This invention relates to the diagnosis and treatment of cancerous diseases, particularly to the mediation of cytotoxicity of tumor cells; and most particularly to the use of cancerous disease modifying antibodies (CDMAB), optionally in combination with one or more chemotherapeutic agents, as a means for initiating the cytotoxic response. The invention further relates to binding assays which utilize the CDMAB of the instant invention.

CD44 in Cancer: Raising monoclonal antibodies against human white blood cells led to the discovery of the CD44 antigen; a single chain hyaluronic acid (HA) binding glycoprotein expressed on a wide variety of normal tissue and on all types of hematopoietic cells. It was originally associated with lymphocyte activation and homing. Currently, its putative physiological role also includes activation of inflammatory genes, modulation of cell cycle, induction of cell proliferation, induction of differentiation and development, induction of cytoskeletal reorganization and cell migration and cell survival/resistance to apoptosis.
In humans, the single gene copy of CD44 is located on the short arm of chromosome 11, 11p13. The gene contains 19 exons; the first 5 are constant, the next 9 are variant, the following 3 are constant and the final 2 are variant. Differential splicing can lead to over 1000 different isoforms. However, currently only several dozen naturally occurring variants have been identified.
The CD44 standard glycoprotein consists of a N-terminal extracellular (including a 20 a.a. leader sequence, and a membrane proximal region (85 a.a.)) domain (270 a.a.), a transmembrane region (21 a.a.) and a cytoplasmic tail (72 a.a.). The extracellular region also contains a link module at the N-terminus. This region is 92 a.a. in length and shows homology to other HA binding link proteins. There is high homology between the mouse and human forms of CD44. The variant forms of the protein are inserted to the carboxy terminus of exon 5 and are located extracellularly when expressed.
A serum soluble form of CD44 also occurs naturally and can arise from either a stop codon (within the variable region) or from proteolytic activity. Activation of cells from a variety of stimuli including TNF-α results in shedding of the CD44 receptor. Shedding of the receptor has also been seen with tumor cells and can result in an increase in the human serum concentration of CD44 by up to 10-fold. High CD44 serum concentration suggests malignancy (ovarian cancer being the exception).
The standard form of CD44 exists with a molecular weight of approximately 37 kD. Post-translational modifications increase the molecular weight to 80-90 kD. These modifications include amino terminus extracellular domain N-linked glycosylations at asparagine residues, O-linked glycosylations at serine/threonine residues at the carboxy terminus of the extracellular domain and glycosaminoglycan additions. Splice variants can range in size from 80-250 kD.
HA, a polysaccharide located on the extracellular matrix (ECM) in mammals, is thought to be the primary CD44 ligand. However, CD44 has also been found to bind such proteins as collagen, fibronectin, laminin etc. There appears to be a correlation between HA binding and glycosylation. Inactive CD44 (does not bind HA) has the highest levels of glycosylation, active CD44 (binding HA) the lowest while inducible CD44 (does not or weakly binds HA unless activated by cytokines, monoclonal antibodies, growth factors, etc.) has glycosylation levels somewhere in between the active and inactive forms.
CD44 can mediate some of its functions through signal transduction pathways that depend on the interaction of the cell, stimulus and the environment. Some of these pathways include the NFκB signaling cascade (involved in the inflammatory response), the Ras-MAPK signal transduction pathway (involved with activating cell cycling and proliferation), the Rho family of proteins (involved with cytoskeleton reorganization and cell migration) and the PI3-K-related signaling pathway (related to cell survival). All of the above-mentioned functions are closely associated with tumor disease initiation and progression. CD44 has also been implicated in playing a role in cancer through a variety of additional mechanisms. These include the presentation of growth factors, chemokines and cytokines by cell surface proteoglycans present on the cell surface of CD44 to receptors involved in malignancy. Also, the intracellular degradation of HA by lysosomal hyaluronidases after internalization of the CD44-HA complex can potentially increase the likelihood of tumor invasiveness and induction of angiogenesis through the ECM. In addition, the transmission of survival or apoptotic signals has been shown to occur through either the standard or variable CD44 receptor. CD44 has also been suggested to be involved in cell differentiation and migration. Many, if not all, of these mechanisms are environment and cell dependent and several give rise to variable findings. Therefore, more research is required before any conclusions can be drawn.
In order to validate a potential functional role of CD44 in cancer, expression studies of CD44 were undertaken to determine if differential expression of the receptor correlates with disease progression. However, inconsistent findings were observed in a majority of tumor types and this is probably due to a combination of reagents, technique, pathological scoring and cell type differences between researchers. Renal cell carcinoma and non-Hodgkin's lymphoma appear to be the exception in that patients with high CD44 expressing tumors consistently had shorter survival times than their low or non-CD44 expressing counterparts.
Due to its association with cancer, CD44 has been the target of the development of anti-cancer therapeutics. There is still controversy as to whether the standard or the variant forms of CD44 are required for tumor progression. There is in vivo animal data to support both views and again it may be tumor type and even cell type dependent. Different therapeutic approaches have included injection of soluble CD44 proteins, hyaluronan synthase cDNA, hyaluronidase, the use of CD44 antisense and CD44 specific antibodies. Each approach has led to some degree of success thereby providing support for anti-CD44 cancer therapeutics.
Both variant and standard CD44 specific monoclonal antibodies have been generated experimentally but for the most part these antibodies have no intrinsic biological activity, rather they bind specifically to the type of CD44 they recognize. However, there are some that are either active in vitro or in vivo but generally not both. Several anti-CD44 antibodies have been shown to mediate cellular events. For example the murine antibody A3D8, directed against human erythrocyte Lutheran antigen CD44 standard form, was shown to enhance CD2 (9-1 antibody) and CD3 (OKT3 antibody) mediated T cell activation; another anti-CD44 antibody had similar effects. A3D8 also induced IL-1 release from monocytes and IL-2 release from T lymphocytes. Interestingly, the use of A3D8 in conjunction with drugs such as daunorubicin, mitoxantrone and etoposide inhibited apoptosis induction in HL60 and NB4 AML cells by abrogating the generation of the second messenger ceramide. The J173 antibody, which does not have intrinsic activity and is directed against a similar epitope of CD44s, did not inhibit drug-induced apoptosis. The NIH44-1 antibody, directed against an 85-110 kD and 200 kD form of CD44, augmented T-cell proliferation through a pathway the authors speculated as either cross-linking or aggregation of CD44. Taken together, there is no evidence that antibodies such as these are suitable for use as cancer therapeutics since they either are not directed against cancer (e.g. activate lymphocytes), induce cell proliferation, or when used with cytotoxic agents inhibited drug-induced death of cancer cells.
Several anti-CD44 antibodies have been described which demonstrate anti-tumor effects in vivo. The antibody 1.1ASML, a mouse IgG1 directed to the v6 variant of CD44, has been shown to decrease the lymph node and lung metastases of the rat pancreatic adenocarcinoma BSp73ASML. Survival of the treated animals was concomitantly increased. The antibody was only effective if administered before lymph node colonization, and was postulated to interfere with cell proliferation in the lymph node. There was no direct cytototoxicity of the antibody on the tumor cells in vitro, and the antibody did not enhance complement-mediated cytotoxicity, or immune effector cell function. Utility of the antibody against human cells was not described.
Breyer et al. described the use of a commercially-available antibody to CD44s to disrupt the progression of an orthotopically-implanted rat glioblastoma. The rat glioblastoma cell line C6 was implanted in the frontal lobe, and after 1 week, the rats were given 3 treatments with antibody by intracerebral injection. Treated rats demonstrated decreased tumor growth, and higher body weight than buffer or isotype control treated rats. The antibody was able to inhibit adhesion of cells in vitro to coverslips coated with extracellular matrix components, but did not have any direct cytotoxic effects on cells. This antibody was not tested against human cells.
A study was carried out which compared the efficacy of an antibody to CD44s (IM-7.8.1) to an antibody to CD44v10 (K926). The highly metastatic murine melanoma line B16F10, which expresses both CD44 isoforms, was implanted intravenously into mice. After 2 days, antibodies were given every third day for the duration of the study. Both antibodies caused a significant reduction of greater than 50% in the number of lung metastases; there was no significant difference in efficacy between the two antibodies. The antibody did not affect proliferation in vitro, and the authors, Zawadzki et al., speculated that the inhibition of tumor growth was due to the antibody blocking the interaction of CD44 with its ligand. In another study using IM-7.8.1, Zahalka et al. demonstrated that the antibody and its F(ab′)2 fragment were able to block the lymph node infiltration by the murine T-cell lymphoma LB. This conferred a significant survival benefit to the mice. Wallach-Dayan et al. showed that transfection of LB-TRs murine lymphoma, which does not spontaneously form tumors, with CD44v4-v10 conferred the ability to form tumors. IM-7.8.1 administration decreased tumor size of the implanted transfected cells in comparison to the isotype control antibody. None of these studies demonstrated human utility for this antibody.
