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Cancer Therapy: Clinical
High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, m170, Linked to Indium-111/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human Anti-mouse Antibody
Carol M. Richman, Sally J. DeNardo, Robert T. O'Donnell, Aina Yuan, Sui Shen, Desiree S. Goldstein, Joseph M. Tuscano, Ted Wun, Helen K. Chew, Primo N. Lara, David L. Kukis, Arutselvan Natarajan, Claude F. Meares, Kathleen R. Lamborn and Gerald L. DeNardo
Carol M. Richman
Sally J. DeNardo
Robert T. O'Donnell
Aina Yuan
Sui Shen
Desiree S. Goldstein
Joseph M. Tuscano
Ted Wun
Helen K. Chew
Primo N. Lara
David L. Kukis
Arutselvan Natarajan
Claude F. Meares
Kathleen R. Lamborn
Gerald L. DeNardo
DOI: 10.1158/1078-0432.CCR-05-0211 Published August 2005
Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer.
Experimental Design: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody.
Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine.
Conclusions:111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.
Combined modality radioimmunotherapy
Peripheral blood stem cell support
Fractionated radioimmunotherapy
Radioimmunotherapy using systemically administered monoclonal antibodies linked to radioisotopes has proven effective in clinical trials in hematologic malignancies (1–8). Commercially available agents are now in routine use for treatment of non-Hodgkin's lymphoma (9–12). However, the efficacy of radioimmunotherapy in solid tumors has been limited (13–21). Given the exquisite radiosensitivity of hematologic tumors, it is likely that the treatment of more resistant solid tumors will require the administration of higher doses of radiation and the addition of radiation-enhancing approaches, as are often employed with external beam irradiation (22–27). In these two parallel phase I clinical trials in metastatic prostate and breast cancer, we employed strategies to (a) enhance the antitumor effect of radioimmunotherapy by the addition of radiosensitizing chemotherapy, (b) decrease the potential toxicity of radioimmunotherapy with the use of a new cleavable linker that facilitates elimination of the radiometal from the liver, and (c) maintain the potential for administration of "fractionated" multidose radioimmunotherapy by using cyclosporine to prevent the development of antibody to the murine, tumor-targeting antibody.
Patients. Patients with hormone-refractory metastatic prostate cancer and patients with metastatic breast cancer who failed at least one prior chemotherapy for metastatic disease were eligible for imaging/therapy with indium-111 (111In)/yttrium-90 (90Y)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide-m170 (one trial for prostate and one for breast cancer) if they had absolute neutrophil counts >1,500/μL, platelet counts >100,000/μL, serum creatinine and bilirubin <1.5 mg/dL, pulmonary function tests at least 65% of predicted, a cardiac left ventricular ejection fraction of at least 50%, Karnofsky performance status of at least 70%, and documentation of reactivity of their tumor with the MUC-1 antibody, m170, by 111In-DOTA-peptide-m170 imaging showing uptake in areas of known tumor (both prostate and breast cancer patients) and by immunohistochemical staining of fresh or frozen tumor tissue (breast cancer patients). Patients were free of other serious medical illnesses, had no active central nervous system disease, had no chemotherapy or radiation for at least 4 weeks, and had a negative serum human anti-mouse antibody (HAMA; ref. 28) before protocol entry. Computed tomography and bone scans as well as serum tumor markers (prostate-specific antigen, CA 15-3, and carcinoembryonic antigen) were obtained before protocol entry and thereafter to document disease location and to assess response. Serial clinical and laboratory evaluations, including pulmonary function tests, cardiac function studies, and hematology and chemistry studies, were done to assess toxicity. All patients who participated in these studies signed written informed consent in accordance with the institutional review board guidelines, as well as the Radiation Use Committee, under investigational new drug authorizations from the Food and Drug Administration.
