The invention discloses compositions and methods for increasing chemotherapeutic specificity to endocrine dependent cancers, and reducing systemic toxicity, through administration of endocrine hormones in conjunction with administration of phase specific chemotherapeutics. The invention also discloses why prior art phase specific chemotherapeutic regimens fail to achieve high cure rates for cancer. The failure relates to the Gompertzian acceleration, or reduction in cancer cell cycle time, induced by the chemotherapeutic reduction of tumor size, which in turn results in the cancer""s lack of phase synchronicity to subsequent administrations of the phase specific chemotherapeutic(s). The invention discloses how to avoid this failure in endocrine dependent cancers by using endocrine blockers between chemotherapeutic administrations to halt the cancer cells from passing the S-Phase and then using endocrine hormones to restart and accelerate S-Phase progression in conjunction with administration of appropriate phase specific chemotherapeutic(s).

Prior art has used endocrine downregulation therapy to downregulate the growth of endocrine dependent cancers. Present invention takes exactly the opposite approach, using endocrine upregulation to accelerate the growth of cancer in conjunction with administration of phase specific chemotherapeutics to increase tumor kill rates and reduce systemic toxicity over prior art.
Additionally, prior art has been unable to achieve high cure rates using phase specific chemotherapeutics in non endocrine dependent metastatic cancers as well. Applicant has discovered that the primary reason is prior art""s failure to adjust the chemotherapeutic administration intervals for cancer""s accelerated growth rate over successive chemotherapeutic administrations. This failure results in the cancer""s return to an asynchronously cycling population which is mathematically a catastrophic event in the context of a phase specific administration regimen. Accordingly, applicant has disclosed methods for computing variable administration intervals that will keep the phase specific chemotherapeutic synchronized with the susceptible phase in the target cancer population. Alternatively, applicant has also disclosed methods of modulating the growth rate of endocrine dependent tumors by using endocrine hormones so as to keep a target cell population synchronized to a given administration regimen.
Definitions
As used in this application, the term xe2x80x9cendocrine dependent cancer(s)xe2x80x9d is used to mean cancers that have retained the functional hormone receptors normally present in the underlying tissue from which they arose and whereby cancer cells possessing these receptors will respond to administration of exogenous hormones by upregulating DNA synthesis. Examples of hormone receptors include, but are not limited to, estrogen receptors, progesterone receptors, and testosterone receptors.
Harrison""s Principles of Internal Medicine (14th ed. p. 527-536) categorizes prior art drug treatments used for cancer into four broad categories Chemotherapy, Endocrine Therapy, Immunotherapy, and Hematopoietic Growth Factors. Chemotherapy relates to substances toxic to cancer. Endocrine Therapy relates to inactivating or inhibiting steroids produced by the body that promote growth of certain cancers. Immunotherapy relates to enhancing various aspects of the natural human immune system to inhibit growth of cancer. Hematopoietic Growth Factors focus on enhancing recovery of bone marrow products for patients receiving myelosuppressive chemotherapy. Chemotherapy and Endocrine therapy have relevance to present invention and as such a brief background of prior art is provided.
Prior Art Chemotherapeutics (HPIM 14th ed. pgs. 527-534)
Most chemotherapeutic agents in use today are cell cycle active; that is, they are cytotoxic mainly to actively cycling cells. In addition, some cell cycle active agents are phase specific; that is, they are cytotoxic to cells in a particular phase of the cell cycle.
Alkylating agents are among the most widely used anti tumor agents and are efficient at cross-linking DNA, leading to strand breakage. Alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine (nitrogen mustard), chlorambucil, thiotepa, carmustine, lomustine as well as platinum compounds such as cisplatin and carboplatin, which are not true alkylating agents also lead to covalent cross linking of DNA. These agents are best regarded as cell-cycle active but non-phase specific.
Purine/pyrimidine analogs/antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. They are cell cycle active and specific mainly for the S phase. They include cytarabine, fluorouracil, gemcitabine, cladribine, fludarabine, pentostatin, hydroxyurea, and methotrexate.
Topoisomerase inhibitors interfere with the enzymes topoisomerase 1 and topoisomerase 2, responsible for mediating conformational and topological changes in the DNA required during transcription and replication. These agents include daunorubicin, doxorubicin, idarubicin, etoposide, teniposide, dactinomycin, and mitoxantrone.
Plant Alkaloids include vincristine, vinblastine, and vinorelbine which inhibit microtubule assembly by binding to tubulin and docetaxel and paclitaxel which function by stabilizing microtubules and preventing their disassembly. They are cell cycle active and cytotoxic predominately during the M phase of the cell cycle.
Antitumor Antibiotics include bleomycin that induces DNA strand breakage through free radical generation and Mitomycin C which cross links DNA. They are cytotoxic mainly during the G2 and M phase.
Other Agents include dacarbazine and procarbazine which act as alkylating agents to damage DNA and L-Asparaginase, the only enzyme used as a anti tumor agent, which acts by depletion of extracellular pools of asparagine.
Chemotherapeutic agents exhibit a dose response effect. At sufficiently low concentrations no cytotoxicity is observed. At increasing concentrations, cell kill is proportional to drug exposure. At high concentrations, the effect reaches a plateau. Drugs that are cell cycle active, but not phase specific, such as alkylating agents, characteristically have steep dose response curves: An increase in the drug concentration by an order of magnitude or more results in a proportional increase in tumor cell kill. By contrast, the dose response curve of phase specific agents, such as the antimetabolites, typically is linear over only a narrow range. These agents are less suitable for dose escalation and increased tumor cell kill is observed after prolonged exposure as a larger percentage of the tumor cells enter the cell cycle.
Chemotherapy employs two principles in administration: Therapeutic Index Dosaging and Cyclical Administration (HPIM 14th ed. 527-528 Pharmocodynamics section).
The therapeutic index represents the difference between the response of the tumor and response of normal tissue for a given dose of chemotherapeutic. Normal cells are also susceptible to the cytotoxic effects of chemotherapeutic drugs and exhibit a dose-response effect, but the response curve is shifted relative to that of malignant cells (see HPIM 14th ed. P. 528, FIGS. 86-3 enclosed). This difference represents the therapeutic index. The toxicity to normal tissue that limits further dose escalation is the xe2x80x9cdose-limiting toxicityxe2x80x9d. The dose just below this point is the xe2x80x9cmaximum tolerated dosexe2x80x9d. Proliferative normal tissues such as the bone marrow and gastrointestinal mucosa are generally the most susceptible to chemotherapy-induced toxicity. The usefulness of many chemotherapeutics is limited by the fact that they have a narrow therapeutic index (HPIM 14th ed. p.527).
Tumor regression in response to chemotherapy is logarithmic. A given dose of chemotherapy kills a constant percentage of cells. The xe2x80x9ccell kill ratexe2x80x9d (CKR) as used in this application is hereby defined as the percentage of cells that are killed during one cell division cycle at a given dosage of chemotherapeutic. The xe2x80x9ctumor kill ratexe2x80x9d as used in this application is hereby defined as the percentage of cells of a tumor that are killed during one administration cycle of a chemotherapeutic, which is directly proportional to the CKR and the number of cell division cycles that occur over the chemotherapeutic""s administration (or efficacy) period. As an example, if a 90% CKR chemo is administered over one cell division cycle, the tumor kill rate is also 90%. If the 90% CKR is administered over two cell division cycles the tumor kill rate is 99%. Conventional methods typically focus on xe2x80x9cmaximum tolerated dosesxe2x80x9d and extended administration periods.
Cyclical administration is required to allow normal rapidly proliferating cell populations to recover from the effects of chemotherapy. The number of administration cycles required to completely eradicate a tumor is dependent on the tumor kill rate of the therapeutic. To completely eradicate a tumor it is necessary to get below the mathematical 1 surviving cell number. As an example, to kill a 10 billion cell tumor with a chemotherapeutic that kills 95% of the tumor cells each administration cycle (5% survive) would require 8 cycles of chemotherapy (i.e. 10,000,000,000xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05xc3x970.05=0.39). In contrast, a chemotherapeutic with a 50% tumor kill rate would require 34 administration cycles to get the 10 billion cell tumor below the one surviving cell number (i.e. 10,000,000,000xc3x970.5 (34 times)=0.58). Likewise a 99% tumor kill rate would require only 6 administration cycles to get below the one surviving cell number.
Prior Art Endocrine Therapy (HPIM 14th ed. pgs. 534-535)
Endocrine therapy for hormone responsive malignancies depends on the presence of the appropriate hormone receptors, which in turn depends on the presence of those receptors (e.g. estrogen, progesterone, testosterone) in the underlying tissue from which the malignancy arose. Steroid hormones bind to specific intracellular receptors and induce a conformational change in the hormone-receptor complex that allows DNA transcription to proceed. Prior art hormonal antitumor agents are functional agonists or antagonists of the steroid hormones (HPIM 14th ed. p. 534).
The prior art use of endocrine therapy for malignancies possessing androgen, estrogen or progesterone receptors is presented in more detail by the specific cancers possessing these receptors.
Prostate Cancer: The androgen therapies for prostate cancer (HPIM 14th ed. p. 601) are all focused on reduction of androgen blood levels. The 4 methods under prior art are: 1) surgical castration and adrenalectomy to remove glands that produce androgens; 2) inhibition of pituitary gonadotropin and/or adrenocorticotropin production by estrogen therapy, hypophysectomy, or treatment with luteinizing hormone releasing hormone (LHRH) analogues such as Leuprolide or buserelin; 3) inhibition of androgen synthesis by the testes and adrenals (aminoglutethimide); and 4) inhibition of the binding of androgen to its receptor protein (cyproterone, flutamide, or bicalutamide).