GKW.A3, a mouse IgG2a, is specific for human CD44 and prevents the formation and metastases of a human melanoma xenograft in SCID mice. The antibody was mixed with the metastastic human cell line SMMU-2, and then injected subcutaneously. Treatments were continued for the following 3 weeks. After 4 weeks, only 1 of 10 mice developed a tumor at the injection site, compared to 100 percent of untreated animals. F(ab′)2 fragments of the antibody demonstrated the same inhibition of tumor formation, suggesting that the mechanism of action was not dependent on complement or antibody-dependent cellular cytotoxicity. If the tumor cells were injected one week prior to the first antibody injection, 80 percent of the animals developed tumors at the primary site. However, it was noted that the survival time was still significantly increased. Although the delayed antibody administration had no effect on the primary tumor formation, it completely prevented the metastases to the lung, kidney, adrenal gland, liver and peritoneum that were present in the untreated animals. This antibody does not have any direct cytotoxicity on the cell line in vitro nor does it interfere with proliferation of SMMU-2 cells, and appears to have its major effect on tumor formation by affecting metastasis or growth. One notable feature of this antibody was that it recognized all isoforms of CD44, which suggests limited possibilities for therapeutic use.
Strobel et al. describe the use of an anti-CD44 antibody (clone 515) to inhibit the peritoneal implantation of human ovarian cancer cells in a mouse xenograft model. The human ovarian cell line 36M2 was implanted intraperitoneally into mice in the presence of the anti-CD44 antibody or control antibody, and then treatments were administered over the next 20 days. After 5 weeks, there were significantly fewer nodules in the peritoneal cavity in the antibody treated group. The nodules from both the anti-CD44 and control treated groups were the same size, suggesting that once the cells had implanted, the antibody had no effect on tumor growth. When cells were implanted subcutaneously, there was also no effect on tumor growth, indicating that the antibody itself did not have an anti-proliferative or cytotoxic effect. In addition, there was no effect of the antibody on cell growth in vitro.
VFF-18, also designated as BIWA 1, is a high-affinity antibody to the v6 variant of CD44 specific for the 360-370 region of the polypeptide. This antibody has been used as a 99mTechnetium-labelled conjugate in a Phase 1 clinical trial in 12 patients. The antibody was tested for safety and targeting potential in patients with squamous cell carcinoma of the head and neck. Forty hours after injection, 14 percent of the injected dose was taken up by the tumor, with minimal accumulation in other organs including the kidney, spleen and bone marrow. The highly selective tumor binding suggests a role for this antibody in radioimmunotherapy, although the exceptionally high affinity of this antibody prevented penetration into the deeper layers of the tumor. Further limiting the application of BIWA 1 is the immunogenicity of the murine antibody (11 of 12 patients developed human anti-mouse antibodies (HAMA)), heterogenous accumulation throughout the tumor and formation of antibody-soluble CD44 complexes. WO 02/094879 discloses a humanized version of VFF-18 designed to overcome the HAMA response, designated BIWA 4. BIWA 4 was found to have a significantly lower antigen binding affinity than the parent VFF 18 antibody. Surprisingly, the lower affinity BIWA 4 antibody had superior tumor uptake characteristics than the higher affinity BIWA 8 humanized VFF-18 antibody. Both 99mTechnetium-labelled and 186Rhenium-labelled BIWA 4 antibodies were assessed in a 33 patient Phase 1 clinical trial to determine safety, tolerability, tumor accumulation and maximum tolerated dose, in the case of 186Re-labelled BIWA 4. There appeared to be tumor related uptake of 99mTc-labelled BIWA 4. There were no tumor responses seen with all doses of 186Re-labelled BIWA 4, although a number had stable disease; the dose limiting toxicity occurred at 60 mCi/m2. There was a 50-65 percent rate of adverse events with 12 of 33 patients deemed to have serious adverse events (thrombocytopenia, leucopenia and fever) and of those 6, all treated with 186Re-labelled BIWA 4, died in the course of treatment or follow-up due to disease progression. Two patients developed human anti-human antibodies (HAHA). A Phase 1 dose escalation trial of 186Re-labelled BIWA 4 was carried out in 20 patients. Oral mucositis and dose-limiting thrombocytopenia and leucocytopenia were observed; one patient developed a HAHA response. Stable disease was seen in 5 patients treated at the highest dose of 60 mCi/m2. Although deemed to be acceptable in both safety and tolerability for the efficacy achieved, these studies have higher rates of adverse events compared to other non-radioisotope conjugated biological therapies in clinical studies. U.S. patent application US 2003/0103985 discloses a humanized version of VFF-18 conjugated to a maytansinoid, designated BIWI 1, for use in tumor therapy. A humanized VFF 18 antibody, BIWA 4, when conjugated to a toxin, i.e. BIWI 1, was found to have significant anti-tumor effects in mouse models of human epidermoid carcinoma of the vulva, squamous cell carcinoma of the pharynx or breast carcinoma. The unconjugated version, BIWA 4, did not have anti-tumor effects and the conjugated version, BIWI 1, has no evidence of safety or efficacy in humans.
Mab U36 is a murine monoclonal IgG1 antibody generated by UM-SCC-22B human hypopharyngeal carcinoma cell immunization and selection for cancer and tissue specificity. Antigen characterization through cDNA cloning and sequence analysis identified the v6 domain of keratinocyte-specific CD44 splice variant epican as the target of Mab U36. Immunohistochemistry studies show the epitope to be restricted to the cell membrane. Furthermore, Mab U36 labeled 94 percent of the head and neck squamous cell carcinomas (HNSCC) strongly, and within these tumors there was uniformity in cell staining. A 10 patient 99mTc-labelled Mab U36 study showed selective accumulation of the antibody to HNSCC cancers (20.4+/−12.4 percent injected dose/kg at 2 days); no adverse effects were reported but two patients developed HAMA. In a study of radio-iodinated murine Mab U36 there were 3 cases of HAMA in 18 patients and selective homogenous uptake in HNSCC. In order to decrease the antigenicity of Mab U36 and decrease the rate of HAMA a chimeric antibody was constructed. Neither the chimeric nor the original murine Mab U36 has ADCC activity. There is no evidence of native functional activity of Mab U36. 186Re-labelled chimeric Mab U36 was used to determine the utility of Mab U36 as a therapeutic agent. In this Phase 1 escalating dose trial 13 patients' received a scouting dose of 99mTc-labelled chimeric Mab U36 followed by 186Re-labelled chimeric Mab U36. There were no acute adverse events reported but following treatment dose limiting myelotoxcity (1.5 GBq/m2) in 2 of 3 patients, and thrombocytopenia in one patient treated with the maximum tolerated dose (1.0 GBq/m2) were observed. Although there were some effects on tumor size these effects did not fulfill the criteria for objective responses to treatment. A further study of 186Re-labelled chimeric Mab U36 employed a strategy of using granulocyte colony-stimulating factor stimulated whole blood reinfusion to double the maximum-tolerated activity to 2.8 Gy. In this study of nine patients with various tumors of the head and neck, 3 required transfusions for drug related anemia. Other toxicity includes grade 3 myelotoxicity, and grade 2 mucositis. No objective tumor responses were reported although stable disease was achieved for 3-5 months in 5 patients. Thus, it can be seen that although Mab U36 is a highly specific antibody the disadvantage of requiring a radioimmunoconjugate to achieve anti-cancer effects limits its usefulness because of the toxicity associated with the therapy in relation to the clinical effects achieved.
To summarize, a CD44v6 (1.1ASML) and CD44v10 (K926) monoclonal antibody have been shown to reduce metastatic activity in rats injected with a metastatic pancreatic adenocarcinoma or mice injected with a malignant melanoma respectively. Another anti-CD44v6 antibody (VFF-18 and its derivatives), only when conjugated to a maytansinoid or a radioisotope, has been shown to have anti-tumor effects. Anti-standard CD44 monoclonal antibodies have also been shown to suppress intracerebral progression by rat glioblastoma (anti-CD44s), lymph node invasion by mouse T cell lymphoma (IM-7.8.1) as well as inhibit implantation of a human ovarian cancer cell line in nude mice (clone 515), lung metastasis of a mouse melanoma cell line (IM-7.8.1) and metastasis of a human melanoma cell line in SCID mice (GKW.A3). The radioisotope conjugated Mab U36 anti-CD44v6 antibody and its derivatives had anti-tumor activity in clinical trials that were accompanied by significant toxicity. These results, though they are encouraging and support the development of anti-CD44 monoclonal antibodies as potential cancer therapeutics, demonstrate limited effectiveness, safety, or applicability to human cancers.
Thus, if an antibody composition were isolated which mediated cancerous cell cytotoxicity, as a function of its attraction to cell surface expression of CD44 on said cells, a valuable diagnostic and therapeutic procedure would be realized.
Monoclonal Antibodies as Cancer Therapy: Each individual who presents with cancer is unique and has a cancer that is as different from other cancers as that person's identity. Despite this, current therapy treats all patients with the same type of cancer, at the same stage, in the same way. At least 30% of these patients will fail the first line therapy, thus leading to further rounds of treatment and the increased probability of treatment failure, metastases, and ultimately, death. A superior approach to treatment would be the customization of therapy for the particular individual. The only current therapy which lends itself to customization is surgery. Chemotherapy and radiation treatment cannot be tailored to the patient, and surgery by itself, in most cases is inadequate for producing cures.
With the advent of monoclonal antibodies, the possibility of developing methods for customized therapy became more realistic since each antibody can be directed to a single epitope. Furthermore, it is possible to produce a combination of antibodies that are directed to the constellation of epitopes that uniquely define a particular individual's tumor.
