the end of a bar of the inner grid between the abutment surface of the upper cavity and the clamping surface of the wedge member.
In another aspect, the invention includes the clamping device itself for attaching the bars of an inner grid to the outer frame of the lower blanking tool of a carton die cutting machine. The clamping device includes the upright plate member, U-shaped upper cavity and upper wedge member described above. However, in an alternate embodiment, the clamping device may also include a lower U-shaped cavity and a lower wedge member disposed within the lower cavity for sliding movement along an upwardly sloped surface between clamped and released positions. The lower cavity is preferably a mirror image of the upper cavity, and is used to clamp a bar of the inner grid at two points rather than only a single point if only the upper cavity and upper wedge is utilized. This is particularly useful to attach the lengthwise or machine direction bars of the inner grid as these bars may be taller than the crosswise bars.

Clamp pieces for lower frame assembly of blanking tool


A torque limiting clutch which transmits gradually increasing torque up to a prescribed limit at which limit the clutch disengages from its load. An embodiment designed for light service use in dentistry encloses all the working parts in a housing through which torque is applied to the load, and is autoclavable. This embodiment can be attached to known dental headpieces for assembling components of dental restorations with prescribed limited torque.

Improvements in the field of dental implantology have given restorative dentists and their partially or wholly edentulous patients the increasing option to support new artificial teeth on artificial roots. Prominent among the artificial roots that have become available is the osseointegrated dental implant fixture; commonly, this fixtures takes a cylindrical form which is implantable in the patient's jawbone and has an axially located internally-threaded bore for receiving an externally threaded bolt which is used to attach to the implant fixture an artificial tooth, or an intermediate component between the fixture and the tooth. In practice one or more such bolts may be used to attach one tooth to an artificial root. The artificial tooth itself is frequently built on, or includes in its structure, a component which is designed and intended for cooperation with such a bolt. Thus, threaded bolts are important subcomponents in the structures of artificial teeth in a dental restoration supported on a dental implant fixture or fixtures.
With experience has come the realization that the bolts used in such dental restorations may have certain critical properties. The implant fixtures and the components assembled on them are made of materials chosen for suitability in dental use; presently the metal titanium is the material of choice. The bolts may suitably but not necessarily be made of gold. These are not hard metals such as steel that are commonly used in industrial structures, yet the bolts must be tightened enough so that the restored dentition will not fail in use. Attention has been given to designing and making the implant fixtures and related components to a high degree of dimensional precision and repeatability to minimize the opportunity of components to rock against each other and the implant fixture and thereby bending the attaching bolts and eventually breaking them. And, more recently, attention has been given to tightening the bolts just enough so that they will hold all the assembled parts tightly together throughout the range of forces those parts will encounter in use, but not so much that the bolts will be stretched beyond their elastic limit and break. The small sizes in which these bolts are made, as low as 1/16th of an inch, and generally not more than 1/8th of an inch in diameter at the peaks of their threads, have made this a critical and burdensome problem. To respond to the problem some tool manufacturers have provided complicated machines for controlling the torque applied to the bolts during assembly of the teeth and components on dental implant fixtures. Such machines that are currently available employ cabinets enclosing complex electronic motor control circuitry, a motor-driven handpiece for holding and driving a screwdriver bit, and a long flexible cable connecting the handpiece to the cabinet. Along with all this gadgetry is a group of settable controls on the cabinet and a handbook telling the dentist how to operate and maintain the equipment, and, of course, a correspondingly-high price.


A host Virtual Machine Monitor (VMM) operates “blindly,” without the host VMM having the ability to access data within a guest virtual machine (VM) or the ability to access directly control structures that control execution flow of the guest VM. Guest VMs execute within a protected region of memory (called a key domain) that even the host VMM cannot access. Virtualization data structures that pertain to the execution state (e.g., a Virtual Machine Control Structure (VMCS)) and memory mappings (e.g., Extended Page Tables (EPTs)) of the guest VM are also located in the protected memory region and are also encrypted with the key domain key. The host VMM and other guest VMs, which do not possess the key domain key for other key domains, cannot directly modify these control structures nor access the protected memory region. The host VMM, however, using VMPageIn and VMPageOut instructions, can build virtual machines in key domains and page VM pages in and out of key domains.