Breast Cancer: Normal breast tissue contains both estrogen and progesterone receptors. Malignant breast tissue usually retain one or both of these phenotypes and methods for detecting the presence of these receptors is well established in prior art (HPIM 14th ed. p. 566). The Endocrine therapies for breast cancer are are grouped into 7 categories and summarized in Table 91-4 (HPIM 14th ed. p.566). They all focus on inhibiting endocrine dependent cancer cells from cycling by inhibiting or decreasing endogenous endocrine levels. 1) Castration removes the organs responsible for estrogen production, dropping endogenous estrogen levels and reducing the cancer""s rate of growth. 2) Antiestrogens (e.g. tamoxifen) compete with estrogens at the receptors and thus act as inhibitors. 3) Progestogens are anti-estrogenic. 4) Adrenalectomy is removal of the adrenal glands which decreases formation of estrogen precursors. 5) Aromatase inhibitors prevent aromatase from catalyzing reactions along several metabolic pathways involved in the synthesis of estrogens (BP p.94), thus reducing estrogen levels. 6) Hypophysectomy is surgical removal of the hypophysis or pituitary gland, thus reducing estrogen production by removing the upstream cascades that initiate its synthesis. And lastly, 7) additive androgen or estrogen therapyxe2x80x94androgens reduce estrogen by ablation of the ovaries (PDR p. 1407) and high estrogen concentrations stimulate 17xcex2-hydroxysteroid dehydrogenase which converts estradiol (the most potent estrogen) into a much less active form as well as reducing progesterone receptor formation (BP p. 92).
HPIM 14th ed. p. 565 also discloses use of adjuvant regimens which are summarized in Table 91-3. Four of the six methods use combinations of chemotherapeutics only. The other two use Tamoxifen, either by itself or after chemotherapy. Tamoxifen competes with estrogen at the receptors and thus acts as an inhibitor (BP p.94), once again consistent with the prior art approach of inhibiting the growth of the endocrine dependent cancer. A further prior art search was performed by reviewing the list of 44 articles posted by the University of Pennsylvania Cancer Center Website titled xe2x80x9cChemotherapy for Breast Cancerxe2x80x9d, a copy of which is included under the IDS. The prior art articles were consistent with HPIM""s disclosures. None of the studies proposed the use of endocrine cancer accelerants in conjunction with chemotherapeutics as proposed by present invention.
Additionally, prior art""s fairly high dose chemotherapy alone causes endocrine downregulation through ablation of organs responsible for endocrine production. In a study of 49 women undergoing chemotherapy for early stage breast cancer, 71% were subsequently diagnosed with ovarian failure (Science News, vol. 160 p. 89). Ovaries produce estrogen. The early and rapid bone loss in these women further corroborated this under-appreciated side effect of chemotherapy, which also results in endocrine downregulation. The adverse effect of endocrine downregulation and subsequent unresponsiveness of tumors to chemotherapeutics because of the resulting xe2x80x9cS-Phase Haltxe2x80x9d will be discussed in more detail below. Use of cancer accelerants proposed by present invention will allow for much lower doses of chemotherapeutic which will also provide the novel benefit of preventing the inadvertent xe2x80x9cchemotherapeutic castrationxe2x80x9d caused by prior art administration regimens.
In summary, all prior art endocrine therapies are used to inhibit cancer cells from cycling. The statement xe2x80x9c . . . combinations of chemotherapy with endocrine therapy are not usefulxe2x80x9d (HPIM 14th ed. p. 566, Endocrine Therapy section) are correct in light of prior art. However, this statement will no longer be true under present invention. It will be shown that combinations endocrine hormones with chemotherapy can be extremely useful and yield novel benefits over prior art such as increased tumor kill rates, reduced systemic toxicity, and the ability to maintain chemotherapeutic-to-cancer phase synchronization.
Unobviousness Over Prior Art
The compositions and methods of present invention are not obvious over prior art because they are exactly opposite to prior art. Prior art teaches use of endocrine therapies to inhibit cancer growth. Present invention teaches use of endocrine therapy to accelerate cancer growth. Prior art endocrine therapy is not used concurrent with chemotherapy whereas current invention uses endocrine administration concurrent with administration of chemotherapeutic(s) and is integrally dependent on its interaction with said chemotherapeutics unlike prior art endocrine therapy.
Novelty and Utility Over Prior Art
xe2x80x9cCancer Accelerantxe2x80x9d compositions and methods of present invention will yield a broad spectrum of new benefits over prior art including increased kill rate at a given dose of chemotherapeutic, or reduced dose of chemotherapeutic needed to achieve a given kill rate. Applicant will also show how to use endocrine accelerants to create user defined curative administration regimens, retain S-phase proportionality during chemotherapeutically induced accelerated growth, and how to create the 100% S-Phase tumor.
Additionally, applicant will disclose why prior art phase specific chemotherapeutic regimens are not curative but only moderately palliative. Corrected administration methods will be disclosed for maintaining phase specific chemotherapeutic-to-cancer phase synchronization in non endocrine dependent cancers. Applicant will also apply these corrected methods to endocrine dependent cancers, using endocrine accelerants to retain S-Phase proportionality and maintaining proper chemotherapeutic-to-cancer phase synchronization throughout the administration regimen. The novel compositions and methods disclosed will provide great utility over prior as they will yield curative versus palliative regimens.
The statement xe2x80x9c . . . combinations of chemotherapy with endocrine therapy are not usefulxe2x80x9d will no longer be true under present invention.
Utility of Present Inventionxe2x80x94Novel Mechanism of Action over Prior Art
The mechanism of action (MOA) of present invention has no comparable in prior art and can be summarized as follows: Current invention proposes releasing the brakes on the endocrine dependent cancer""s S phase halt, or greatly upregulating DNA transcription, at just the right time to result in a several-fold increase in the amount of damage inflicted by chemotherapeutic(s) to cancer cells during said accelerated DNA replication period or subsequently during DNA separation (S phase and M Phases respectively). Applicant also uses this stop/start (i.e. slow/fast) potential to maintain chemotherapeutic-to-cancer phase synchronization.
S Phase Halt: Endocrine dependent cancers are different from other cancers in one significant respect. In endocrine dependent cells, mutations indigenous to a malignant cell drive the cell through G1 just like in any other cancer. The difference, however, comes in the S phase, since endocrine hormones are not indigenously produced by the malignant cell. DNA transcription requires the endocrine hormones produced by some other organ to dock with and activate appropriate nuclear endocrine receptors which in turn activate or upregulate DNA transcription. The relevant schematized pathway for estrogen, progesterone, and androgens for upregulating DNA transcription in the S-Phase is shown in Biochemical Pathways p. 227 FIGS. 17.6-2 enclosed (i.e. via Group A nuclear receptors). In the absence of hormone, an inhibitory protein (Hsp 90, possibly also Hsp 70 and Hsp 56) binds to the receptor and covers the DNA binding/dimerization domain. Hormone binding causes a conformational change in the receptor that results in the dissociation of the inhibitory protein, formation of homodimers, entry of the homodimers into the nucleus and binding to the palindromic DNA response element, interacting with TFIIB and accelerating formation of the pre-initiation complex of transcription.
When endocrine levels are low or absent, the S phase can become disproportionately long as DNA transcription is stalled or greatly slowed down (i.e. what applicant refers to as the xe2x80x9cS Phase Haltxe2x80x9d). In this situation, a tumor would appear to have a disproportionate amount of cells in the S Phase, which can readily be determined under prior art flow cytometry and indirect S-Phase assessments using antigens associated with the cell cycle such as PCNA and Ki67 (HPIM 14th ed. p. 564).
Preface to Examplesxe2x80x94Cell Cycle Times and Cancer
The cell cycle time of normal rapidly proliferating cells (e.g. bone marrow, gastrointestinal stem cells, hair, and skin) is between 19 to 25 hours, in which time the cell spends xcx9c45% of its time in the G1 Phase, xcx9c32% in the S Phase, 18% in the G2 Phase and 5% of its time in the M Phase. Epithelial cells that line the lumen of the gut have an even shorter cell cycle time of xcx9c11 hours (MBOC 896).
A tumor""s cell cycle time is much longer by contrast. A typical tumor follows a Gompertzian growth curve (HPIM 15th ed . . . p. 530 FIGS. 84-1). In the fairly fast, non endocrine dependent tumor portrayed in the example, the growth from the first clinically detectable mass of 1 billion cells (xcx9c1 cubic cm) at day 100 to lethal burden of 1 trillion cells (xcx9c1 kg) at day 200 requires 10 cell cycles (i.e. 1 bil., 2, 4, 8, 16, 32, 64. 128, 256, 512, 1 tril) over a 100 day period which mathematically works out to a cell cycle time of 10 days (i.e. 100 days/10 cell cycles=10 days/cell cycle). The fastest growth rate occurs in the 50 days prior to the tumor reaching a clinically detectable mass and averages 2 days per cell cycle.
Non endocrine tumors such as colon cancer have a significantly longer cell cycle time than implied in the above representation. The colon cancer median survival of 6.5 months with only best supportive care (BSC) (PDR p. 2414) implies an xcx9c19 day colon cancer cell cycle time (i.e. 6.5 mo.=195 days and xcx9c10 cell cycles required from the first clinically detectable tumor of xcx9c1 bil. cells to lethal burden at xcx9c1 tril. cells=xcx9c19 days per cell cycle).