Having recognized that a significant difference between cancerous and normal cells is that cancerous cells contain antigens that are specific to transformed cells, the scientific community has long held that monoclonal antibodies can be designed to specifically target transformed cells by binding specifically to these cancer antigens; thus giving rise to the belief that monoclonal antibodies can serve as "Magic Bullets" to eliminate cancer cells. However, it is now widely recognized that no single monoclonal antibody can serve in all instances of cancer, and that monoclonal antibodies can be deployed, as a class, as targeted cancer treatments. Monoclonal antibodies isolated in accordance with the teachings of the instantly disclosed invention have been shown to modify the cancerous disease process in a manner which is beneficial to the patient, for example by reducing the tumor burden, and will variously be referred to herein as cancerous disease modifying antibodies (CDMAB) or "anti-cancer" antibodies.
At the present time, the cancer patient usually has few options of treatment. The regimented approach to cancer therapy has produced improvements in global survival and morbidity rates. However, to the particular individual, these improved statistics do not necessarily correlate with an improvement in their personal situation.
Thus, if a methodology was put forth which enabled the practitioner to treat each tumor independently of other patients in the same cohort, this would permit the unique approach of tailoring therapy to just that one person. Such a course of therapy would, ideally, increase the rate of cures, and produce better outcomes, thereby satisfying a long-felt need.
Historically, the use of polyclonal antibodies has been used with limited success in the treatment of human cancers. Lymphomas and leukemias have been treated with human plasma, but there were few prolonged remission or responses. Furthermore, there was a lack of reproducibility and there was no additional benefit compared to chemotherapy. Solid tumors such as breast cancers, melanomas and renal cell carcinomas have also been treated with human blood, chimpanzee serum, human plasma and horse serum with correspondingly unpredictable and ineffective results.
There have been many clinical trials of monoclonal antibodies for solid tumors. In the 1980s there were at least four clinical trials for human breast cancer which produced only one responder from at least 47 patients using antibodies against specific antigens or based on tissue selectivity. It was not until 1998 that there was a successful clinical trial using a humanized anti-Her2/neu antibody (HERCEPTIN® trastuzumab)) in combination with Cisplatin. In this trial 37 patients were assessed for responses of which about a quarter had a partial response rate and an additional quarter had minor or stable disease progression. The median time to progression among the responders was 8.4 months with median response duration of 5.3 months.
HERCEPTIN® (trastuzumab) was approved in 1998 for first line use in combination with TAXOL® (paclitaxel). Clinical study results showed an increase in the median time to disease progression for those who received antibody therapy plus TAXOL® (paclitaxel) (6.9 months) in comparison to the group that received TAXOL® (paclitaxel) alone (3.0 months). There was also a slight increase in median survival; 22 versus 18 months for the HERCEPTIN® (trastuzumab) plus TAXOL® (paclitaxel) treatment arm versus the TAXOL® (paclitaxel) treatment alone arm. In addition, there was an increase in the number of both complete (8 versus 2 percent) and partial responders (34 versus 15 percent) in the antibody plus TAXOL® (paclitaxel) combination group in comparison to TAXOL® (paclitaxel) alone. However, treatment with HERCEPTIN® (trastuzumab) and TAXOL® (paclitaxel) led to a higher incidence of cardiotoxicity in comparison to TAXOL® (paclitaxel) treatment alone (13 versus 1 percent respectively). Also, HERCEPTIN® (trastuzumab) therapy was only effective for patients who over express (as determined through immunohistochemistry (IHC) analysis) the human epidermal growth factor receptor 2 (Her2/neu), a receptor, which currently has no known function or biologically important ligand; approximately 25 percent of patients who have metastatic breast cancer. Therefore, there is still a large unmet need for patients with breast cancer. Even those who can benefit from HERCEPTIN® (trastuzumab) treatment would still require chemotherapy and consequently would still have to deal with, at least to some degree, the side effects of this kind of treatment.
The clinical trials investigating colorectal cancer involve antibodies against both glycoprotein and glycolipid targets. Antibodies such as 17-1A, which has some specificity for adenocarcinomas, has undergone Phase 2 clinical trials in over 60 patients with only 1 patient having a partial response. In other trials, use of 17-1A produced only 1 complete response and 2 minutes or responses among 52 patients in protocols using additional cyclophosphamide. To date, Phase III clinical trials of 17-1A have not demonstrated improved efficacy as adjuvant therapy for stage III colon cancer. The use of a humanized murine monoclonal antibody initially approved for imaging also did not produce tumor regression.
Only recently have there been any positive results from colorectal cancer clinical studies with the use of monoclonal antibodies. In 2004, ERBITUX® (cetuximab) was approved for the second line treatment of patients with EGFR-expressing metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy. Results from both a two-arm Phase II clinical study and a single arm study showed that ERBITUX® (cetuximab) in combination with irinotecan had a response rate of 23 and 15 percent respectively with a median time to disease progression of 4.1 and 6.5 months respectively. Results from the same two-arm Phase II clinical study and another single arm study showed that treatment with ERBITUX® (cetuximab) alone resulted in an 11 and 9 percent response rate respectively with a median time to disease progression of 1.5 and 4.2 months respectively.
Consequently in both Switzerland and the United States, ERBITUX® (cetuximab) treatment in combination with irinotecan, and in the United States, ERBITUX® (cetuximab) treatment alone, has been approved as a second line treatment of colon cancer patients who have failed first line irinotecan therapy. Therefore, like HERCEPTIN® (trastuzumab), treatment in Switzerland is only approved as a combination of monoclonal antibody and chemotherapy. In addition, treatment in both Switzerland and the US is only approved for patients as a second line therapy. Also, in 2004, AVASTIN® (bevacizumab) was approved for use in combination with intravenous 5-fluorouracil-based chemotherapy as a first line treatment of metastatic colorectal cancer. Phase III clinical study results demonstrated a prolongation in the median survival of patients treated with AVASTIN® (bevacizumab) plus 5-fluorouracil compared to patients treated with 5-fluourouracil alone (20 months versus 16 months respectively). However, again like HERCEPTIN® (trastuzumab) and ERBITUX® (cetuximab), treatment is only approved as a combination of monoclonal antibody and chemotherapy.
There also continues to be poor results for lung, brain, ovarian, pancreatic, prostate, and stomach cancer. The most promising recent results for non-small cell lung cancer came from a Phase II clinical trial where treatment involved a monoclonal antibody (SGN-15; dox-BR96, anti-Sialyl-LeX) conjugated to the cell-killing drug doxorubicin in combination with the chemotherapeutic agent TAXOTERE® (docetaxel). TAXOTERE® (docetaxel) is the only FDA approved chemotherapy for the second line treatment of lung cancer. Initial data indicate an improved overall survival compared to TAXOTERE® (docetaxel) alone. Out of the 62 patients who were recruited for the study, two-thirds received SGN-15 in combination with TAXOTERE® (docetaxel) while the remaining one-third received TAXOTERE® (docetaxel) alone. For the patients receiving SGN-15 in combination with TAXOTERE® (docetaxel), median overall survival was 7.3 months in comparison to 5.9 months for patients receiving TAXOTERE® (docetaxel) alone. Overall survival at 1 year and 18 months was 29 and 18 percent respectively for patients receiving SNG-15 plus TAXOTERE® (docetaxel) compared to 24 and 8 percent respectively for patients receiving TAXOTERE® (docetaxel) alone. Further clinical trials are planned.
Preclinically, there has been some limited success in the use of monoclonal antibodies for melanoma. Very few of these antibodies have reached clinical trials and to date none have been approved or demonstrated favorable results in Phase III clinical trials.
The discovery of new drugs to treat disease is hindered by the lack of identification of relevant targets among the products of 30,000 known genes that unambiguously contribute to disease pathogenesis. In oncology research, potential drug targets are often selected simply due to the fact that they are over-expressed in tumor cells. Targets thus identified are then screened for interaction with a multitude of compounds. In the case of potential antibody therapies, these candidate compounds are usually derived from traditional methods of monoclonal antibody generation according to the fundamental principles laid down by Kohler and Milstein (1975, Nature, 256, 495-497, Kohler and Milstein). Spleen cells are collected from mice immunized with antigen (e.g. whole cells, cell fractions, purified antigen) and fused with immortalized hybridoma partners. The resulting hybridomas are screened and selected for secretion of antibodies which bind most avidly to the target. Many therapeutic and diagnostic antibodies directed against cancer cells, including HERCEPTIN® (trastuzumab) and rituximab, have been produced using these methods and selected on the basis of their affinity. The flaws in this strategy are twofold. Firstly, the choice of appropriate targets for therapeutic or diagnostic antibody binding is limited by the paucity of knowledge surrounding tissue specific carcinogenic processes and the resulting simplistic methods, such as selection by overexpression, by which these targets are identified. Secondly, the assumption that the drug molecule that binds to the receptor with the greatest affinity usually has the highest probability for initiating or inhibiting a signal may not always be the case.
Despite some progress with the treatment of breast and colon cancer, the identification and development of efficacious antibody therapies, either as single agents or co-treatments, has been inadequate for all types of cancer.