Peripheral blood stem cell mobilization and collection for breast cancer patients. Patients with breast cancer were treated on a protocol using a higher starting dose of 90Y based on prior experience in breast cancer with m170-radioimmunotherapy and autologous peripheral blood stem cell (PBSC) transplantation (29). After fulfilling eligibility, but before imaging or therapy, patients were given granulocyte colony-stimulating factor (10 μg/kg) s.c. daily, and PBSCs were harvested by apheresis starting on day 5 as described previously (30) until a minimum of 2 × 106 CD34+ cells/kg were collected and cryopreserved. Per Food and Drug Administration mandate, the cells were infused only if the patient had prolonged grade 4 hematologic toxicity or neutropenic fever. The on-study date for the breast cancer trial was the day granulocyte colony-stimulating factor was initiated for PBSC collection. PBSCs were not harvested for prostate cancer patients, and the on-study date was the day cyclosporine was initiated.
Imaging and therapy with indium-111/yttrium-90-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide-m170 with or without paclitaxel. Because 90Y has only β emissions and is thus not suitable for imaging, 111In was used as a tracer for pharmacokinetic studies, imaging, and calculation of 90Y radiation dosimetry (20, 29, 31–33). See Figure 1 for treatment schematic. After an imaging dose of 111In-DOTA-peptide-m170 (∼5 mCi 111In on 5-10 mg m170), serial blood and urine specimens and whole body scans were obtained immediately after injection and at 4, 24, and 48 hours, with one additional study between 72 and 144 hours. Methods for collecting and analyzing the pharmacokinetic and dosimetry data have been described previously (20, 33, 34). One week after the imaging dose, the therapy dose of 90Y-DOTA-peptide-m170 was administered after verification that the imaging/dosimetry showed tumor targeting and no unexpected normal organ uptake. A tracer dose of 111In-DOTA-peptide-m170 was administered concurrently. Prior studies have shown comparable pharmacokinetics and dosimetry of the initial "imaging" and the subsequent administration of 11II in conjunction with 90Y-m170 treatment (20, 29). Imaging and therapy doses were administered in the radioimmunotherapy outpatient facility. Patients were instructed on precautions according to Radiation Use Committee policies. Serial blood counts, chemistries, clinical examinations, and tumor measurements were done following therapy. Criteria for removal from the study included unacceptable toxicity, progressive disease, and HAMA. The starting dose of 90Y was 12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer. Because of our prior experience with high-dose radioimmunotherapy and autologous stem cell transplantation in breast cancer, Food and Drug Administration permitted a higher starting dose for the these patients. The first cohort of patients on each protocol received radioimmunotherapy without paclitaxel. The second cohort received the same dose of radioimmunotherapy as the first cohort, but at 48 hours after radioimmunotherapy the patients in both prostate and breast cancer studies received 75 mg/m2 paclitaxel, a dose level and timing determined from preclinical studies that showed synergistic antitumor effect without additional toxicity in mouse xenograft models of both prostate and breast cancer (35, 36). 90Y dose escalation by 10 mCi/m2 with the same low-dose paclitaxel was planned for the third and subsequent cohorts of patients, unless grade 3 or 4 nonmarrow toxicity was observed in two or more of an extended six-patient cohort, which would define the maximum tolerated dose. Acute toxicity (within 3 days of injection) and delayed toxicity (within weeks to months of injection) were graded according to the National Cancer Institute Common Toxicity Criteria of 1998.
Treatment schematic: (1) PBSC harvest after granulocyte colony-stimulating factor (G-CSF) mobilization before imaging/therapy for breast cancer patients only; (2) cyclosporine for a total of 28 days, beginning 3 days before imaging, to prevent HAMA; (3) imaging with 111In DOTA-peptide-m170 to determine dosimetry and assure uptake in tumor and no unexpected uptake in normal tissue; (4) 90Y-DOTA-peptide-m170 given 1 week after 111In-imaging at a starting dose of 12 mCi/m2 for prostate and 22 mCi/m2 for breast cancer; (5) second cohort received paclitaxel 48 hours after 90Y-DOTA-peptide-m170 (a time when radiation has concentrated in tumor and cleared normal tissues); (6) PBSC infusion in breast cancer patients if neutropenic fever or >5 days of grade 4 neutropenia, thrombocytopenia.