An endocrine dependent tumor can have an even longer cell cycle time. Although surgical removal of a tumor from the breast area and adjuvant chemotherapy is used as a first line of treatment for breast cancer, nearly half of patients treated for the apparently localized breast cancer develop metastatic disease. The median survival for metastatic disease to death for breast cancer is xcx9c2 years (HPIM 14th ed . . . p. 566). Starting with a metastasis that was at a clinically undetectable mass of xcx9c1 million cells (xcx9c1 xcexcL) when the primary breast tumor was detected, lethal burden of the metastasis would be reached in xcx9c20+ cell cycles over xcx9c2 years implying a cell cycle time in the ballpark of xcx9c30 days for the endocrine dependent metastatic cells. The similarity in duration of an endocrine dependent breast cancer""s cell cycle time to the menstrual cycle is not likely to be a mere coincidence. Normal breast tissue contains both progesterone and estrogen receptors. FIGS. 337-5 from HPIM 14th ed. p. 2101 shows the natural progesterone and estradiol levels over a menstrual cycle. A double peak of both estradiol and progesterone occurs only once a month around 24 days after start of menses. This likely acts as a natural, once a month, xe2x80x9cbrake releasexe2x80x9d on the S-Phase Halt which would also effect malignant breast cells that retained the progesterone and estrogen receptors.
Prior art endocrine downregulation/endocrine blocking therapies can extend the median survival to xcx9c4 years ( 3-5 or more per HPIM 14th ed . . . p. 566). Doubling the median survival time means doubling the cell cycle time from roughly 30 day to 60 days. Since, endocrines function in the S-Phase, the additional 30 day cell cycle extension would manifest itself as an unusually large proportion of cells stuck in the S-Phase.
The difference between the 19 day non-endocrine dependent colon tumor, the 30 day endocrine dependent breast tumor and the 60 day endocrine blocked tumor is outlined in TABLE 1 below as it will be used for illustrative purposes in some examples, particularly in determining frequency of administration. TABLE 1 starts with the colon tumor cell cycle of 19 days and displays the number of days it takes a cell to get through that phase as well as the corresponding % of cells one would expect to be in a given phase at any given time, based on the normal cell cycle phase distribution and before any chemotherapeutic administration regimen. The endocrine dependent tumors use the colon cancer model as a baseline and add any additional cell cycle time into the S-Phase as this is the phase where the lack of endocrines has an effect, both naturally in the 30 day breast cancer and artificially in the 60 day endocrine blocked tumor.
Chemotherapy is a balancing act between toxicity to the tumor and toxicity to normal rapidly proliferating cells in the body. The slower rate of tumor cell cycling (10 days to 30 days) versus xcx9c1 day for normal rapidly proliferating cells has been a major impediment to effective treatment of tumors under prior art. Present invention will show how to get around this issue.
Reduction to Practicexe2x80x94Redefining Administration Intervals
Due in part to the novel methods of present invention which use phase specific chemotherapeutics and in part to the inability of prior art to define or implement proper methods of using phase specific chemotherapeutics, it is also necessary to define novel methods for computing appropriate administration intervals for use with phase specific chemotherapeutics. This method will yield curative results versus prior art""s palliative results.
Prior art tends to favor high dose regimens administered several weeks apart. There is no rational basis for doing this and mathematically it can never provide a curative result. To the contrary, present invention favors the lowest dose that will induce a desired kill rate in the phase (i.e. 95-100%) and has the shortest in vivo efficacy time (i.e. shortest terminal half life) and administration that is rationally synchronized with respect to the cancer cell cycle. The optimal phase specific chemotherapeutic under present invention should induce a kill rate in the phase of xcx9c95-100% and have an in vivo efficacy period (terminal half life) of 3 or 4 hours to minimize systemic cytotoxicity.
The major flaw in prior art is that it erroneously uses a fixed administration interval (AI), usually based on some calendar schedule. A variable AI is required to adjust for the accelerated tumor growth and proportionately reduced cell cycle and phase times as the tumor moves backward along the Gompertzian growth curve (HPIM 15th ed . . . p. 530 FIGS. 84-1) over the course of a chemotherapeutic regimen. Without this adjustment the AI will very quickly be much greater than both the cancer cell cycle time, susceptible Phase time, and most importantly administration of the chemotherapeutic will no longer be appropriately synchronized to the cancer cell population.
The Gompertzian growth curve shows a fairly abrupt growth rate change on either side of the 1 billion cell level. Below that level a tumor grows up to 5 times faster than above it. Cancer is the accumulation of about half dozen or so genetic xe2x80x9caccidentsxe2x80x9d or lesions in proto-oncogenes and/or tumor suppressor genes. So far about 60 proto-oncogenes (MBOC 1279) have been discovered and presumably there are roughly as many tumor suppressor genes. Examples of proto-oncogene products include practically every type of molecule involved in growth from protein growth factors, growth factor receptors, growth signal transduction molecules, to gene regulatory proteins. Growth is a balancing act where normally inhibitory influences predominate. Cancer""s oncogenes and/or defective tumor suppressor genes tip the balance to where growth predominates. As tumor cells grow they become crowded and starved of oxygen an nutrients, causing them to upregulate production of angiogenic growth factors ( a process normal to all cells under such conditions) and neovascularize the tumor. Endothelial cells (i.e. blood vessel cells) however are not mutated and are still subject to growth controls (such as density dependent inhibition of cell division vial P27 Kip 1 upregulation) which means they will eventually slow or stop angiogenesis, especially in particularly crowded areas, even in light of the high levels of angiogenic factors issued by the crowded tumor cells. As tumor cells crowd each other beyond a certain point they can no longer get enough nutrients to sustain their overexpression of growth related proteins, angiogenic growth factors, or the 2,000 to 5,000 other structural and regulatory proteins required for cell growth and division.
Of critical relevance to present invention is understanding what happens when a chemotherapeutic hits a tumor like the one described above. Wiping out a large part of the crowded tumor is a windfall for the surviving cells. They now find themselves in a well neovascularized, oxygen and nutrient rich, empty space. Add to that a genetic mutation profile that is permanently switched on for growth and they will immediately resume fulfilling their genetic destiny. This will manifest itself as them resuming their earlier accelerated growth (or possibly even faster) until they have once again crowded themselves to the point of a lower growth rate.
In our colon cancer example, that would imply the 19 day cancer cell cycle time above the 1 Bil. cell level becomes a 3.8 day cell cycle time after a chemotherapeutic reduces the tumor""s size below the 1 bil. cell level. Using a typical S-Phase chemotherapeutic which kills 100% of cells in the S-Phase, for a total tumor kill rate of 32%, the surviving cancer cells will be able to run through nearly 2 cell cycles (i.e. quadruple) before the next dose on chemotherapeutic is administered on day 7. In reality, this will never happen because well before they complete even 1 cycle the cell mass will once again reach the 1 billion mark and downregulate itself to the 19 day cell cycle.
When an AI becomes longer than the susceptible phase of the cycle, cells slip through the phase into non susceptible phases. When the AI becomes longer than the cell cycle itself, one or more cell cycles of the cancer can occur before the next chemotherapeutic administration. Regrowth, or even accelerated growth, results in the cancer cell population being phase asynchronous again, which is a catastrophic event for a phase specific administration regimen. AI""s of a phase specific chemotherapeutic must precisely follow the phase progression of the cancer cells through the cycle, with each successive administration of chemotherapy occurring shortly before each successive batch of cells that entered the susceptible phase during the administration interval have had time to exit into a non susceptible phase. The return to an asynchronously cycling population will mathematically yield a result over time that is basically indistinguishable from using a non phase specific chemotherapeutic with a kill rate equal to the phase kill rate of the chemotherapeutic times the percent of cell in that phasexe2x80x94which at a best case 100% S-Phase kill rate times the 32% of cells in S-Phase is comparable to a non phase specific chemotherapeutic with a paltry 32% kill rate.
As an example, the studies of Camptosar(copyright) follow the prior art administration methods of using a fixed AI. TABLE 2 below was constructed from Study 3 (PDR p. 2413 Table 2) and shows the mathematically predicted progression of the tumor from the first clinically detectable mass to lethal burden for best supportive care as well as under the two different administration regimens used in Study 3. The 125 mg dose was administered once every 7 days for 4 weeks, followed by 2 weeks off for 4 months (3 cycles). The 100 mg dose was administered in the same manner but for only 3 months (2 cycles). In TABLE 2 below, the tumor""s typical exponential growth rate has been computed using the equation: (starting # of cells)xc3x972(xcex94t/19); where xcex94t the relevant time period in days and 19 days is the colon cancers self limiting growth rate cell cycle. Tumor regression was computed using 32% of cells being killed each administration as if with a non phase specific chemotherapeutic. The mathematical model projects a lethal burden for the 125 mg regimen somewhere between 315-322 days compared to the 321 days (10.7 mo.xc3x9730 days) median survival observed, and projects lethal burden for the 100 mg dose at between 273-280 days compared to 279 days (93 mo.xc3x9730 days) median survival observed. The math supports that this S-Phase chemotherapeutic has a close to 100% S-Phase kill rate at both doses, however in the absence of the proper AI results in only modest palliative rather than curative affect.
Present invention proposes a method of administering phase specific chemotherapeutics using an administration interval defined by the equation:
AI=(DCCC)xc3x97(% CIP)xc3x97(CF)
Where:
AI=Administration Interval (in days)
DCCC=Duration of the Cancer Cell Cycle (in days)
% CIP=the percentage of cancer Cells in the Phase in which the chemotherapeutic exhibits toxicity (e.g. determined by flow cytometry for S-Phase)
CF=Confidence Factor, which is a number between 0 and 1, preferably between 0.6-0.8 that reduces the AI to account for margin of averaging error
Note: Any suitable time increment may be used, e.g. days may be substituted with hours as long as the same time increment is used for all variables
Note: The equation may be also written as AI=(Duration of Relevant Phase in days)(CF)