Cytotoxicity mediation of cells evidencing surface expression of CD44


In order to keep the deterioration of water distribution pipes from progressing, a tap water management system is provided with: a water pressure detection unit for detecting the water pressure in at least one location in a water distribution pipe for carrying clean water from a water distribution site to a consumer. and transmitting the detection result as water pressure information; a deterioration detection unit for detecting deterioration in at least one location in a water distribution pipe, and transmitting the detection result as deterioration information; a water distribution planning unit for causing a water distribution plan that is a plan for water distribution pressure to be determined on the basis of information regarding past water demand; a deterioration-reducing water distribution planning unit for deciding, on the basis of the water distribution plan, the water pressure information, and the deterioration information. a deterioration-reducing water distribution plan according to the extent of deterioration; a water distribution pressure changing unit for changing the water distribution pressure of the water distribution pipe; and a water distribution pressure control unit for controlling the water distribution pressure changing unit on the basis of the deterioration-reducing water distribution plan.

In a tap water management system, clean water is supplied from a service reservoir to a consumer that is an end user through the water distribution pipe network. In this case, the tap water management system supplies clean water by increasing a water pressure (water distribution pressure) in a water distribution pipe by using a pump pressurization method in which water is pressurized by a pump or the like or a gravity pressurization method in which water is pressurized by using a height difference between the service reservoir located on a high place and a customer's premises. The tap water management system controls this water distribution pressure to maintain the water pressure at the customer's premises at a predetermined level.
As a first example of controlling the water distribution pressure, a control method in which the water distribution pressure is controlled according to a water distribution plan that is previously determined based on the supply and demand forecast or the like can be used. In patent literature 3, there is described a system in which a water distribution amount based on the water distribution plan is calculated by simulating the water distribution pipe network.
As a second example of controlling the water distribution pressure, a method in which an output of a water distribution control device located near the service reservoir is controlled by feedback control while monitoring the current water pressure in the water distribution pipe network or the water pressure at the customer's premises can be used. For example, in patent literature 2, there is described a technology for suppressing the control performance deterioration due to the secular change of the water distribution pipe network by using a model based on actual process data of an inflow amount, a discharge pressure, a water pressure at the customer's premises, and a demand. Further, in patent literature 1, there is described a water distribution pressure control device to which a modeling error is taken into consideration.
On the other hand, a metal such as a stainless steel, a carbon steel, or the like or a resin such as vinyl chloride or the like is used for the water distribution pipe of which the water distribution pipe network is composed. It is known that by secular change (aged deterioration), a water delivery performance is decreased or a failure such as water leakage, water distribution pipe burst, or the like occurs. In non-patent literature 1, it is described that this deterioration is caused by corrosion on the inner surface of the water distribution pipe, scale deposition, reduction of a pipe diameter or blockage of a pipe caused by slime attachment, a pipe wall thickness loss due to corrosion, or corrosion on the external surface of the pipe when the pipe is buried in the ground.
Further, a technology for diagnosing and analyzing a degree of deterioration of the water distribution pipe is known. For example, in patent literature 4, there is described a technology for diagnosing a state of deterioration of a pipeline network by comparing event data of a pipeline measured by a vibration sensor or a flow rate sensor with a graph showing the aged deterioration characteristic. Further, in patent literature 5, there is described a technology for determining an opening and closing state of an opening and closing device based on opening-closing information detected by an opening and closing sensor and analyzing a state of a pipe laying based on vibration information detected by the vibration sensor.
On the other hand, with the development of IT (Information Technology), a technology to instantly deal with a large amount of sensor information at a hub side is available at present. For example, in non-patent literature 2, there is described a technology for dealing with stream data such as sensor data in several seconds and comparing it with the stored data.

Tap water management system, tap water management device, tap water management method, and tap water management program recording medium


A connector device comprising: a housing made of an insulating material, which has a groove including connection terminals for coming into electrical contact with a row array of connection terminals of a first circuit board inserted therein and with a second circuit board, the first circuit board being partially housed in the groove; latching means having a pair of metal strips mutually oppositely provided one at each end of the housing at an interval corresponding to a length of the first circuit board in a direction in which the connection terminals are arranged as the row array; the pair of metal strips elastically holding the partially inserted first circuit board therebetween under an elastic force acting in a direction perpendicular to that in which the connection terminals of the first circuit board are arranged as the row array; holding means for holding the latching means relative to the housing; and fixing means for positionally fixing the first circuit board, which is held by the latching means, relative to the housing in a direction of the thickness of the first circuit board.

1. Field of the Invention
The present invention relates to a connector device for connecting, for example, printed circuit boards to each other.
2. Description of the Related Art
A connector device 50 as shown, for example, in FIG. 1 is known as a connector device for making an electrical connection between, for example, printed circuit boards. The connector device 50 is used to electrically connect a first circuit board 53 to a second circuit board 63 and has a housing 51 made of plastics. The first circuit board 53 is diagonally inserted into a groove 52 of the housing 51 and swung, in a direction as indicated by an arrow 54, to an upright position as shown in FIG. 2. The upright circuit board 53 makes electrical contact with connection terminals 55 by being sandwiched by spring force of the connection terminals 55 held in a groove. A pair of latching sections 56, 57 are provided on both the end portions of the housing 51 to securely hold the circuit board in the upright position. During the swinging of the circuit board 53, the latching sections 56 and 57 are pushed, while being elastically flexed outwardly of the housing, away from each other by the circuit board 53 and, upon the reaching the upright position, returned back to an original position, thus holding end surfaces 58 and 59 of the circuit board 53 therebetween. At the same time, those mutually facing faces 60 and 61 of projections of the latching sections S6 and S7 support a surface 62 of the circuit board, holding the circuit board 53 to the upright position. Upon the detachment of the circuit board 53 from the connector device 50, the latching sections 56 and 57 are pushed and outwardly flexed, away from each other, removing the circuit board 53 from the connector device. The latching sections 56 and 57 are made of plastics and formed integral with the housing 51.
However, the plastics latching sections 56 and 57 used in the conventional connector device are liable to crack, break, etc., failing to impart any adequate withstand property to the connector device. Further, upon the repeated attachment and detachment of the circuit board to and from the connector device, the latching sections are not returned back to the original position and the board holding force of the latching sections is decreased, enabling no adequate electrical connection to be made between the circuit board and the connection terminals. The latching sections are also liable to be damaged or worm out due to a frictional force involved upon the attachment and detachment of the circuit board to and from the connector device. It is difficult to manufacture the latching sections of complex shape such that they are formed integral with the housing with the use of plastics. High accuracy is required upon the manufacture of such complex latching sections. Due to the limited flexibility of the plastics, a considerable force is also required when the latching sections are pushed away from each other upon the attachment and detachment of the circuit board.


My invention is a device for pulling and securing rope. It includes a power driven disk with annular groove having a V-shaped cross section. Bearing surfaces are transversally spaced around the periphery of the inner faces of the grooves. Gripping, without slippage occurs when a taut rope wedges into the groove and against the bearing surfaces.

My improved device is structured for use in lineal movement or securing of a load attached to a rope. The present method of pulling such rope is with a winch. The well-known disadvantages of a winch may now be avoided. For example, the application of manual labor to keep tension on a rope is not needed. Slippage of the rope is obviated with my assembly. Pulling a rope of any length for any distance may now be accomplished without winding the same on a drum or the like. Use in power-take-offs on trucks; pulling wire through conduits and hoisting loads of great weights for various distances are examples of the use of my device. When it is used to secure rope under tension, disk rotation of only 120 degrees is sufficient for all requirements.


A light detection device includes laser sources arranged at both ends in the scanning direction and at one end in the paper feed direction for emitting laser beams intersecting with each other, and light receiving elements arranged at both ends in the scanning direction and at the other end in the paper feed direction for receiving the laser beams emitted from the laser sources. An ink-jet head is adapted to be capable of reciprocating in the scanning direction, and a plurality of nozzle ejection ports are formed between the laser sources and the light-receiving elements in terms of paper feed direction. When ink drops ejected from a nozzle are overlapped with the laser beams, the laser beams are interrupted by the ink drops, and hence the light-receiving elements do not receive the laser beams any longer. The detection of these light beams may be used to determine an amount of deviation in liquid drops ejected from the nozzles, and corrective measures may be taken.

1. Field of the Disclosure
The present application relates to a liquid drop ejection apparatus for ejecting liquid drops from nozzles.
2. Description of the Related Art
There is a known liquid drop ejection apparatus for ejecting liquid drops from nozzles that is configured to detect when liquid drops are not ejected from nozzles, and the fact that the direction of ejected liquid drop is deviated. For example, an ink-jet printer (liquid drop ejection apparatus) may be provided with a laser nozzle check device including a laser source for emitting a laser beam (light beam) and a light receiving element for receiving the laser beam below a line head. In this ink-jet printer, ink drops are ejected from a plurality of nozzles on the line head one by one in sequence. A laser beam is emitted from the laser source, and if the laser beam is not interrupted by an ink drop ejected from a certain nozzle, the laser beam will reach the light receiving element, and non-ejection of ink, or deviation of an ink landing position (deviation in the direction of ejection), in the nozzle is detected.
However, in such an ink-jet printer, the laser beam is interrupted by the ink drops, and the laser beam is not received, even when the direction of ink ejected from the nozzle is deviated in a direction parallel to the direction of the laser beam emission. Therefore, in such a case, the deviation in the direction in ink ejection is not detected.


A method of, and apparatus for, detecting level and blockages in an ore pass or other near-vertical shaft is described. The level and blockage detector includes a flexible metal strip in which a plurality of strain gages have been located, spaced apart from one another, preferably at known distances. A plurality of anchors secure the metal strip to the interior surface of the shaft such that the metal strip is displaced a fixed distance from the interior surface. The anchors are located intermediate the strain gages. When the ore pass fills up with bulk material, the bulk material causes the metal strip to deflect toward the interior surface of the shaft. This causes the resistance of the strain gage in the region of the deflection to change. To detect the location of the blockage, a microcontroller cycles through each strain gage, placing it as the fourth arm of a bridge circuit. When a change in the output voltage across the bridge circuit is detected, the location of the strain gage causing the change in output voltage is an indication of the presence of bulk material (ore). A series of LEDs, one for each strain gage, may be used to indicate which strain gage senses the presence of bulk material and which strain gage does not.