Cyclosporine to prevent human anti-mouse antibody. Previous studies with m170-radioimmunotherapy in prostate cancer showed a 71% frequency of HAMA (37). In an effort to provide information for future trials using multidose fractionated radioimmunotherapy, patients enrolled in the present trial received cyclosporine 5 mg/kg orally every 12 hours beginning 3 days before the imaging dose and continuing for a total of 25 days to reduce HAMA frequency (Fig. 1). Cyclosporine trough levels were measured twice weekly by high-performance liquid chromatography and maintained between 150 and 250 ng/mL. Pretherapy and post-therapy HAMA studies were done using a standard enzyme-linked immunoabsorbent assay as described previously (28, 29).
Radioimmunoconjugates of m170 with a novel tetrapeptide linker, 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide. The antibody used to target prostate and breast tumors was a murine monoclonal IgG1, m170.82, developed using a synthetic asialo-GM1 terminal disaccharide immunogen (related to the Thompson-Friedenreich disaccharide (38–40). M170 binds with high affinity (4 × 108 mol/L−1; ref. 41) to aberrant carbohydrate residues on MUC-1, an epithelial mucin expressed on a variety of adenocarcinoma cells, including prostate and breast cancer. The m170 antibody (Biomira, Inc., Edmonton, Alberta, Canada) was prepared as described previously (30) using good manufacturing practices (current good manufacturing practice grade), was >95% monomeric IgG by PAGE, and met U.S. Food and Drug Administration specifications. Ninety percent of metastases from patients with breast cancer showed abundant immunohistochemical reactivity with m170 (42). In previous trials, scintigraphy showed targeting of prostate and breast cancers (21, 29, 37–39).
DOTA-peptide-m170 (DOTA-glycyl-glycyl-glycyl-Phe-m170) was prepared and purified by methods described previously (33, 43–46). The unlabeled immunoconjugate was labeled with either 111In for imaging or 90Y for treatment. The resulting radioimmunoconjugates were 99% pure by molecular sieving chromatography. Immunoreactivity was comparable with that of the unmodified antibody; cellulose acetate electrophoresis showed that 98% of all radioimmunoconjugates were in monomeric form, and high-performance liquid chromatography indicated that >95% of the radiometal was associated with the radioimmunoconjugates. Radiolabeled DOTA-peptide-m170 was prepared and confirmed to be sterile and pyrogen-free before infusion.
Statistical methods. To test for differences between the DOTA-tetrapeptide linker used in the present study and the 2IT-BAD linker used in prior studies or for differences between prostate and breast cancer patients, a Wilcoxon rank sum test was used. All reported Ps were two tailed.
Nine prostate cancer patients had pharmacokinetics and an imaging study (three as part of a Food and Drug Administration–requested imaging-only study before approval of the therapy trial and six received therapy doses of radioimmunotherapy at 12 mCi/m2; Table 1). Three of the six patients were given paclitaxel 48 hours after radioimmunotherapy. Eight breast cancer patients were enrolled. One did not have an adequate stem cell collection and was thus "off study"; the other seven proceeded to pharmacokinetics and imaging. One of these patients developed rapidly progressive disease with spinal cord compression between the day of imaging and the day scheduled for treatment. Six of the seven patients imaged received therapy doses of 22 mCi/m2. Two of the six treated breast cancer patients received paclitaxel 48 hours after radioimmunotherapy.