Cancer accelerants and phase synchronization methods


In a computer with a trusted platform module (TPM), an expected hash value of a boot component may be placed into a platform configuration register (PCR), which allows a TPM to unseal a secret. The secret may then be used to decrypt the boot component. The hash of the decrypted boot component may then be calculated and the result can be placed in a PCR. The PCRs may then be compared. If they do not, access to the an important secret for system operation can be revoked. Also, a first secret may be accessible only when a first plurality of PCR values are extant, while a second secret is accessible only after one or more of the first plurality of PCR values has been replaced with a new value, thereby necessarily revoking further access to the first secret in order to grant access to the second secret.

Security has become a widespread concern for computer users. Viruses, worms, Trojan horses, identity theft, software and media content piracy, and extortion using threats of data destruction are rampant. An operating system can provide numerous security features to guard against such attacks. However, the security features of an operating system are ineffective if they are disabled. Disabling such security features, if it is attempted, will likely be attempted during the boot of the operating system. After boot, an operating system may have numerous features in place for protecting itself and the data and processes which it manages. During boot, however, those features may not yet be initialized and are vulnerable to bypass and/or tampering.
Exemplary security features presently used by operating systems are the Encrypted File System (EFS), and the Trusted Platform Module (TPM). The EFS feature encrypts selected sensitive data. An operating system does not need to access EFS data until a user is logged on. After operating system boot, a user may provide a password to a logon process. The password grants access to a decryption key that can decrypt the EFS data. By way of example, the MICROSOFT WINDOWS® operating systems employ a system key, or "SYSKEY," that is used to protect various processes by making the correct performance of those processes dependent on the availability of SYSKEY. For example, the key needed to decrypt EFS data that is stored by the operating system in encrypted form may be derivable from the SYSKEY.
The key(s) needed to perform restricted operations are thus protected by the logon procedure. Typically, the user must correctly authenticate himself prior to commencing use of the system. Use of the keys is enabled only if the user correctly authenticates. However, using the logon procedure to protect access to keys assumes that the operating system loaded the correct logon program, and that the use of the keys has not been otherwise enabled by rogue code that may be running. If a rogue operating system loader was used during boot instead of the correct operating system loader, the rogue loader may cause a rogue logon program to be loaded with the operating system. The rogue logon program may in turn enable the use of EFS keys without entry of the proper password. Since the loading of the operating system provides an opportunity for a security breach, protection of the keys in such a situation requires that the loading of the operating system take place under circumstances where it can be verified to take place correctly.
Because EFS is a feature supported by a booted operating system it is likewise ineffective at protecting certain data that is divulged during a boot process. EFS cannot protect user data that is required before the user is logged on, such as the secrets required for some system services; databases used by network services (e.g. personal or public web server); and RAS credentials for connecting to a company domain.
A Trusted Processing Module (TPM) ensures trustworthiness of software that is run on a computer. This is accomplished, in general, by submitting trusted measurements of data to the TPM, and relying on the TPM to determine if the measurement is what it should be. Computer security is often dependent on being able to predict the behavior of software components. In general, the security of a system may flow from the premise that a known program whose behavior is understood, which proceeds from a known good state, will act in a predictable manner. Conversely, the thwarting of security—which may involve getting a computer system to behave in ways that are outside the contemplation of its designer—can generally be realized by replacing or changing a known program, or running it in a state in which its behavior is not understood. Thus, one aspect of providing security for a computing environment includes verifying that a known program is being used, and that it is proceeding from a known good state. The TPM accomplishes this by validating that data is what it should be because a measurement such as a hash of the data matches a value previously sealed in the TPM.
Like EFS, the TPM has been successfully employed to provide a degree of assurance as to the integrity of applications running on a booted computer. A number of additional limitations also exist for the TPM. For example, a machine using the TPM in a standard way cannot be reconfigured in the field (for example, inserting a network card into a laptop whilst at a conference). The TPM creates severe limitations and complexities for an initialized operating system.
Most TPMs today conform to the TRUSTED COMPUTING GROUPS® (TCG) standard, presently available at https://www.trustedcomputinggroup.org/home and entitled "Trusted Platform Module (TPM) Specification Version 1.2." The TPM is a subsystem that may be incorporated into computing platforms to establish trust for the code that is executed by a platform. Standardization of mechanisms for establishing trustworthy code is beneficial because it allows the security and cryptographic community to assess the mechanisms for providing security, and because it promotes customer understanding and trust of new software features. It also encourages innovation in implementing and improving the standard, as contemplated and encouraged by the TCG®. As stated in the TCG® specification, "[m]anufacturers will compete in the marketplace by installing subsystems with varying capabilities and cost points."
The above exemplary security mechanisms employed by operating systems are supplemented by some techniques for securing boot. Machine password authentication can be used to protect secrets using a machine global password. This however requires a password to be entered before a machine boots. The password must be shared by multiple users of a machine, which is a first security flaw. A second flaw is that usability issues are introduced, because a typical user interface cannot be presented for the password input. This is particularly cumbersome for a tablet PC. Often the machine global password may be written on a piece of paper and left in the presence of the machine. Thus, the password is effective but does not allow sophisticated user protection of the type that is frequently desired.
Secondly, a secret may be stored on removable media. Again, this feature is effective in theory from a security standpoint, however in practice it is often problematic. The fundamental issue in this case is that to ensure a usable functioning system, the removable media will almost always be left inside the machine.
In the absence of adequate assurances of a secure operating system boot, the ability of a user to protect the data on a computer is limited by the security of the building that such a computer is locked in, rather than the security functions of the operating system running on the computer. With the popularity of laptops, and the rising increase of computer thefts, in particular, laptop thefts, a solution is desirable that allows the security of an operating system to remain uncompromised when the computer enters into the hands of a thief.
Systems and methods for using a TPM to secure a boot process remain largely unexplored. In addition to the use of a TPM in a boot process, systems and methods for performing maintenance of boot processes and for controlling access to data on such a computer may prove useful. Description of such systems and methods can be found in a patent entitled "Systems and Methods for Boot Recovery in a Secure Boot Process on a Computer with a Hardware Security Module," , U.S. patent application Ser. No. 11/035,715, filed Jan. 14, 2005, a patent entitled "Systems and Methods for Updating a Secure Boot Process on a Computer with a Hardware Security Module,"U.S. patent application Ser. No. 11/036,018, filed Jan. 14, 2005,and a patent entitled "Systems and Methods for Controlling Access to Data on a Computer with a Secure Boot Process," U.S. patent application Ser. No. 11/036,415, filed Jan. 14, 2005. Also generally related to this invention is U.S. patent application Ser. No. 10/882,134, filed Jun. 30, 2004, entitled "System and method for protected operating system boot using state validation."

Systems and methods for securely booting a computer with a trusted processing module


A weight sensing system for retail shelves includes multiple shelves having an electrical communication and power distribution system, and weight sensors located on the top surfaces of the shelves and coupled to the electrical communication and power distribution system for detecting the placement of retail products on the shelves. A controller monitors real-time at-the-shelf inventory and issues alerts when a retail product becomes out-of-stock, is anticipated to become out-of-stock, or is misplaced on a shelf. Collection of real-time inventory data enables comprehensive inventory control at the shelf and in storage areas.