This invention relates to a method and apparatus for detecting fill level and blockages in ore passes and other vertical or near-vertical shafts.
Large commercial mining operations often involve mining several different ore bearing layers. The mined ore is delivered to trucks or the like in a main drive shaft located below the lowest ore bearing layer. Ore pass shafts are vertical or near-vertical shafts used to transport ore mined in the bearing layers down to the main drive shaft. The ore pass shafts can be from eight feet in diameter for cutout shafts and up to fifty feet in diameter for blasted out shafts. They run from fifty feet to two hundred feet in length, and in some occasion up to one thousand feet in length.
Ore passes, backfill raises, mine draw points, chutes and other near vertical raises frequently get blocked due to bridging material. Chutes and grain hoppers usually contain access panels for inspection of internal areas and are also relatively easily accessible outside. Ore passes are only accessible from the inside and present an extremely harsh environment. Because of this it is not easy to determine the location and source of the blockage.
Several methods exist for locating and detecting blockages in material handling systems. U.S. Pat. No. 5,063,729 to Fox et al. describes a cotton blockage detector for a harvester which uses an acoustic output directed toward the discharge door floor of the cotton picking unit. When the cotton picking unit is operating properly, the floor area is clear. When a blockage occurs, the area begins to fill with cotton and debris, causing a decrease in the monitored distance. U.S. Pat. No. 4,068,223 to R. Steffen describes a monitoring system for agricultural harvesting apparatus in which flow sensing means is mounted in a duct for the passage of the harvest. The apparatus senses changes in airflow, indicating when a blockage occurs. U.S. Pat. No. 4,546,346 to Wave et al. describes a sewer line backup detection, alarm and detention apparatus include a series of pneumatic switches coupled to a pressure sensitive diaphragms extending into the sewer at various locations. In the event of a sewer blockage, the blocked material exerts pressure on the diaphragm which closes the switch. None of these techniques is suitable for the rough environment of an ore pass.
Many bulk material level indicators are currently in use. The most common technologies involve the use of radio frequency (RF) and laser beams. A major disadvantage of these technologies is that they require an external mounting arrangement. Ore passes require an internal mounting arrangement since only the internal walls can be accessed.
Once a blockage is determined, the ore pass must be unblocked. Several techniques exist for unblocking ore passes and other near-vertical shafts: running water, boring and in extreme cases, explosives. While it is important for safety and productivity reasons to unblock the ore pass, it is also important to be able to locate the blockage areas quickly and efficiently. Knowledge of the extent and location of the blockage can also help determine the type and safest method for clearing it.
There is a need for an apparatus for detecting level and locating blockages in the rugged environment of an ore pass. There is a need for a low cost and easily installed level detector and blockage locator. There is a further need for a level detector and blockage locator which can withstand most non-explosive cleanout techniques. There is a need for a level detector and blockage locator which can be installed on the internal walls of an ore pass or other vertical rise.

Ore pass level and blockage locator device

The United States of America as represented by the Department of Health and Human Services


The instrument panel assembly is made by initially forming an instrument panel substrate having a door-receiving notch, initially forming a door substrate, and attaching the door substrate to the instrument panel substrate so that the door substrate covers the notch and its sides extend beyond the notch and overlie portions of the instrument panel substrate. A single decorative cover layer is also initially formed. The attached substrates are positioned in a mold in spaced relation to the cover layer, and a foamable material is forced into the space to provide a foam padding for both the instrument panel and the door. The sides of the door substrate overlying the instrument panel substrate are braced to prevent distortion thereof during molding.

The door covering the passenger air bag in an automotive vehicle opens only when the air bag deploys. At all other times the door remains closed.
In the past, the door covering the air bag has been made separately from the instrument panel. The door and the instrument panel might both be covered with the same decorative material which could be vinyl or the like. It was expected that the door would then blend in and not stand out as something different from the rest of the instrument panel.
This was not always the case. Often the decorative material used to cover the door was taken from a different lot having a slightly different shade or texture or gloss or grain, or the grain ran in a different direction. This was particularly noticeable along the seam lines of adjacent edges.
In accordance with the present invention, the door is attached to the instrument panel before the decorative material is applied. The decorative material is then applied as a single, continuous layer covering both the door and the instrument panel. The decorative material covering the door is an integral extension of the decorative material covering the instrument panel proper,and extends across the integral hinge at the top of the door.
Further, in accordance with the invention, the door is disposed between a pair of air vent apertures. An air outlet distributor is placed in each aperture and the inner edges of the distributors are substantially flush with the side edges of the door. The distributors are made of a different material than the decorative layer covering the instrument panel and door. Fit and finish along the side edges of-the door is therefore not as critical as if the edges formed a seam with the similarly covered instrument panel proper.
It is an object of this invention to provide a method of making an instrument panel assembly having the features referred to above.
These and other objects, features and advantages of the invention will become more apparent as the following description proceeds, especially when considered with the accompanying drawings.

Method of making an instrument panel assembly


A magnetic recording and reproducing device with an automatic tracking control function which can record and reproduce signals by means of a rotary head incorporating plural heads. The device performs tracking control by detecting, based on a timing of a synchronizing signal of a track, crosstalks of pilot signals obtained from adjacent tracks and comparing the crosstalks to use the difference as a tracking error signal. In a first example of the invention, the device comprises means which, when time points at which the tracking error signals is obtained are located at uneven time interval, transmits the tracking error signal to the tracking control system with a transfer gain which varies substantially in inverse proportion to the time interval. According to the invention, when the time interval for obtaining the tracking error signal is long, the transfer gain becomes low whereas when the time interval is short, the transfer gain becomes high. Therefore, even if the tracking error detection interval varies, its effect on the tracking servo is substantially equalized whereby the amount of data untraced by the heads can be minimized. In a second example of the invention, the device includes circuitry for separately sampling and holding alternate tracking error signals. The alternate tracking error signals are held until the next corresponding tracking error signal occurs, typically corresponding to a half rotation of the rotary head. Therefore, although the alternating tracking error signals occur at uneven time intervals, the time which these signals are held is the same with the result that the influence of the tracking error signals is equal and tracking is optimized.