Clinical characteristics of patients with metastatic prostate (patients 1-9) and breast (patients 10-17) cancer imaged/treated with 111In/90Y-DOTA-peptide-m170
Pharmacokinetics, imaging, and dosimetry. Blood and urine clearances of 111In-labeled DOTA-peptide were similar in prostate and breast cancer patients and similar to the clearances of 111In-DOTA-2IT-m170 in prostate and breast cancer patients as reported previously (21, 29, 33, 37, 47). Bone or soft tissue metastases from prostate and breast cancer were targeted in 15 of the 16 patients imaged with no unexpected uptake in normal tissues (Fig. 2). Radiation dose (rads/mCi) to the whole body, normal organs, and tumors was calculated from the pretherapy 111In imaging in eight prostate cancer and six breast cancer patients. [One of nine prostate patients imaged had small volume nodal and bone disease that did not image as noted in Table 1 (patient 4). One of the seven breast cancer patients imaged (Table 1, patient 16) became too ill to complete the serial studies needed for dose calculations.] Pharmacokinetics and dosimetry of the initial "imaging" dose of 111In-DOTA-peptide-m170 and the 111In coadministered with 90Y-radioimmunotherapy were comparable as has been observed in our previous studies (20, 29). In Table 2, dosimetry results for patients imaged with the DOTA-tetrapeptide-linked m170 were compared with results obtained using 2IT-BAD-linked m170 in 24 patients studied previously [17 prostate cancer patients (37) and 7 breast cancer patients (29)]. As expected for radiometal-labeled antibodies, the liver was the nonmarrow organ receiving the highest radiation dose. The median liver dose was 10.1 rads/mCi for the nine patients with prostate cancer imaged with the DOTA-peptide linker [dosimetry for eight of these patients reported previously (33)] versus 15.7 rads/mCi in prior studies using the 2IT-BAD linker (37). In the six breast cancer patients described in the present study using DOTA-peptide, the median liver dose was 12.6 rads/mCi compared with 16.7 rads/mCi in a prior study using 2IT-BAD (29). The liver dose was significantly lower using the DOTA-peptide linker for the prostate cancer patients (33) and for the combination of prostate and breast cancer patients (P < 0.001, Wilcoxon rank sum test). When breast cancer patients were evaluated separately, the reduction in liver dose approached statistical significance (P = 0.063). The radiation dose to tumors was not significantly affected by the linker (P = 0.41; refs. 33, 47).
111In-DOTA-peptide-m170 targets prostate and breast cancer. A,111In-DOTA-peptide-m170 targeting at 6 days in a prostate cancer patient. Posterior view of the pelvic region shows areas of known tumor uptake in soft tissue lesions (white arrows) and most of the bones, including left femur, right sacroiliac joint, sacrum, lumbar vertebrae, and multiple sites in the ilia. B, anterior view in a breast cancer patient shows targeting at 6 days of right supraclavicular and infraclavicular nodal metastases (white arrow) and cardiac blood activity (black arrow). In the complete sequence of images in these patients, uptake was seen as early as 1 hour and metastases were well defined by 3 days. 111In activity is shown in color intensity modulated images with hottest colors (white, red, and orange), reflecting greater activity than cooler colors (green and blue).
Radiation dosimetry comparison of 2IT-BAD and DOTA-peptide-linked-m170
Toxicity. Sixteen patients received an imaging dose of 111In-DOTA-peptide-m170 and 12 of those patients received a treatment dose of 90Y/111In-DOTA-peptide-m170. The first cohort of patients received the radioimmunoconjugate alone (three prostate and four breast cancer patients) at doses of 12 mCi/m2 for prostate and 22 mCi/m2 for breast cancer. One of the four breast cancer patients had pulmonary function tests slightly below the entry criteria and was treated but could not be "counted" in the first cohort. The second cohorts received the same dose of radioimmunotherapy followed by paclitaxel at 48 hours after radioimmunotherapy (three prostate and two breast cancer patients). The 28 doses of radioimmunoconjugate were well tolerated. No patient had fever, chills, urticaria, or shortness of breath suggestive of an immunologic reaction to the antibody/radioconjugate. During the first 3 days following the imaging study, two prostate and one breast cancer patients had grade 1 anorexia/nausea that may have been associated with cyclosporine administration. One prostate cancer patient had grade 2 headache possibly secondary to cyclosporine. One breast cancer patient had transient intermittent grade 3 nausea and vomiting before, during, and after her participation in this trial due in part to large doses of narcotic analgesics. Her symptoms did not seem to be related to the study agent(s).