A perennial challenge among retailers around the world is effective inventory management. Although retailers bear the consequences of this challenge in the form of lost sales or eroded customer loyalty, the entire supply chain is implicated. A product may go out of stock at the retailer's shelf due to failure to replenish products at the shelf, improper volume control at the store, poor demand forecasting, problems with distributional logistics, and complications at the manufacturing center.
One manifestation of this challenge to effectively control inventory of retail products is the failure to detect and correct when a retail product is "out of stock" on a shelf. In the United States alone retailers lose an estimated 4% of annual sales due to this problem. Lost sales are only one aspect of this problem; customers also become frustrated when an product they need is not available, eroding customer satisfaction and loyalty to retailers.
In most retail stores, out of stocks are detected only when a store employee visually identifies that an product is no longer stocked on the shelf. The employee must then record the product needed, find the product in the storage or warehouse area of the store, and re-stock the product. This process is time-consuming, costly, and inefficient. The process is particularly inefficient because a substantial amount of time may pass between the last product being removed from the shelf and identification of the out of stock product by a store employee.
A second manifestation of this challenge is the overstocking of shelves in a retail store. Many retailers fail to optimize the allocation of shelf space for their products, resulting in some products being stocked on a shelf at a volume such that the product would not sell out for several days or even weeks. This practice creates an inventory glut of some products, which increases the inventory cost or holding cost of a retailer.
A third manifestation of the challenge of effective inventory management is out of place inventory. It is not uncommon for customers to change their purchasing decisions during shopping, sometimes returning products to shelves not designated for the returned product. This may result in lost inventory, spoilage, and/or and unnecessary restocking of the product.
There is thus a well-established desire in the field of retail inventory control to implement a new system or apparatus for improving the inventory control and management of retail products. More specifically, there is a demand among retailers for a system or apparatus capable of optimizing at-the-shelf inventory of retail products, predicting when an product may go out of stock, identifying out of place inventory, and notifying the retailer in sufficient time to avoid the problems associated with out of stock inventory identified above.


A re-encryptor compares hashed digests of updated segments and original segments to located changed segments that must be re-encrypted. A new initialization vector is input to a block cipher engine for each changed segment. Since only changed segments need to be re-encrypted, transmission bandwidth to remote encrypted storage may be reduced. The amount of cipher text that is changed by a single update is reduced to a segment. Segments have a variable length and are bound by bits matching a segment delimiter. Each segment may have many fixed-length blocks that are encrypted by the block cipher engine with the same initialization vector for that segment. The segment delimiter is a randomly-generated word that is included with the initialization vectors in the metadata. Variable-length segments limit update disruption of the cipher text while fixed-length blocks are more efficiently encrypted. Combining segments and blocks provides for better re-encryption of updates.

Encryption is a common way to secure data, whether the data is sent over a non-secure network such as the Internet, or is stored remotely where security breaches might occur. Many encryption systems and standards are known. While such existing encryption systems are effective, such systems are not always efficient.
Cloud-based storage has become popular today. Rather than store documents and files locally, such as on personal computers or servers at a company premesis, the documents and files are stored or backed up at a remote location. When a user wishes to update a document, the user fetches the document from the remote storage, makes the updates, and sends the updated document back to the remote storage location.
The remote storage is typically accessed through the Internet. For security, the documents and files may be stored in an encrypted format at the remote storage location. The remote storage sends an encrypted document to the user, who then decrypts the document, makes the updates, and re-encrypts the document. The re-encrypted document is then sent over the Internet to the remote storage.
FIG. 1 highlights that prior-art encryption of a small change in clear text usually results in a large change in the encrypted cipher text. Sometimes only a small portion of encrypted data is changed, such as when a user updates a single sentence in a large document that is stored remotely.
FIG. 1 shows that the user made a small change in the unencrypted plain text or clear text, such as by changing the first letter from a lower-case "a" to a capital "A". The rest of the document is unchanged.
In a traditional encryption system, once the updates are made and saved by the user, the entire document is encrypted again and new encrypted cipher text is generated. The new cipher text is typically completely different from the original cipher text. For example, the original clear text is encrypted to the string "UuEOKHa8yp" while the updated cipher text is encrypted to the string "cMWceJsjgo6".
While such a complete change in cipher text is secure, it typically requires that the new cipher text for the whole document be re-transmitted to the remote storage location. Thus a small change in a document requires that a large amount of encrypted data be transmitted over limited-bandwidth networks.
What is desired is an encryption system that more efficiently updates encrypted cipher text. A re-encryption system is desired that changes only a portion of the cipher text, allowing a partial update of cipher text to be transmitted over networks for remote storage. A re-encryption system is desired that locates a segment of changed text within a sequence of encrypted blocks, and then re-encrypts only that changed segment. An encryption system that uses fixed-size cipher blocks and variable-sized segments is desired.

Partial CipherText updates using variable-length segments delineated by pattern matching and encrypted by fixed-length blocks

Hong Kong Applied Science & Technology Research Institute Company, Limited


A horizontal lifeline traversing device is capable of traversing intermediate lifeline supports without detachment from the lifeline but is easily attached to or detached from the lifeline. A paddle wheel having a plurality of radially spaced apart paddles prevents the device from vertical movement. The paddles are made of first and second sets of paddles rotatable about the same axle. The first set is substantially fixed on the axle but the second set is movable axially between a first position where it is axially spaced from the first set and a second position where it is in substantial axial alignment with the first set. A spiral spring biases the second set into the first position. By rotating the second set of paddles slightly, it can be moved axially into the second position where the device can be attached to or detached from a horizontal lifeline.

The present invention is directed toward a safety apparatus and more particularly toward a safety apparatus in the form of a load attachment system such as commonly used as a horizontal lifeline. The invention includes a load attachment traversing device that engages the lifeline for movement therealong and which can traverse intermediate supports without detachment from the line. More significantly, the load attachment traversing device can be easily attached to or removed from the horizontal lifeline while the lifeline is in place and without having to detach any part of the lifeline from its supports.
Horizontal lifelines have been employed for many years to provide fall protection for workers on elevated structures. In fact, such horizontal lifelines are required and have been mandated by safety rules and regulations in many jurisdictions. Such lifelines normally consist of a rope or cable suspended between two structures such as the vertical beams of a building or the like which may be 10, 20 or even 100 feet apart. A safety harness or safety belt is worn by a worker and a lanyard connected to the harness or belt attaches to the horizontal lifeline or cable. The end of the lanyard may include either a loop which can freely move along the length of the lifeline or it may include a grooved roller in the form of a pulley or the like that rolls along the line. This allows the worker to move freely along the length of the lifeline to accomplish his intended tasks. In the event that the worker losses his footing or otherwise falls, the horizontal lifeline, through the lanyard and harness or safety belt will arrest the fall and prevent the worker from suffering injury. The use of such a lifeline is described, for example, in U.S. Pat. Nos. 5,332,071; 5,458,214 and 5,598,900.
In order to function properly, the horizontal lifeline must be sufficiently taught so that the worker's lanyard can easily move across the same and so that the lifeline can function as a steadying rail for the worker, if necessary. However, when the lifeline is sufficiently taught so that the same assumes a linear or substantial linear configuration, the resistance force magnitude required to effectively withstand the load impact of a falling worker becomes theoretically exceedingly large. In the event of a fall, the construction worker ordinarily generates many times his weight in the impact force exerted by the lanyard against the cable or lifeline. Thus, the tension in the lifeline is critical since this determines the amount of sag in a lifeline which, in turn, determines the load amplification by which a vertical fall arrest force applied to the lifeline is multiplied by. Therefore, it is important to know the amount of tension applied to a lifeline. In fact, the amount of tension is frequently dictated by safety rules or regulations in many jurisdictions.
A winch or similar type device is frequently used to tension a horizontal lifeline when the same is in use. The lifeline is normally connected to one anchoring point and then passes through the winch. The winch, in turn, is connected through an anchoring line to the second anchor point. A winch-like device for tightening a horizontal lifeline is described, for example in U.S. Pat. No. 5,957,432 issued to the present applicant, the subject matter of which is incorporated by reference herein.
On short runs of 10 or 20 feet or so, the horizontal lifeline is normally supported only at the ends thereof. With substantially longer runs, however, it frequently becomes necessary to provide intermediate supports to prevent the line from sagging. This creates problems when a worker is attempting to move along the length of the line as the intermediate supports will prevent the loop or pulley at the end of his lanyard from passing. Thus, it would become necessary for the worker to detach his lanyard, move the same to the other side of the intermediate support and then reattach it again. This obviously creates a significant safety hazard.
Devices have been available and proposed in the past which are capable of traversing the intermediate supports. One such device, sold under the name Transfastener by Hy-SafeTechnology, of Silver Lake, Wis., is produced by Latchways Ltd., of Wiltshire, England. Similar devices are shown, for example, in U.S. Pat. Nos. 1,122,024; 1,429,007; 4,265,179; 4,462,316 and 4,470,354.
Each of these devices is comprised essentially of an upper portion and a lower portion where one of them is essentially in the form of a rotatable star wheel or the like and the other includes a track adapted to cooperate with the ends of the star wheel. As the device moves along a line, the star wheel is caused to rotate when it engages an intermediate support and the ends of the star wheel roll or slide across a track on the second portion of the device. It is, therefore, the interaction between the ends of the star wheel and the track on the second member which must support the weight should a worker fall or in the event that loads are being transported by the device. This can create excessive wear and ultimately possible failure which could create a safety hazard. In addition, because of the tolerances that are required in ensuring that the ends of the star wheel properly meet with the second portion of the device, these products can be expensive to produce and maintain.
Applicant overcame many of the foregoing problems with the improved horizontal lifeline traversing device described in his U.S. Pat. Nos. 6,311,625 and 6,640,727 the subject matter of which is incorporated herein by reference. The system described in those patents includes a load attachment device having a pair of grooved rollers that rides on the lifeline. A load is supported from the bottom of a C-shaped member which has its top connected to the rollers thereby allowing the device to traverse the supports. The bottom of the C-shaped member also carries a rotatable paddle wheel which prevents the device from being removed from the line. The paddle wheel rotates when a paddle is engaged by the support's horizontal bar as the device traverses the support.
Although Applicant's patented device is an improvement over the prior art, it still had one drawback that it shared with similar prior art systems. In order to attach the device to the horizontal lifeline, it was necessary to remove one end of the lifeline from its support so that it could be passed through the traversing device. Similarly, when it was desired to remove the device from the lifeline, an end of the lifeline again had to be removed from its support.
While devices have proposed that can allegedly be attached to and detached from a horizontal lifeline while it remains in place, Applicant is not aware of any that have been successful. See, for example, U.S. Pat. Nos. 5,245,931; 6,125,766 and 6,945,357. These are either too cumbersome or difficult to maneuver into position or simply do not function as intended. There is, therefore, a need for a load attachment traversing device that can be easily attached to or removed from a horizontal lifeline while the lifeline is in place and without having to detach any part of the lifeline from its supports