This invention relates to a magnetic recording and reproducing device and, more particularly, to a tracking control with improved accuracy during reproduction in a magnetic recording and reproducing device such as an R-DAT (rotary head type digital audio tape recorder) in which a tracking error signal can be obtained only at uneven intervals.
The R-DAT is a device which converts analog signals such as an audio signal into PCM signals, records the PCM signals on a magnetic tape and reproduces the same.
As shown in FIG. 2, the device comprises a rotary head 2 having two magnetic heads A and B separated by 180 degree interval on the circumferential surface of a cylinder 1. A tape 3 is loaded from a cassette housing 4 with a vertical post 5 or with an inclined post 6, wound on the circumferential surface of the rotary head 2 for 90 degrees, supported by a fixed guide 7, and run by a capstan 8 and a pinch roller 9.
The diameter of the rotary head 2 is 30 mm, and the winding angle for the tape is 90 degrees. For recording and reproduction, at the mode I which is usually used, the rate of the rotary head 2 is 2,000 rpm (circumferential speed: 3.14 m/sec) and the speed of the tape 3 is 8.15 mm/sec in the direction identical to that of the rotary head 2. The relative speed of the head 2 as against the tape 3 is 3.13 m/sec.
The recording system with R-DAT is a helical scanning azimuth recording. Its tape format as shown in FIG. 3 defines a track angle of 6.degree. 22' 59.5'' and azimuth angle of .+-.20.degree. with the tracks alternately traced by two heads A and B.
FIG. 4 shows a track format wherein audio data are recorded at the center of a PCM region, and sub-codes and control signals such as ATF (automatic track finding) are recorded on both sides thereof.
The PCM region comprises 128 blocks as shown in FIG. 5 each of which has recording regions for a block synchronizing (indicating the starting position of the block), ID (identification) code, block address, parity check code, and audio data. At the mode I, audio data uses 2's complement codes of quantization bit of 16 bits of the sampling frequency of 48 kHz, and the PCM data is divided into 8 bits in higher order and 8 bits of lower order, modulated from 8 bits into 10 bits (8-10 modulation) and recorded in 10 bits.
For tracking control during reproducing in the R-DAT, an automatic tracking system with ATF is employed. ATF system detects and compares crosstalks from two adjacent tracks by ATF signals recorded on the tracks, and controls the speed of the capstan motor for running the tape so as to make the crosstalks identical.
The principle of ATF will now be described below.
ATF signals are recorded at two locations on one track, i.e., ATF1 and AFT2, as shown in FIG. 4. As shown in the format in FIG. 6, pilot signal f1 and synchronizing signal f2 (or f3) are recorded on each track. The frequencies are specified respectively:
f1=130.67 kHz PA1 f2=522.67 kHz PA1 f3=784.00 kHz
These frequencies are low enough not to have much azimuth loss. The head A traces the track of the synchronizing signals of f2. The head B traces the tracks of the synchronizing signals of f3. The track length of a synchronizing signal differs between an odd number frame and an even number frame, which are defined as one (1) block and 0.5 block respectively.
If it is assumed that the head A is tracing the track T4, pilot signals f1 of adjacent tracks T3 and T5 are obtained from the head A due to crosstalks in addition to a reproduced signal from the track T4. This is because the head has a width 1.5 times as large as a track. If the head A is tracing the track T4 correctly, crosstalks from the tracks T3 and T5 become equal, but if the head is deviated to either direction, the crosstalks from them become different from each other. The crosstalks from the adjacent tracks T5 and T3 are detected by detecting amplitude levels of the pilot signal f1 on the track T5 and of the pilot signal f1 of the track T3 at the detection timing of the synchronizing signal f2 of the track T4. The difference in the crosstalks therefore is presumed to represent tracking errors.
FIG. 7 shows a prior art ATF device based on the above mentioned principle. A reproduced signal from the head A is applied to a low-pass filter 16 via a reproduction amplifier 14 to extract pilot signal f1. The extracted pilot signal f1 is applied to a tracking error detection circuit 21, detected in envelope by an envelope detection circuit 18, and applied to a sample hold circuit 26. A synchronizing signal detector 19 detects synchronizing signal f2 with an equalizer 20 and a comparator 22, and the comparator 22 outputs "1" during the period when the synchronizing signal is being detected.
A logic circuit 24 outputs sample hold signals SP1 and SP2 at the timing of the detected synchronizing signal f2. As the sample hold signal SP1 is provided at a timing immediately after the start of detection of the synchronizing signal f2, if the output from the circuit 18 is sampled with the SP1, a sample hold circuit 26 can hold crosstalk amplitude level of the pilot signal f1 on the track T5 which is the track next to the track T4 currently being traced. A subtractor 28 implements subtraction between the output of the sample hold circuit 26 and the output of the detector 18. A sample hold signal SP2 is produced after the time equivalent to 2 blocks after the start of detection of the synchronizing signals f2 (timing substantially at the center of the pilot signal f1 on the track T3). By sample holding the output from the subtractor 28 with this signal SP2, the difference in crosstalk amplitude levels between the pilot signals f1 of the track T3 and of the track T5 positioned on both sides of the track T4 which is currently being traced is sample held at the circuit 30.
The output from the circuit 30 is applied to a capstan servo circuit 34 as a tracking error signal. The circuit 34 controls the speed of the capstan motor 36 in such a manner that the tracking error becomes zero. This eventually controls the running speed of the tape 10 thereby correcting the tracking error.
In the ATF device shown in FIG. 7, when the head A is deviated to the left from the center, crosstalks of the pilot signal from the track T3 increases. A negative signal is therefore held at the sample hold circuit 30. In order to correct this, the capstan motor 36 increases the speed.
When the head A is deviated to the right, the crosstalk of the pilot signal from the track T5 increases, and a positive signal is held at the circuit 30. For correcting this, the speed of the capstan motor 36 is decreased.
The ATF system can thus control tracking as stated in the foregoing.
In the track format of R-DAT, tracking errors are detected at only two locations, i.e., ATF1 and ATF2 for one track. A tracking error detected, at one detection timing is retained for tracking control until the next time of the tracking error detection. However, the interval of tracking error detection is not uniform as shown in FIG. 8; e.g., in terms of angle, interval from ATF1 to ATF 2 is 64.746.degree. whereas that from ATF2 to ATF1 of the next track is 115.254.degree.. The difference in the interval is about 1 : 2. Therefore, the error signal detected at ATF2 is used for tracking control for a duration of time twice as long as the error signal detected at ATF1. The error signal detected at ATF2 exercises a stronger influence than the one detected at ATF1 with a resulting imbalance in the tracking control.
The head preferably traces a track in parallel thereto as shown in FIG. 9 with a solid line A, but due to errors in the manufacture of the head (uneven circumferential surface of a cylinder or eccentricity of the rotational axis) or warps of the tape due to uneven tension, the head often zig-zags as shown in the figure with a dotted line B or deviates from the center by angle error as shown in a dot-and-chain line C in practice.
In order to correct such defects, there has been proposed a dynamic tracking method which directs a magnetic head with a piezo electric element incorporated in the head so as to force the head to correctly follow the track (for video tape recorder). However, the method has the disadvantage that the structure of the head becomes extremely complicated.
It is therefore necessary to devise a method which allows a head to trace a track optimally without the necessity of addition of such a complicated system even if deviation or zigzagging of the head is unavoidable. The optimal state herein means that the head is placed upon a track at the center of the track width at the center in the longitudinal direction of a track having the audio data PCM region. So far as the head remains in the area, as the width of the head is 1.5 times as large as the width of the track, it can sufficiently read the PCM region to minimize missing data.
If, however, the detection interval is not uniform as mentioned above, such an optimal state cannot be sustained. More specifically, the tracking error signals in the state shown in FIG. 10 become substantially the same in absolute value in ATF1 and ATF2 but with opposite polarities as shown in FIG. 11. Since, however, the tracking servo uses timewise average values of tracking error signals, if the detection interval is not uniform, the average value does not become zero. Tracking error signal in ATF2 therefore exercises a stronger influence. The tracing therefore is controlled in such a manner that the error in ATF2 is corrected to a greater extent, which makes the head to deviate from the center of the track as shown in FIG. 12. Under these state, as the areas where head is deviated from the PCM region becomes enlarged and more PCM data will be missing, making correct reproduction thereof extremely difficult.
It is, therefore, an object of the invention to solve this problem encountered in the prior art and provide a magnetic recording and reproducing device which can conduct tracking in an optimal manner by equalizing effect of tracking error signals when the detection thereof is performed with an uneven interval.

Rotating head magnetic recording and reproducing device having automatic tracking control function


An apparatus for a crane comprises a large-cavity pressure sensor, a small-cavity pressure sensor, a controller, a telescopic oil cylinder, and a telescopic oil cylinder regulator. The large-cavity pressure sensor can measure the oil pressure in a large cavity of the telescopic oil cylinder. The small cavity pressure sensor can measure the oil pressure in a small cavity of the telescopic oil cylinder. The controller can control an output electrical signal according to a large-cavity oil pressure fed back by the large-cavity pressure sensor and a small-cavity oil pressure fed back by the small-cavity pressure sensor, and, by means of the electrical signal, control a change of the amount of hydraulic oil flowing into and out of the large cavity and the small cavity of the telescopic oil cylinder so as to regulate the oil pressures in the large cavity and the small cavity.

Since the hoisting performance of a main boom of a crane may be improved significantly by a single-cylinder pin-plug-in telescopic system, the system is widely used in large/medium tonnage crane products.
One end of a telescopic oil cylinder piston rod of the single-cylinder pin-plug-in system is fixed on the main boom, and a telescopic oil cylinder barrel slides in the sliding groove within each boom. Connections and separations between the telescopic oil cylinder and booms can be achieved through different combinations of a boom pin and a cylinder pin on the telescopic oil cylinder, and then stretching and contracting with a boom and stretching and contracting with the cylinder being idle can be achieved.
FIG. 1 is an exemplary schematic diagram of a dual-boom single-cylinder pin-plug-in telescopic system, wherein a telescopic oil cylinder can drive, through a cylinder pin, a secondary boom to stretch and contract, and a boom pin is used for connecting the secondary boom rigidly with the main boom. In practical application, the combination mostly includes five or more booms.
With a plurality of states such as stretching with a boom, contracting with a boom, stretching with the cylinder being idle and contracting with the cylinder being idle, different variable amplitude angles, and the number and combined operating conditions of telescopic booms, the load of the corresponding telescopic oil cylinder is not the same, and thus the value of oil pressure in the telescopic oil cylinder is not the same. The larger the opening of the solenoid valve on the oil way pipeline, the larger the flow and the swifter the stretching and contracting motion, so that regulating the opening size of the solenoid valve is a demanding task in order to ensure the smoothness of the stretching and contracting motion.
When oil leakage caused by damage of the oil way pipeline and damage of the valve circuit happens, the pressure in the telescopic oil cylinder cannot build up, and thus the value of the oil pressure will be relatively small. For example, as shown in FIG. 1, after the secondary boom stretches out, if the hydraulic oil in the large cavity is leaked off completely due to trouble in the large-cavity oil way, then after the boom pin is pulled off, there is no pressure support in the large cavity, so subjected to the gravity of the cylinder and the telescopic boom itself and under the huge pressure action of the small-cavity oil pressure, the stretching boom will fall rapidly, and it is very easy to cause the damage of the vehicle and a safety accident.
When the resistance to the stretching and contracting motion of the telescopic oil cylinder becomes greater due to the deformation of the main boom under force, lack of lubrication and maintenance for a long time, etc., so that the main boom cannot normally stretch and contract, it is easy to cause the pressure in the cylinder to be too high, and forced pressurization will cause damage to the whole system.
When it is detected that the end boom fails, the telescopic oil cylinder stretches excessively and the head of the telescopic oil cylinder collides with the head of the main boom, affected by the instant impact, the fluctuation in oil pressure will be very violent.
In the case of contracting with a boom, the pressure of the large cavity should be a bit lower than that of the small cavity; if the pressure difference is too large, the speed of contracting will be too fast; if the pressure difference is too small, the motion will be too slow. The system smoothness performance may be improved by real-time regulation of the solenoid valve and oil pump according to the pressure difference value.
In the prior art, the overflow valve technique is often used to prevent the oil pressure from being too high: an overflow valve is added to the hydraulic oil way pipeline, and when the oil pressure reaches the upper limit value of the overflow valve, the hydraulic oil flows back to the oil tank through the overflow valve, so as to ensure that the pressure in the oil way is not higher than a certain upper limit value, and then protect the system safety. However, the overflow valve technique can only ensure that the oil way pressure is not higher than a certain upper limit value, but the change in oil pressure cannot be known clearly. When the oil pressure is too low, the information about the oil pressure cannot be obtained, and at the same time the pump, solenoid valve and engine, etc. cannot be regulated or otherwise treated accordingly.
A boom position detection technique is also used in the prior art. According to that technique, the position of each bloom is detected by a proximity switch, and the boom position information, namely which boom's range the telescopic oil cylinder is within, is determined. When the end boom is detected, a corresponding judgment is made, so as to prevent overstretching of the cylinder. However, according to the boom position detection technique, the preventive effect can be exerted only on the overstretching, but when the boom stretching speed is too fast so that the cylinder and the head of the main boom collide, no corresponding treatment is given.
In addition, also used in the prior art is a telescopic oil cylinder length measuring technique: the stretching/contracting length of the single-cylinder pin-plug-in telescopic oil cylinder is measured by a boom position length sensor. However, that technology is only for detection of the results, and the reason why the stretching speed becomes faster or slower, or why incapability of stretching occurs cannot be determined.
In the prior art, mainly by operating a control handle, an operator controls the size of the solenoid valve opening and/or the pump displacement, and then controls the speed of the stretching and contracting motion. For example, the more the control handle is turned, the larger the solenoid valve opening and the flow are, the swifter the stretching and contracting motion will be. However, this way is based on the operator's operation on the control handle, so that a high requirement on the operator's operational skill is imposed. In addition, there is no quantified feedback information on the controlled variable of the controlled object (stretching/contracting speed of the telescopic oil cylinder). Thus, it is difficult to ensure the smoothness and safety of the system.
Actually, it is often difficult to pull the boom pin in the single-cylinder pin plug-in system. There are two main reasons: 1) the oil pressure in the telescopic oil cylinder cannot build up, the boom cannot stretch out, and thus the boom pin cannot be unhooked; and 2) the boom pin cylinder fails, so the boom pin cannot be pulled off. However, based on the prior art, the reason why the boom pin cannot be pulled out still cannot be determined.
All of the above examples have actually occurred, so it is necessary to detect the state of the telescopic oil cylinder.