The term "cloud computing" is used to describe network-based computing (typically over the Internet). According to Wikipedia, "cloud computing provides shared processing resources and data to computers and other devices on demand. Cloud computing is a model for enabling ubiquitous, on-demand access to a shared pool of configurable computing resources (e.g., networks, servers, storage, applications and services), which can be rapidly provisioned and released with minimal management effort. Cloud computing and storage solutions provide users and enterprises with various capabilities to store and process their data in third-party data centers. Cloud computing relies on sharing of resources to achieve coherence and economy of scale, similar to a utility (like the electricity grid) over a network." (Source: Wikipedia, https://en.wikipedia.org/wiki/Cloud_computing, visited Aug. 11, 2016, citations omitted.)
The present availability of high-capacity networks, low-cost computers and storage devices as well as the widespread adoption of hardware virtualization, service-oriented architecture, and autonomic and utility computing have led to a growth in cloud computing. Companies can scale up by requesting additional resources from cloud services provider as computing needs increase and then scale down again as demands decrease.
Cloud computing provides resources as services. "Cloud-computing providers offer their 'services' according to different models, of which the three standard models per the National Institute of Standards and Technology (NIST) are Infrastructure as a Service (IaaS), Platform as a Service (PaaS), and Software as a Service (SaaS). These models offer increasing abstraction; they are thus often portrayed as layers in a stack, with infrastructure-as-a-stack serving as the bottom layer; platform-as-a-service serving as the middle layer; and software-as-a-service serving as the top layer. These layers can be implemented independently of one another. For example, one can provide SaaS implemented on physical machines (bare metal), without using underlying PaaS or IaaS layers; and conversely one can run a program on IaaS and access it directly, without wrapping it as SaaS." (Source: Wikipedia, https://en.wikipedia.org/wiki/Cloud_computing, visited Aug. 11, 2016, citations omitted.)
"The NIST's definition of cloud computing defines the service models as follows:
Software as a Service (SaaS). The capability provided to the consumer is to use the provider's applications running on a cloud infrastructure. The applications are accessible from various client devices through either a thin client interface, such as a web browser (e.g., web-based email), or a program interface. The consumer does not manage or control the underlying cloud infrastructure including network, servers, operating systems, storage, or even individual application capabilities, with the possible exception of limited user-specific application configuration settings.
Platform as a Service (PaaS). The capability provided to the consumer is to deploy onto the cloud infrastructure consumer-created or acquired applications created using programming languages, libraries, services, and tools supported by the provider. The consumer does not manage or control the underlying cloud infrastructure including network, servers, operating systems, or storage, but has control over the deployed applications and possibly configuration settings for the application-hosting environment.
Infrastructure as a Service (IaaS). The capability provided to the consumer is to provision processing, storage, networks, and other fundamental computing resources where the consumer is able to deploy and run arbitrary software, which can include operating systems and applications. The consumer does not manage or control the underlying cloud infrastructure but has control over operating systems, storage, and deployed applications; and possibly limited control of select networking components (e.g., host firewalls)." (Source: Wikipedia, https://en.wikipedia.org/wiki/Cloud_computing, visited Aug. 11, 2016, citations omitted.)
One enabling technology for cloud computing is virtualization. "Virtualization software separates a physical computing device into one or more 'virtual' devices, each of which can be easily used and managed to perform computing tasks. Hardware virtualization is the virtualization of computers as complete hardware platforms, certain logical abstractions of their componentry, or only the functionality required to run various operating systems. Virtualization hides the physical characteristics of a computing platform from the users, presenting instead another abstract computing platform," often referred to as a 'virtual machine.' (Source: Wikipedia, https://en.wikipedia.org/wiki/Hardware_virtualization, visited Aug. 11, 2016, citations omitted.) The software that controls virtualization is referred to as a "hypervisor" or "virtual machine monitor." The provisioning and execution of a hypervisor/virtual machine monitor to create virtual machines on behalf of the consumer is an example of a service provided by a public cloud services provider.

Secure public cloud using extended paging and memory integrity


Methods, computing systems and computer program products implement embodiments of the present invention that include detecting, by a file-level storage system such as a network attached storage system, a user operating a first computer in communication with the file level storage system via a network, and maintaining, while the user is operating the first computer, multiple states for the user. In some embodiments, the user may operate the first computer by logging on to the first computer, and executing one or more applications and data files. Upon detecting the user operating a second computer in communication with the file level storage system via the network, the file-level storage system can synchronize applications and data files on the second computer to the multiple states. In embodiments of the present invention, the user operates the second computer by logging on to the second computer while still logged on to the first computer.

Network attached storage (NAS) is file-level computer data storage system connected to a computer network that provides data access to a heterogeneous group of clients. A NAS system typically comprises a computer connected to a network that provides file-based data storage services to other client devices on the network. In operation a NAS system appears to the clients as a file server (the client can map network drives to shares on that server) storing files in a single rooted tree of directories.
The description above is presented as a general overview of related art in this field and should not be construed as an admission that any of the information it contains constitutes prior art against the present patent application.

Synchronizing user states across multiple clients of a NAS system

INTERNATIONAL BUSINESS MACHINES CORPORATION


A virtual gift credit system that automatically attaches gift credit to a payment account or vehicle of the gift recipient upon issuance of the gift credit is herein described. By attaching the gift credit amount to the recipient's payment account, subsequent purchases made using the payment account, and of the type associated with the gift credit, are automatically settled by applying the gift credit amount to the purchase amount. Further, the invention does not require gift recipients to share confidential account information with gift providers in order for the gift providers to bestow gift credit upon the gift recipients. Through the use of aliases, which serve to tie an identifier, such as a gift recipient's telephone number, email address or the like to a gift recipient's payment account, the invention does not require that the gift provider know any information about the financial accounts of the intended gift recipient.

Most merchants have replaced traditional gift certificates with gift cards, which are credit card-like in design and allow for the merchant to program the magnetic strip in the amount that the gift-providing customer desires. In the online realm, merchants provide gift credit in the form of gift codes, which upon purchase may be electronically communicated, via email or the like, to the gift-recipient.
In either instance, the gift recipient must remember to bring the gift card to the merchant or remember the gift code or location of the gift code when redeeming the credit towards a subsequent purchase. In many instances the recipient of a gift card may forget to bring the card with them to the associated merchant or otherwise forget that they have an outstanding gift card for that particular merchant. Likewise, the recipient of a gift code may be unable to locate the gift code or may have deleted the gift code communication prior to redeeming the gift code.
Therefore, a need exists to develop systems, methods, computer program products and the like that allows for gift-providing customers to gift credit to a gift-recipient, such that upon receipt of the credit, the gift-recipient can ostensibly forget that they have the credit yet subsequently have the credit automatically applied towards future purchases. In effect, the desired invention eliminates the need for the gift-recipient to remember to bring a gift card or gift code to a merchant and, moreover, allows the gift-recipient to redeem the credit even if they forget that they have the gift credit.