Presented is a system and method for testing a digital video distribution environment. A digital video signal generator transmits a reference video bit stream to a distribution path. A digital video signal analyzer receives a test video bit stream from the distribution path. The digital video signal analyzer generates a diagnostic video bit stream as a function of the reference video bit stream and the test video bit stream.

Technical Field
The present invention generally relates to digital video distribution and more particularly to testing digital video distribution environments for pixel errors.
Background Art
A digital video distribution environment is a common installation in residences and commercial buildings. Increasingly, more sophisticated and expansive digital video distribution environments are employed to distribute digital video. There is now a demand for an improved system and method for testing such digital video distribution environments.
Prior art FIG. 1 is a block diagram of an illustrative digital video distribution environment 10. The digital video distribution environment 10 links four (4) digital video sources 11A-D, such as a Blu-ray player, with eight (8) digital video sinks 15A-H, such as a television. Between the four digital video sources 11A-D and eight digital video sinks 15A-H are processing components, such as encoders and decoders. Each path from a source to a sink including all intermediary processing components is a distribution path 16. For example, the distribution path 16 between the first digital video source 11A and the first digital video sink 15A includes the first processing component 12 and the second processing component 13.
Digital video streams comprise a plurality of pixels organized into a plurality of frames. The number of pixels per frame corresponds to the resolution of the digital video. For example, one frame of video at a resolution of 1080 p (i.e. 1920 horizontal pixels×1080 vertical pixels), a common resolution, comprises 2,073,600 pixels. At a frame rate of 60 frames per second (fps), ten seconds of digital video at a resolution of 1080 p comprises 1,244,160,000 pixels.
Each pixel further comprises color coordinates, which define the color of the pixel. For example, in the red green blue (RGB) color coordinate system, each pixel comprises a red color coordinate, a green color coordinate and a blue color coordinate. A full red pixel in the RGB color coordinate system with 8 bit color depth comprises a red color coordinate of 255, a green color coordinate of zero, and a blue color coordinate of zero.
As the complexity of digital video distribution environments 10 increases, video issues become increasingly more difficult to diagnose and correct. Various factors including intermediary processing and interference may cause visible errors in the displayed video. These visible errors can adversely affect a user's viewing experience and must be diagnosed and corrected. One malfunctioning component of a digital video distribution environment 10 can cause video issues with the entire digital video distribution environment 10, potentially causing consumer dissatisfaction with the other fully functional components.
More specifically, pixel errors are known to those skilled in the art as a factor related to less than optimal viewing experience. A pixel error is a pixel that has one or more color coordinates altered during transmission from the digital video source 11A-D to the digital video sink 15A-H, resulting in discolored pixels displayed by the digital video sink. Pixel errors commonly occur when distributing compressed or encoded digital video or digital video processed with other lossy methods.
Methods and systems for testing a digital video distribution environment 10 are known in the prior art. However, due to the precise nature of digital video there is currently a trend toward automated diagnosis of video issues. Increasingly, diagnostic data is processed to achieve an objective score or result, taking human analysis and subjective criteria out of the equation. In instances where an objective score is not computed, the diagnostic results are often provided as a set of data values. This is undesirable, as the methodology for objective scores can be opaque and diagnostic data can be difficult to interpret or understand.
Visually displaying pixel errors provides a technician with a diagnostic tool for use in the field. The technician may make quick diagnoses of display issues by recognizing common patterns of pixel errors. Additionally, with a visual display of pixel errors, the installer may more intuitively relate the diagnoses to untrained clients. Methods and systems for visually diagnosing pixel errors are known in the prior art. More specifically, methods and systems are known for generating a differential video including pixels computed from the mathematical differences between a reference video bit stream before and after processing. Accordingly, pixel errors in the differential video are displayed according to their magnitude and at their native resolution.
Refer to prior art FIG. 2. As an example of the above prior art method assume a pixel 211 of the reference video bit stream 21 has a red color coordinate of two hundred forty (240), a green color coordinate of one hundred (100) and a blue color coordinate of one hundred (100) before processing. Next, assume that after passing through the distribution path 16, the pixel 221 has a red color coordinate of two hundred (200), a green color coordinate of one hundred fifty (150), and a blue color coordinate of one hundred fifty (150) after processing. According to known methods, a differential pixel is displayed having color coordinates that are the differences between the pixel color values before and after processing. Accordingly, a differential video would be displayed having a corresponding pixel with red, green and blue coordinates of fifty (50), forty (40), and forty (40), respectively.
Those skilled in the art will recognize that this method is suitable for locating pixel errors of a large magnitude or large contiguous clusters of pixel errors. However, pixels errors of a small magnitude may be visually indistinguishable from pixels without errors. Similarly, individual pixels or small clusters of pixels are difficult to detect. Consequently, there is a need for a system and method of testing digital video to emphasize the location of pixel errors.

This patent is subject to a terminal disclaimer.


A system for storing and dispensing articles, containers and the like includes stacks of opposing, vertically staggered shelf assemblies. A shelf associated with each shelf assembly is pivotally mounted for movement at least between an upwardly tilted receiving position and a downwardly tilted discharge position. A fluid-operating system is disclosed for maintaining each shelf in its upwardly tilted receiving position until a container is received and to prevent the lowering of the shelf to the discharge position until the next lower shelf is prepared to receive a container.

1. Field of the Invention
The invention relates to automated storage and dispensing systems for containers, articles and the like. More particularly, the invention relates to systems for storing containers and automatically advancing the containers in the storing apparatus as a container is dispensed from the apparatus.
2. Description of the Relevant Art
Vertically accumulating container storage and retrieval apparatus is shown by Grace, U.S. Pat. No. 4,621,745. This construction consists of opposing stacks of vertically staggered shelves which are pivotable between an upwardly tilted, receiving position, a storage position, and a downwardly tilted, discharge position. Movement of the shelves is controlled such that an upper shelf cannot pivot downwardly to the discharge position unless the next lower shelf is in the upwardly tilted, receiving position. Containers travel down the stack of opposing shelves in zig-zag fashion to come to rest at the lowest unoccupied shelf. Grace, U.S. Pat. No. 5,11,963, discloses a two-position shelf assembly which increases efficiency in some applications. The disclosures of U.S. Pat. No. 4,621,745 and U.S. Pat. No. 5,111,963 are incorporated herein by reference.
There is a continuing need for improved container storage and retrieval apparatus which are adaptable to special situations such as light product weight, variable product weight and heavy product weight. Prior apparatus may not work properly with very light weight containers, which do not have sufficient weight or momentum for mechanical actuation to function properly. Also, very heavy loads may cause jarring, vibration, excessive wear and improper operation.
During operation, a transferred container can topple or lodge between shelf assemblies if the receiving shelf assembly is not prevented from pivoting downwardly from the receiving position before the container is completely disposed on the receiving shelf surface. Accordingly, the descent of the receiving shelf assembly should be delayed until the container is fully received.

Fluid-operated container storage and dispensing system


An injection-locked frequency divider includes a selecting module for generating a control signal; a biasing module coupled to the selecting module, for receiving an original signal and generating a biasing signal according to the control signal; and an oscillating module coupled to the biasing module, for receiving the biasing signal to generate a target signal. A ratio exists between the frequency of the target signal and the frequency of the original signal.