Apparatus and method for detecting and protecting telescopic oil cylinder of crane


A path of travel used by an autopilot operation system for auto-guidance of a mobile machine is defined, transparently to a human operator, in response to the human operator engaging and disengaging operation of an implement coupled with the mobile machine. The auto-guidance of the mobile machine is activated, transparently to the human operator, in response to the human operator engaging the implement a second time.

Autopilot systems are used to control the trajectory that a vehicle travels without the human operator constantly having their hands on the steering wheel. An autopilot system does not replace the human operator but instead allows the human operator to focus on a broader spectrum of tasks.
Autopilot systems require sophisticated human operators to configure them and to interact with them using, for example, some type of graphical user interface display, such as a touch screen. For example, the sophisticated human operators need to read long and complicated user manuals that describe, among other things, how to install optical sensors, perform various operations using the graphical user interface display such as tare calibration, flow calibration, pitch/roll calibration, weight test, enter the type of crop that will be harvested, create variety maps of the field, monitor displayed statistics, enter the type of the vehicle, the offset from the axle to the antenna, the antenna height, the wheel base, select antenna type, elevation mask, SNR mask, RTK base station information, radio frequency, among others. An expert may need to be hired to assist in training the human operator on how to interact with the graphical user interface display and on how best to configure the autopilot system.
The autopilot systems cost in the range of $10,000 to $50,000. These expensive autopilot systems come with higher end vehicles that cost anywhere from $300,000 to a $1,000,000 each. Further, these higher end vehicles and their corresponding expensive autopilot systems require a high level of user sophistication. Only very large and profitable farming establishments can afford these expensive autopilot systems and higher end vehicles. These types of vehicles and autopilot systems are frequently used in large commercial farms that have large fleets of vehicles.
Further, due to the complex nature and expense of these conventional autopilot systems and the vehicles, these conventional autopilot systems are typically integrated with the vehicle at the time that the vehicle is manufactured.

This patent is subject to a terminal disclaimer.

Transparently achieving auto-guidance of a mobile machine


An acoustic wave device includes: an IDT provided on a piezoelectric substrate; and gratings provided on both sides of the IDT, wherein: a slowness surface of an acoustic wave has a concave shape; a duty ratio of electrode fingers of the gratings is larger than that of the electrode fingers of the IDT, or a thickness of the electrode fingers of the gratings is larger than that of the electrode fingers of the IDT, or a thickness of an added film provided on the electrode fingers of the gratings is larger than that of an added film provided on the electrode fingers of the IDT; a pitch of the electrode fingers of the gratings is smaller than that of the electrode fingers of the IDT; and a resonant frequency of the gratings is substantially the same as that of the IDT.

Recently, high performance is progressed in mobile communication devices represented by smart phones or mobile phones. For example, handling is rapidly shifted from a third generation system to an LTE (Long Term Evolution). In the LTE, a data communication of a large capacity is performed with a higher speed. Therefore, specs demanded for high frequency components becomes higher. Reduction of an insertion loss of filters or duplexers using an acoustic wave device is being demanded. There are acoustic wave devices in which an IDT (Interdigital Transducer) is provided on a piezoelectric substrate such as surface acoustic wave devices, as acoustic wave devices used in mobile communication devices or the like.
Japanese Patent Application Publications No. 2000-341073, No. 2003-87083, No. 2008-113273, No. 11-298286 and No. 2013-518455 disclose that gratings are provided on both sides of an IDT in an aperture direction thereof in a surface acoustic wave device.


A mower deck cleaning device for a rotary mower for removing clippings from the inside of the mower blade housing. A tubular conduit is mounted on the mower so as to extend through the deck of the mower. A garden hose may be attached to the conduit to flow water through the conduit. A rotor mounted on the conduit receives the water from the hose and projects a rotating pattern of pressurized fluid for cleaning the inside of the housing.

The present invention relates to a mower deck cleaning device for the type of mower having a rotating blade and to an improved method for cleaning a lawn mower.
One of the problems involved in the operation and maintenance of rotary type lawn mowers is the buildup of grass clippings under the deck and within the housing of the mower. The clippings may be removed by hand or with a broom or by scraping. Such a procedure has drawbacks in that lifting and tilting the mower can cause gas and oil to drain out of the engine of the mower. Also, in the situation of a large mower, the weight of the mower may be so great that it cannot be lifted conveniently.
Various devices have been proposed in the prior art to deal with the cleaning of clippings from the mower. One of these solutions involves providing a system for directing a stream of water against the inside wall of the housing and/or onto the rotating blade. Examples of this solution are the U.S. Pat. Nos. to Meuth 5,444,967, Wittwer 3,535,862 and Griffin 3,214,893. The blade then functions to fling the water against the inside surfaces of the housing to remove the grass clippings from those surfaces. The present invention is intended to improve the effectiveness and convenience of a water stream or other fluid stream in cleaning the mower.
One embodiment of the present invention involves a cleaning device for mounting on a lawnmower which lawnmower has a housing about a cutting blade. The cleaning device includes a tubular conduit mounted on the lawnmower and extending through the housing for conducting a cleaning fluid under pressure into the housing. A rotor is rotatably mounted on the conduit for rotation inside of the housing about an axis. The rotor has a series of fluid channels communicating with the conduit which are arranged to discharge fluid in the same rotary direction about the axis whereby pressurized fluid from the conduit entering into the channels of the rotor causes the rotor to rotate and spray pressurized fluid in rotating streams against the inside surfaces of the housing.
Another embodiment of the invention might include a cleaning device for mounting on the lawnmower having a housing about a rotary cutting blade. The lawnmower has a horizontal deck forming a part of the housing and located above the rotary cutting blade. The cleaning device includes an elbow having a elbow fluid passage therethrough. The elbow is fixedly mounted to and above the deck of the lawnmower. A cylindrical member having a first fluid passage therein is fixedly mounted to and below the deck with the first fluid passage in communication with the elbow fluid passage. There is also provided a cylindrical rotor rotatably mounted within the cylindrical member for rotation about a vertical axis. The cylindrical member has a group of second fluid passages extending from the first fluid passage to an area just above and adjacent to the rotor. The cylindrical rotor has a series of fluid channels communicating with the second fluid passages. The fluid channels have exit portions which are directed horizontally and in the same rotary direction about the axis whereby pressurized fluid exiting from the exit portions causes the rotor to rotate and spray pressurized fluid horizontally in rotating streams against the inside surfaces of the housing.
Still another embodiment of the invention is a method of cleaning a lawn mower. A spray nozzle is mounted on the mower for repeated motion through a path. The method also includes forcing pressurized fluid through the spray nozzle to repeatedly strike deposited grass clippings on the mower to wash them from the mower.


The liquid crystal display device of this invention includes a first substrate, a second substrate, a liquid crystal layer disposed between the first substrate and the second substrate and a plurality of picture element regions for producing a display. In each of the plurality of picture element regions, a picture element electrode provided on the face of the first substrate facing the liquid crystal layer and a switching element electrically connected to the picture element electrode are provided. The picture element electrode includes a plurality of sub-picture element electrodes and a plurality of contact portions for mutually electrically connecting at least some of the plurality of sub-picture element electrodes. At least one of the plurality of sub-picture element electrodes is electrically connected to the switching element via a plurality of connection paths.