As expected, myelosuppression was the predominant toxicity of the treatment dose of 90Y-DOTA-peptide-m170 (Table 3). Three of the six breast cancer patients treated required reinfusion of stem cells to hasten hematopoietic recovery. One, treated without paclitaxel (Table 1, patient 10), developed bleeding and neutropenic fever in the setting of disease progression and biliary obstruction and two, treated with radioimmunotherapy plus paclitaxel (Table 1, patients 14 and 17), developed neutropenic fever.
Hematologic toxicity following 90Y-DOTA-peptide m170
Patients treated with paclitaxel had significant but subtotal alopecia. This was noticeable in the prostate cancer patients only, because the breast cancer patients had preexisting alopecia. The only nonmyelosuppressive toxicities above grade 2 included the grade 3 intermittent nausea/vomiting describe above (Table 1, breast cancer patient 11) and that of a 76-year-old prostate cancer patient (Table 1, patient 7) who developed a cardiac arrhythmia requiring hospitalization and eventual ablation of an irritable focus. He had a similar episode of arrhythmia several years before participation in this clinical trial. The stress of grade 1 anemia seems unlikely to be the precipitating event, but the patient was transfused to ameliorate this potential contributing factor. The maximum tolerated dose was not reached, and the study was closed due to slow accrual to an intensive therapy trial in a patient population composed of primarily elderly prostate cancer patients and heavily pretreated breast cancer patients. However, the clinical results indicate that myelosuppression is the limiting toxicity and stem cell support will be necessary to escalate doses to the tolerance of other organ systems using this radioimmunoconjugate in combination with radiosensitizing paclitaxel.
Human anti-mouse antibody. Nine prostate cancer patients who received an imaging dose of m170-DOTA-peptide were followed for 37 to 322 days after exposure and none developed a positive (>5 μg/mL) HAMA. Six breast cancer patients were evaluated for HAMA between 35 and 56 days after exposure to m170-radioimmunotherapy, and only one patient developed a positive HAMA (Table 1, patient 11). The murine protein was the target of the HAMA, not the DOTA-tetrapeptide. This patient who developed HAMA had intermittent vomiting throughout her course (related to narcotic analgesics) and had low cyclosporine levels (<150 ng/mL) for 2 weeks beginning on the day of 90Y-radioimmunotherapy administration. There was no apparent adverse clinical effect of the positive HAMA.
Clinical response. The purpose of these parallel phase I trials was to evaluate pharmacokinetics, imaging, dosimetry, and clinical toxicity of the experimental therapy. However, clinical measures of tumor activity were also monitored (Table 1). Of the six patients with prostate cancer who received a dose of 90Y-DOTA-peptide-m170, two showed a 50% decline in prostate-specific antigen lasting 2 months (Table 1, patients 8 and 9). Two patients described a decrease in bone pain (Table 1, patients 3 and 5). The other patients with prostate cancer had minimal tumor-related pain before therapy. Of six breast cancer patients, all heavily pretreated, who received a therapy dose of 90Y-DOTA-peptide-m170, two patients had minor reduction (<50%) in soft tissue disease lasting <1 month.