1. Field of the Invention
The present invention relates to an injection-locked frequency divider and the frequency dividing method thereof, and more particularly to an injection-locked frequency divider and a frequency dividing method for broadening the frequency bandwidth by controlling the biasing current.
2. Description of the Prior Art
Frequency divider plays a very important role in a frequency synthesizer and is used for performing frequency division to an original signal to generate a target signal. The ratio of the frequency of the target signal to the frequency of the original signal corresponds to a frequency dividing ratio of the frequency divider. As known by those skilled in the art, frequency divider is accomplished by cascading a plurality of frequency dividing units, such as flip-flops. The flip-flops are digital devices, and are driven by a default low voltage (such as 0V) and a default high voltage (such as 5V). Consequently, each flip-flop consumes a significant amount of power during charging and discharging. Hence, the traditional frequency divider consumes more power as the operating frequency is increased.
Therefore, an injection-locked frequency divider has been invented for solving the above-mentioned problem. As disclosed in "Superharmonic Injection-Locked Frequency Dividers", IEEE Journal of Solid-State Circuits, Vol. 34, No. 6, June 1999 by Rategh, whose contents are herein incorporated by reference, the injection-locked frequency divider is an analog device. It directly processes an originally inputted analog signal and outputs ananalog signal with divided frequency. Generally speaking, the injection-locked frequency divider is composed of an oscillating module and a biasing module. The biasing module is utilized to receive an original signal to be divided, wherein the original signal is transferred from a front-end circuit (such as the VCO of the frequency synthesizer), and then the biasing module transfers the original signal to the oscillating module. The well-designed injection-locked frequency divider can output a target signal with divided frequency from the oscillating module, where a ratio of the oscillating frequency of the target signal to the oscillating frequency of the original signal is locked at a specific value, which depends on the circuit characteristics.
Although the injection-locked frequency divider has the advantage of operating at a high frequency and can directly process an analog signal for reducing power consuming, the injection-locked frequency divider must be well-designed to match the oscillating frequency of the original signal and the oscillating frequency of the oscillating module (central frequency), so as to perform frequency division normally. Therefore, the frequency bandwidth of the injection-locked frequency divider is often very narrow.

Injection-locked frequency divider and frequency dividing method thereof


A method for cleaning coke oven gas by washing the gas, whereby a washing liquid is guided into a washing liquid circuit and impurities in the washing liquid are expelled in a desorber. According to the invention, the coke oven gas is washed with caustic soda in a counter flow. The caustic soda is regenerated in the desorber by expelling acid gas components and ammonia.

1. Field of the Invention
The invention relates to a method for cleaning coke oven gas by washing the gas, whereby a washing liquid is guided into a washing liquid circuit and impurities in said washing liquid are expelled in a desorber. Such a method is known from Cheme-Ingenieur-Technik [Chemical Engineer Technology](1974) 15, page 628.
2. The Prior Art
In the known method, washing the gas takes place with a washing liquid that contains ammonia, which causes ammonia to become concentrated in the washing liquid circuit between the gas washer and the desorber. Ahead of the desorber, caustic soda is put into the washing liquid circuit, in order to split non-strippable ammonium salts into ammonia and NaCl. The desorption process is carried out in two stages. In a first desorption stage, the acid gas components are expelled from the charged washing liquid. A partial stream of the liquid stream drawn off from the desorber is passed to a second desorber, in which ammonia is expelled with steam. The ammonia expelled here is passed back to the washing liquid circuit. The two-stage desorption process is complicated, in terms of process technology and control technology, since on the one hand, the aim is to completely remove the acid gas components and, at the same time, a sufficient amount of ammonia must remain in the washing liquid circuit.


A drag control member attachment structure for a lever-drag type reel has a first cam member, a second cam member, a guiding portion, a guide fastening portion and a pivot support portion. The pivot support portion is disposed on an outer periphery side of the guide fastening portion. The second cam member engages with the first cam member and moves in a pivot axis direction in response to pivoting of the first cam member. The guiding portion has a cylindrical section and a hexagonal section that non-rotatably and movably guides the second cam member in the pivot axis direction. The guide fastening portion includes a hexagonal recessed section that is disposed on a side of the reel unit and receives the hexagonal section. The guide fastening portion further includes a through hole that receives the cylindrical section.

1. Field of the Invention
The present invention generally relates to an attachment structure. More specifically, the present invention relates to an attachment structure of a drag control member of a lever drag reel that adjusts a drag force of a drag mechanism.
2. Background Information
A lever-drag reel is known to have a reel that is capable of adjusting drag force by moving a spool shaft in an axial direction by a drag control member that is pivotably attached on the spool shaft. (See, for example, Japanese Publication No. H11-9157.) A base end of this of type drag control member is pivotably supported by a pivot support portion that is formed in a cover member of a reel unit so as to concentrically protrude with the spool shaft. In addition, the base end of the drag control member is provided with a cam mechanism that moves in the axial direction in response to its pivoting. The cam mechanism has a first cam provided in the drag control member and a second cam that engages with the first cam. The second cam moves in a direction of the pivot axis (spool shaft) in response to the pivoting of the drag control member. A guiding portion for non-rotatably and axially movably mounting the second cam is provided in an inner periphery side of the pivot support portion of the reel unit. In order to distributively receive the force of the rotary direction on a number of surfaces, the guiding portion is integrally formed in a hexagonal appearance on the inner periphery side of the pivot support portion with the pivot support portion.
In the case where the cover member of the reel unit is formed by forging, the guiding portion, with the hexagonal appearance, is formed at the same time in formation of the cover member. However, in the case where the reel unit such as the cover member is formed in a metal machining process, the cost of processing is high when the guide member is formed integrally with it by a cutting process. Accordingly, it is conceivable to fasten the guiding portion that is formed separately from the reel unit to the reel unit by crimp fastening. In this case, since the guiding portion should non-rotatably guide the second cam, it is necessary to non-rotatably fasten the guiding portion to the reel unit. Accordingly, it is conceivable to non-rotatably fasten the guiding portion to the reel unit by using the hexagonal appearance. In this case, a hexagonal recessed portion is formed and the guiding portion engages with it. When the hexagonal recessed portion is formed by a machining process with a tool, it is difficult to form a precise hexagon since such a tool for forming the recessed portion is a cylindrical tool (e.g. end mill). For this reason, the number of contact parts between an inner peripheral surface of the recessed portion and an outer periphery surface of the guiding portion varies and is unstable. When the number of these contact parts decreases, a load is concentratedly applied in proximity to a corner of the hexagonal shape. Thus, the part deforms. This may cause wobbling of the fastened part.
In view of the above, it will be apparent to those skilled in the art from this disclosure that there exists a need for an improved drag control member attachment structure to reduce variation of contact parts between a hexagonal guiding portion and a reel unit. This invention addresses this need in the art as well as other needs, which will become apparent to those skilled in the art from this disclosure.

Drag control member attachment structure


A cutting mechanism for dry film laminator includes a main base connected to a dry film laminator. The main base has a cutting space defined therein. The main base has two rollers disposed thereon and located beside the cutting space. The two rollers flatly guide a film above the cutting space. A film-carrying device is movably disposed on the main base. The film-carrying device includes a suction member movably disposed thereon. The suction member has at least one annular groove defined therein and corresponding to a shape of a wafer. A cutting device is movably disposed below the main base. The cutting device includes a film cutter movably disposed thereon. The cutting device includes an elevating device disposed thereon for moving the film cutter upward/downward. The cutting device includes a motor disposed thereon for rotating the film cutter.

1. Field of the Invention
The present invention relates to a cutting mechanism for dry film laminator, and more particularly to a cutting mechanism which pre-cuts a film and laminates the film on a wafer.
2. Description of Related Art
A conventional trimming mechanism for semiconductor wafer in accordance with the prior art comprises a housing, a base received in the housing and horizontally disposed on an inner bottom of the housing, and an upper trimming device received in the housing. The upper trimming device is movably suspended from an inner top of the housing via multiple shafts and is able to move upwardly/downwardly relative to the housing. The upper trimming device includes an annular outer member, an annular inner member, and an annular blade mounted on a bottom thereof. A lower device is received in the housing. The lower device is disposed on a top of the base and corresponds to the upper trimming device for holding a wafer. A supply device is disposed beside the lower device for supplying a protecting film. A take-up device is disposed beside the lower device opposite the supply device for collecting the used protecting film.
When the upper trimming device is operated to move downwardly, the protecting film is laminated on the wafer. The annular blade trims the protecting film around the wafer. However, during trimming, the bleeding resin would not be removed clearly. And afterwards the wafer is moved to another stage for enhancing lamination. The resin may bleed out the wafer again. Therefore, the wafer fabrication may have a low yield.
The present invention has arisen to mitigate and/or obviate the disadvantages of the conventional trimming mechanism for semiconductor wafer.