The present invention relates to a liquid crystal display device and a defect repairing method for the same.
Recently, liquid crystal display devices have been practically used in the fields of OA equipment and AV equipment owing to their advantages in compactness, small weight and size and small consumption power. In particular, an active matrix liquid crystal display device including a switching element (active device) in each picture element is capable of producing a fine dynamic display and hence is used as a display for a variety of equipment.
In an active matrix liquid crystal display device, picture elements are composed of picture element electrodes provided in the form of a matrix, a counter electrode opposing the picture element electrodes and a liquid crystal layer disposed therebetween. Each of a plurality of picture elements is controlled in its display state in accordance with an electric signal supplied through the switching element.
In an active matrix liquid crystal display device, short-circuit may be caused between the picture element electrode and the counter electrode or the like due to a conducting debris mixed in the liquid crystal layer. A normal voltage cannot be applied to a picture element in which the short-circuit through the picture element electrode is caused, resulting in a display defect that desired display cannot be obtained.
As a method for repairing a display defect, Japanese Laid-Open Patent Publication No. 4-178622 discloses a defect repairing method in which a photoresist including a black pigment is applied on the face of a glass substrate and a shield film is formed by exposing and curing a portion of the photoresist positioned on merely a picture element suffering from a display defect, so as to change a bright defect into an opaque point (dark defect). An dark defect is less visually recognized than a bright defect and hence merely slightly affects the display quality.
The present inventors have, however, found that a display defect cannot be effectively repaired by the defect repairing method disclosed in Japanese Laid-Open Patent Publication No. 4-178622.
In the defect repairing method of Japanese Laid-Open Patent Publication No. 4-178622, the entire picture element suffering from a bright defect is covered with a shield film formed so as to change the entire picture element into an opaque point, and therefore, the entire picture element having the display defect cannot make contribution to the display.

Liquid crystal display device with domains formed over solid and open portions of an electrode


A method for forming a packaged semiconductor device includes attaching a first major surface of a semiconductor die to a plurality of protrusions extending from a package substrate. A top surface of each protrusion has a die attach material, and the plurality of protrusions define an open region between the first major surface of the semiconductor die and the package substrate. Interconnects are formed between a second major surface of the semiconductor die and the package substrate in which the second major surface opposite the first major surface. An encapsulant material is formed over the semiconductor die and the interconnects.

Field
This disclosure relates generally to semiconductors, and more specifically, to die attachment for packaged semiconductor devices.
Related Art
Packaged semiconductor devices often include die attach materials that attach a semiconductor die to a lead frame. However, use of die attach materials often incur significant material costs, manufacturing costs, and processing costs. Further, a number of reliability issues arise during use of die attach materials, such as misplacement and tilt of the semiconductor die on the lead frame, voids or cracks in the die attach material that cause delamination or other failure, bleed of the die attach material to unwanted places on the lead frame, and the like.
The present invention is illustrated by way of example and is not limited by the accompanying figures, in which like references indicate similar elements, unless otherwise noted. Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.

Die attachment for packaged semiconductor device


One aspect of the present invention relates to enabling rotational flux conduction through magnetic film devices by creating a magnetic film layer with anisotropy perpendicular to the plane of the film layer, the film deposited in sufficient thickness so that there is a rest state rotational conduction path in the plane of the film layer. Another aspect of the invention is to provide for flux spreading in a magnetic device having perpendicular anisotropy. One feature of the present invention enables forming perpendicularly oriented central domains in a magnetic device so that the path for conduction of signal flux by rotation remains open even for very narrow signal flux paths. Another feature of the invention is to orient at rest domain states of a magnetic device pole (or poles) perpendicular to two desired in-plane rotational flux travel directions. Another feature of the invention is to orient edge domains in this type of magnetic device into a plane where their relative widths do not impact substantially on rotational flux flow through the device for narrow track heads.. A preferred embodiment of the present invention includes at least one pole of a magnetic device, formed on a substrate, having a preferred at rest pole domain orientation perpendicular to the substrate plane.

The present invention relates to thin film magnetic devices having perpendicular anisotropy.
Magnetic devices, such as thin film recording heads, whether read, read/write, or write, are designed to have particular magnetic orientations, or domains, within the active regions of the device material. The static state of each of these domains can be configured as desired, by control of the manufacturing process. Performance is critically linked to domain formation, and, therefore, control can be exerted over device performance by controlling domain formation.
Conduction of flux, such as in a thin film magnetic head, is achieved by two mechanisms: domain wall motion and domain rotation. Domain wall motion results in flux being transmitted through a thin film head along the walls of a domain, or domains, the flux spreading out along the domain walls as the flux seeks to return to equilibrium. However, while domain wall motion facilitates conduction of flux at low frequencies, it is a poor vehicle for conduction of flux at high frequencies. Furthermore, defects in the material in a magnetic head can be the source of Barkhausen noise during conduction of flux by wall motion as the flux is perturbed by these defects. Such noise can result in erroneous readings of recorded data.
Conduction of flux by domain rotation may be achieved by configuring a series of neighboring domains axially aligned along parallel axes, where flux impinged upon the first domain at a given angle will cause the magnetization of that domain to rotate from its static orientation by that angle radially into and impinging upon the neighboring domain. Such rotation can be transmitted in a like manner along an axis of flux transmission by each neighboring domain of the series. Hence, flux can be conducted in the pole and through the yoke of a thin film head in a series of domain rotations.
The yoke enables conduction of flux through a transducer which produces electrical signals proportional to flux levels or the rate of change of flux. Where the yoke reluctance is high, a significant amount of flux will bypass the transducer, and thus the device output will be reduced.
Certain prior art devices, such as thin film heads, are commonly produced having an anisotropy (at rest domain orientation) parallel to the plane of the substrate and transverse to the signal flux axis. In heads of this type, as track width gets smaller (with the push for higher track density), the region of transverse magnetization, which can transmit flux by rotation, shrinks toward zero. This results from edge domains (longitudinally oriented flux closure regions) dominating the flux path and preventing conduction by rotation. The head will therefore exhibit high reluctance at high frequencies.
A further artifact in conventional recording heads having the above orientation is that even where flux is conducted by rotation, the flux cannot substantially spread as it travels longitudinally from the pole tip through the yoke, since domain rotation can conduct flux efficiently only in the in-plane longitudinal direction in such devices, the other available direction being out-of-plane and of high reluctance.
Further discussion of flux conduction mechanisms will be found in a copending application entitled: Flux Spreading Thin Film Magnetic Devices, U.S. Ser. 07/227,808, No. filed Aug. 3, 1988, now U.S. Pat. No. 5,089,334, and is incorporated herein by reference.

Perpendicular anisotropy in thin film devices


Coils 38 and magnetostriction elements 41 are disposed inside casings 32, 33 fixed to a driving pulley housing 2, and an end of an outer tube 5o of a Bowden cable 5 is brought into abutment with the magnetostriction element 41 via a slider 42. When a steering torque is inputted into the steering wheel and an inner cable 5i is pulled in a direction indicated by an arrow B, an axial compression force acting on the outer tube 5o is transmitted to the magnetostriction element 41 via the slider 42 and a compression load p is applied thereto. This changes the magnetic permeability of the magnetostriction element 41, thereby changing the inductance of the coil 38, whereby the steering torque acting on the steering wheel can be detected based on the change in inductance. The torque detecting device for a cable-type steering device according to the present invention can securely detect a steering torque applied to a steering wheel with a simple construction and also can secure the rigid feel of the steering wheel to thereby prevent the deterioration of the steering feel.

1. Field of the Invention
The present invention relates to a cable-type steering device in which a steering wheel is connected with a steering gearbox with cables, such as Bowden cables, and more particularly, to a steering torque-detecting device for the cable-type steering device.
2. Description of the Prior Art
A cable-type steering device is proposed in which a flexible transmission means, such as a Bowden cable, replaces a steering shaft for connecting a steering wheel with a steering gearbox (for example, as shown in Japanese Patent Unexamined Publication No. Hei. 8-2431). Adopting such a cable-type steering device enables not only the free selection of a position for the steering wheel relative to the position of the steering gearbox but also the transmission of less vibrations of the steering gearbox to the steering wheel.
In a case where a power steering device is combined with a cable-type steering device, such as described above, it is necessary to detect a steering torque that is to be inputted into a steering wheel in order to control the operation of an assist motor. In a conventional steering torque-detecting device, a potentiometer is disposed between a pair of cables extending from a driving pulley, and rollers provided at ends of a V-shaped detecting arm fixed to a detecting shaft of the potentiometer are adapted to be brought into elastically springing abutment with the pair of cables, respectively. When a steering torque applied to the steering wheel rotates the driving pulley, the tension of one of the pair of cables increases, while that of the other decreases, and this rotates, together with the detecting shaft, the detecting arm, the roller of which is pressed against the cable, the tension of which increases, whereby the output from the potentiometer is changed, a steering torque being thereby detected.
With the conventional steering torque-detecting device described above, however, since there are provided therein a number of components and moving portions, the construction of the device becomes complicated, resulting in a drawback that it is difficult to secure sufficient durability. In addition, since the detecting arm generates micro-vibrations when an inner cable made of a stranded metal wire comprising a metallic strand moves along the roller while rotating it, micro-vibrations so-generated are then transmitted to the detecting shaft of the potentiometer leading to a drawback that the detection accuracy of the potentiometer is deteriorated. Moreover, since the inner cable is bent in a substantially V-shape at a portion where it abuts with the roller in response to the fluctuation in tension of the cable itself, there is also provided a drawback that the rigid feeling of the steering wheel is lowered, whereby the steering feeling is deteriorated.

Steering torque detecting device for cable-type steering device