Metastatic prostate and breast cancer are radiotherapy-responsive solid tumors. Targeted systemic irradiation is an attractive treatment option that is being routinely implemented in lymphomas, exquisitely radiosensitive tumors. For the treatment of solid tumors, higher radiation doses will be required. Strategies to optimize radiation delivered to tumor while minimizing radiation exposure to normal organs are essential. In these parallel phase I clinical trials in hormone-refractory prostate cancer and metastatic breast cancer, patients were treated with an adenocarcinoma-targeting MUC-1 antibody, m170, attached to the chelated radiometal (111In and/or 90Y) via a novel tetrapeptide linker (Gly3Phe). This peptide linking the antibody, m170, to the macrocyclic chelate of radiometals, DOTA, was shown in vitro to be susceptible to the endopeptidase activity of intrahepatic cathepsins, responsible for most protein metabolism in hepatic lysosomes (45). Catabolism of the peptide linker by hepatic cathepsins facilitates clearance of the radiochelate from the liver in a form quickly excreted by the kidney, thereby reducing the radiation dose to dose-limiting normal nonmarrow tissue, the liver, and enhancing the amount of radiation that can be safely delivered to tumor.
The 111In-radioimmunoconjugate, DOTA-peptide-m170, showed excellent tumor targeting in sites of known bone and/or soft tissue disease in 15 of the 16 patients imaged. From the successful targeting, as seen in Fig. 2 at 6 days after infusion, it is apparent that the cathepsin-degradable peptide linking the radiochelate to the antibody was not degraded by tumor tissue. Only one patient with prostate cancer and small deep nodal disease failed to image adequately. The injections of both 111In-radioimmunoconjugate and 90Y-radioimmunoconjugate were well tolerated with no acute toxicities associated with the infusion. The pharmacokinetics and dosimetry for prostate and breast cancer were similar. Although the dose-limiting toxicity of radioimmunotherapy is marrow suppression, this can be circumvented by PBSC transplantation as shown in this and prior studies (7, 21, 29, 30). When radiometal radioimmunoconjugates are used, the nonmarrow dose-limiting organ is the liver. The efficacy of the DOTA-tetrapeptide linkage in reducing radiation dose to the liver seen here confirms preclinical (45, 46) and initial clinical data in prostate and breast cancer (20, 33, 47). The clinical dosimetry study in prostate cancer (33) showed a 31% reduction in radiation dose to the liver comparing patients treated with DOTA-peptide-radioimmunoconjugate to patients treated with m170 linked to the radioisotope via the standard DOTA-2IT (37), with no significant difference in radiation dose to tumor. Extrapolating estimates for stem cell–supported radioimmunotherapy, based on the dosimetry from the present clinical trial (33, 47) and an estimated liver dose limit of 3,000 cGy from external beam irradiation (48), a dose of 90Y DOTA-peptide m170 delivering 3,000 cGy to the liver would be expected to deliver as much as two to five times this dose to tumor, a dose that would be expected to have clinical efficacy (33).
In spite of the reduction in radiation dose to normal liver with the cathepsin-degradable tetrapeptide linker, meaningful therapeutic results may require additional enhancement. Based on preclinical studies showing synergy between radioimmunotherapy and paclitaxel (35, 36, 49), the second cohort of patients in the present trial received combined modality therapy. The sequence and timing showing maximum synergy in murine models were translated into the clinical trial reported here. Paclitaxel in a dose comparable with that used in the preclinical model was given 48 hours after radioimmunotherapy. Paclitaxel was chosen because it stabilizes microtubule formation resulting in a mitotic block, bcl-2 dysfunction, and activation of apoptosis (35, 50). It is effective in tumors with mutant p53, a common characteristic of advanced prostate and breast cancers (51–53). Paclitaxel has potentiated the antitumor effect of external beam radiation (22–27) and has been used in conjunction with radioimmunotherapy in ovarian carcinoma (54). Further comparison of the tumor dosimetry in patients described in this study has shown that the administration of paclitaxel after radioimmunotherapy actually modestly increased the tumor cumulated radiation, suggesting an additional mechanism for enhancement of antitumor activity with combined modality radioimmunotherapy (55).
Although paclitaxel seemed to increase transient myelosuppression of radioimmunotherapy in the present study, particularly in the heavily pretreated breast cancer patients, there was no apparent other toxicity, except for alopecia. None of the patients exhibited any delayed organ toxicity. Further escalation of the radioimmunotherapy dose in conjunction with fixed-dose paclitaxel is feasible, although it will require PBSC support.