Cutting mechanism for dry film laminator


In a method for producing hollow fiber membranes which comprises melt kneading a mixture comprising polyvinylidene fluoride and an organic liquid or a mixture comprising polyvinylidene fluoride, an organic liquid and an inorganic fine powder, extruding the kneaded mixture to form hollow fibers, and extracting the organic liquid or the organic liquid and the inorganic fine powder from the hollow fibers, which includes the steps of drawing the hollow fibers before or after termination of the extraction and then shrinking the fibers. According to this method, it is possible to stably produce hollow fiber membranes having dense pores and having a high water permeation performance, excellent endurance and stain resistance, and which are suitable for filtration uses such as removal of turbidity of water.

The filtration operations such as removal of bacteria and turbidity particles using porous membranes such as microfiltration membranes and ultrafiltration membranes are put to practical uses in a wide variety of fields such as the automotive industry (systems for recovery and reuse of electrodeposited paints), semiconductor industry (production of ultra-pure water), and medicine and food industries (removal of bacteria, enzyme purification). Particularly, application to the field of water supply in which potable water and industrial water are prepared by removing the turbidity of river water, etc. and application to the field of sewage in which sewage purification is carried out by removing the turbidity of sewage (secondarily treated sewage) have recently been intensively attempted. In order that the membranes are widely employed in these fields, they are required to be inhibited from staining (clogging) with organic substances, etc.
As materials of the membranes, there are used various materials such as cellulosic materials, polyacrylonitrile-based materials, and polyolefinic materials. Among them, polyvinylidene fluoride is high in strength and heat resistance, and, furthermore, is high in water resistance because its skeleton is hydrophobic and, thus, is suitable as materials of water filtration membranes and is therefore expected to be useful.
As a method for producing polyvinylidene fluoride membranes, U.S. Pat. No. 5,022,990 proposes a method for producing hollow fiber membranes which comprises melt kneading polyvinylidene fluoride, an organic liquid and an inorganic powder, then causing micro-phase separation by cooling and extracting the organic liquid and the inorganic powder. Moreover, WO91/172204 discloses a method for producing hollow fiber membranes comprising polyvinylidene fluoride and a solvent system.
In general, it is known that when filtration of raw water containing turbidity components in large amounts is continued, deposits remaining on the surface of the membranes or in the inside of the membranes which have not been filtered off result in a new filtration resistance to cause deterioration of filtration performance. Therefore, there are employed such means as flushing method according to which the filtration is suspended and the deposits are stripped off by a high speed water stream during the filtration operation, air scrubbing method according to which the deposits are stripped off by applying bubbles to the membrane, back washing method according to which the membranes are washed by reversing the direction of filtration, and the like. Another method is to carry out a periodical cleaning with chemicals to maintain the filtration performance at a high level. The flushing method and air scrubbing method are high in cleaning effect of membranes, but they apply a great load to membranes, which is apt to cause rupture of the membranes, and, furthermore, in the case of conventional membranes, even if these cleaning method are employed, considerable stains are deposited on the membranes (clogging of the membranes) with lapse of time. Thus, satisfactory water permeation performance has not necessarily been obtained.
The object of the present invention is to provide a method for stably and satisfactorily producing polyvinylidene fluoride hollow fiber membranes which have dense pores and high water permeation performance and are excellent in endurance and stain resistance, and are suitable for filtration uses such as removal of turbidity.


A Continuous Query Processor processes queries on continuously updating data sources or data streams and includes a Publication Manager for accepting published structured elements of data from data stream Publishers, a Subscription Manager for giving structured elements of data to one or more data stream Subscribers, a Query Module Manager for processing queries represented by Query Modules, a Query Module Store for maintaining deployed Query Modules, a Query Primitive Manager performing processing for various primitives that comprise a Query Module, and a Schedule Manager for coordinating when a primitive within a Query Module gets processed in order to maintain that each continuous query is continuously updated immediately upon the arrival of structured element data affecting any part of a continuous query.

1. Field of the Invention
The present invention pertains to query processors that receive data continuously from one or more publishers of data streams in order to push query results as data streams to one or more subscribers continuously.
2. Description of the Related Art
There are many real-time information systems today that receive data continuously from multiple information sources. Examples include financial systems tracking traded instrument transactions, geographically distributed weather information systems, industrial systems collecting information from distributed devices, public train systems, credit card systems, real-time military information systems, as well as many others. Each of these systems not only receives data continuously from multiple sources, but also processes the data in order to detect specific conditions and/or merge, sort, transform, and derive meaningful results.
One aspect of continuous processing on multiple heterogeneous data streams that has received minimal attention and standardization in the real-time information industry is a general-purpose and organized approach for processing multiple continuous data streams. In the last few years, the Stanford STREAM project has researched and published many papers describing a Continuous Query Language (CQL) that can be used for general purpose query language processing on data streams. Berkeley's TelegraphCQ project also has researched and published papers describing a Continuous Query system which employs modifications on the OpenSource PostgreSQL Database, which is conventionally known. As such, TelegraphCQ utilizes tables in PostgreSQL to perform the continuous queries. We would expect reduced performance from this approach since PostgreSQL's tables are not meant for continuous processing and because tables naturally reside on disk. Brown University's Aurora data stream Management System project processes query results immediately as each new data stream element arrives, but it does not use SQL-like queries to process information and lacks publish and subscribe sources of data stream information. The Aurora implementation also does not provide support for different incoming and outgoing formats and representations. Celequest's Streaming DataFlow Engine is based on Stanford's STREAM research. Stanford's STREAM data stream Management System, however, employs an implementation that does not process data streams directly. It also lacks the ability to accept and generate data streams of information employing different formats and representations.
Data stream data in STREAM is processed via a description in CQL using three types of operators. They are Stream-to-Relation, Relation-to-Relation, and Relation-to-Stream. All three operators must be employed in a CQL expression in order to produce a resulting output stream. CQL uses SQL constructs to express Relation-to-Relation operators, and most of the data manipulation in CQL is executed via a description of the use of these constructs. Stream-to-Relation operators in CQL are primarily based on sliding windows. This allows CQL to consider recent data (as per a sliding window based on time or amount of data) from a data stream to be in a "Relation", after which the Relation-to-Relation operators may perform. One way of thinking about the operational mechanics of this processing is to consider all of the data in the sliding window to be in a virtual table representing the Relation. Finally, an output stream may be produced via a Relation-to-Stream operator which may be one of IStream, DStream, or RStream representing "insert stream", "delete stream", and "relation stream" respectively. One way of thinking about how these operators work is to think of the virtual table created by the Stream-to-Relation operator. The IStream represents the data produced when considering the data that gets inserted into the virtual table. The DStream represents the data produced when considering the data that gets removed from the virtual table due to the limited sliding window size, while RStream represents the data in the virtual table. Note that this implies that an RStream is a Stream where each datum is a Relation where each Relation, in turn, contains one datum or more. Each query in the STREAM data stream Management System therefore, has the form                Select [Relation-to-Stream Operator] [Stream-to-Relation Operator][Relation-to-Relation Operator]
As in the example:                Select IStream(*) From S1 [Rows [000], S2 [Range 2 Minutes] Where S1.A=S2.A And S1.A>10
While the STREAM data stream Management System does offer general purpose data stream manipulation, the approach incorporates an overly complex object model. STREAM's CQL is overly complex because it requires one to think about the three operator types in order to construct a query. Operators are not applied to pure data streams causing one's development of queries to be overly difficult due to overly sophisticated conceptualization. The support of three Relation-to-Stream operators provides rich functionality but the practical use of the DStream and RStream operators is limited.
The Stanford research does not address how to integrate publish-subscribe semantics in order to support publishers of data streams and subscribers to data streams. Publish-subscribe semantics is an important information flow paradigm to support for continuously updating data sources and targets in enterprise real-time information processing systems.
A drawback of the lack of a general-purpose and organized approach for processing multiple data streams continuously is the development cost for each multiple data stream processor. Each time a new set of behavior and goals is required to be implemented, a new continuous processor must be constructed. These distinct continuous processors tend to perform much of the same core processing comprising receiving data, filtering data, joining data, transforming data, detecting data, and computing derived data. However, the code developed for each continuous processor is different, requires time and resources to design and develop, and time and resources to assure quality as well. Software development, maintenance, and enhancement costs are high and unnecessary when compared to a general-purpose continuous processor that can be reused across different continuous processors. Furthermore, many continuous processing systems merge and process data in ways that can be shown to be equivalent to query-like manipulations. While the Stanford STREAM system provides general purpose processing, it maintains an overly complex object model and lacks support for the key publish-subscribe paradigm. This will result in software development and engineering costs that are not as low as they could be.
Since the Celequest Streaming DataFlow Engine is based on Stanford's STREAM system, it maintains the same software engineering cost issues. Celequest's system appears to treat all streamed data as events and states that it employs XML data between its internal subsystems. While XML maintains known software engineering advantages, its use for core processing in high performance systems is generally discouraged.
In light of the above, there is a need for methods and apparatus for a general-purpose continuous query processor with simplified object model and support for publish-subscribe data stream sources and targets.

Publish and subscribe capable continuous query processor for real-time data streams