Fractionation is one method for increasing the radiation dose to tumor without excessive toxicity to normal tissue and is the standard approach in external beam radiotherapy. Prior preclinical and clinical studies of radioimmunotherapy have shown reduced toxicity with a fractionated dose schedule (56–58). For example, breast cancer patients tolerated three cycles of 131I-radioimmunotherapy at 1,000 cGy per dose, without the pulmonary or cardiac toxicity observed when single doses >2,700 cGy were used in lymphoma patients receiving 131I-radioimmunotherapy (59) Unfortunately, repeated use of a murine or even partially humanized radioimmunoconjugate may result in formation of antibodies to the targeting antibody that could prevent multidose therapy. In prior studies using m170 in prostate cancer (as 90Y/111In-2IT-BAD-m170), 12 of 17 patients developed HAMA after a single pair of imaging/treatment doses 1 week apart (37). Supporting previous reports (20, 60, 61), only one patient developed HAMA in the present trial using cyclosporine, making fractionated therapy feasible in future trials.
Although bone marrow is the dose-limiting tissue for non–stem cell–supported radioimmunotherapy, the dose to the marrow from high-dose radioimmunotherapy is low compared with the dose of total body irradiation used in conventional myeloablative bone marrow transplantation (∼1,200 cGy). Radiopharmaceuticals that specifically target hematopoietic cells have been successfully used in clinical bone marrow transplant trials and can be added to standard total body irradiation and to chemotherapy without apparent increase in nonmarrow toxicity (62, 63). There is no evidence of damage to the marrow stroma or other injury that would interfere with either autologous or allogeneic engraftment at the dose levels used in these trials (64). With PBSC, the radiation dose of 90Y-radioimmunotherapy is limited by the dose to normal liver tissue. Within that limit, combination of radioimmunotherapy with radiation-sensitizing chemotherapy delivered at an optimal time, when it will sensitize the tumor and not normal tissue, has the potential for delivering systemic tumoricidal doses of radioimmunotherapy.
Further developments may improve tumor targeting with reduced toxicity to normal tissues. Molecules smaller than intact immunoglobulins, such as single-chain antibodies, may better penetrate deeper into sites of tumor (65, 66). Pretargeting approaches first target the tumor with antibody and then remove unbound antibody from the bloodstream/tissues before administration of the radioactive small molecule. Radioactivity that does not bind to the tumor-linked antibody is rapidly excreted by the kidney, minimizing nonspecific normal tissue exposure (67). In preliminary trials in non-Hodgkin's lymphoma patients, clinically effective doses were delivered without significant marrow toxicity (68). However, successful treatment of solid tumors will likely require higher radiation doses. Additional approaches, such as radiosensitizing chemotherapy, PBSC support, and fractionated therapy, may be important strategies to enhance the efficacy of the methodologies and targeting agents being developed. The tetrapeptide-linked radiometal-labeled radiopharmaceutical used in this study decreased liver cumulated activity and radiation dose compared with the conventional 2IT-BAD linker, without a change in dosimetry or pharmacokinetics to tumor or other tissues. Additionally, the tetrapeptide linker was not immunogenic in patients treated with cyclosporine to prevent HAMA; thus, multiple dose therapy in this setting is feasible. The addition of paclitaxel, in the dose employed here, did not seem to alter pharmacokinetics, although it did cause alopecia, may have added to hematologic toxicity, and is associated with a modest enhancement of cumulated tumor radiation dose (55). Although the maximum tolerated dose was not reached in these trials, transient evidence suggesting antitumor response was observed. Further studies will be needed to optimize targeted radiation therapy in solid tumors.
We thank the clinical staff at University of California-Davis Cancer Center and the Bone Marrow Transplant Unit for their assistance with patient care, G.R. Mirick for performing the HAMA assays, and S. Percey for assistance with article preparation.
Grant support: National Cancer Institute grant PO1 CA47827, National Cancer Institute/NIH grant PO1-CA47829, Veteran's Administration Northern California Healthcare System (R.T. O'Donnell, J.M. Tuscano, and T. Wun), and American Cancer Society Clinical Research Training grant (P.N. Lara).
Note: Presented in part at the 2004 American Society of Clinical Oncology Annual Meeting, New Orleans, Louisiana.
Accepted May 24, 2005.
Revision received May 11, 2005.
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Tishler RB, Geard CR, Hall EJ, Schiff PB. Taxol sensitizes human astrocytoma cells to radiation. Cancer Res 1992;52:3495–7.
Belani CP, Aisner J, Bahri S, et al. Chemoradiotherapy in non-small cell lung cancer: paclitaxel/carboplatin/radiotherapy in regionally advanced disease. Semin Oncol 1996;23:113–6.
Choy H, Akerley W, Glantz M, et al. Concurrent paclitaxel and radiation therapy for solid tumors. Cancer Control 1996;3:310–8.
Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB. Changes in radiation survival curve parameters in human tumor and rodent cells exposed to paclitaxel (Taxol). Int J Radiat Oncol Biol Phys 1994;29:559–64.
Geard CR, Jones JM. Radiation and taxol effects on synchronized human cervical carcinoma cells. Int J Radiat Oncol Biol Phys 1994;29:565–9.
Lokeshwar BL, Ferrell SM, Block NL. Enhancement of radiation response of prostatic carcinoma by taxol: therapeutic potential for late-stage malignancy. Anticancer Res 1995;15:93–8.
DeNardo GL, Mirick GR, Kroger LA, O'Donnell RT, Meares CF, DeNardo SJ. Antibody responses to macrocycles in lymphoma. J Nucl Med 1996;37:451–6.
Richman CM, DeNardo SJ, O'Donnell RT, et al. Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A. Clin Cancer Res 1999;5:3243–8s.
Richman CM, DeNardo SJ, O'Grady LF, DeNardo GL. Radioimmunotherapy for breast cancer using escalating fractionated doses of 131I-labeled chimeric L6 antibody with peripheral blood progenitor cell transfusions. Cancer Res 1995;55:5916–20s.
DeNardo SJ, O'Grady LF, Macey DJ, et al. Quantitative imaging of mouse L-6 monoclonal antibody in breast cancer patients to develop a therapeutic strategy. Int J Rad Appl Instrum B 1991;18:621–31.
Erwin WD, Groch MW, Macey DJ, DeNardo GL, DeNardo SJ, Shen S. A radioimmunoimaging and MIRD dosimetry treatment planning program for radioimmunotherapy. Nucl Med Biol 1996;23:525–32.
DeNardo SJ, DeNardo GL, Yuan A, et al. Enhanced therapeutic index of radioimmunotherapy (RIT) in prostate cancer patients: comparison of radiation dosimetry for 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide versus 2IT-DOTA monoclonal antibody linkage for RIT. Clin Cancer Res 2003;9:3938–44S.
DeNardo G, DeNardo S, Macey D, Mills S. Quantitative pharmacokinetics for radiolabeled monoclonal antibodies for imaging and therapy in patients. In: Srivastava S, editor. Radiolabeled monoclonal antibodies for imaging and therapy. New York: Plenum Publishing Corp.; 1998. p. 293–310.
DeNardo SJ, Kukis DL, Kroger LA, et al. Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. Proc Natl Acad Sci U S A 1997;94:4000–4.
DeNardo SJ, Richman CM, Kukis DL, et al. Synergistic therapy of breast cancer with Y-90-chimeric L6 and paclitaxel in the xenografted mouse model: development of a clinical protocol. Anticancer Res 1998;18:4011–8.
O'Donnell RT, DeNardo SJ, Yuan A, et al. Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer. Clin Cancer Res 2001;7:1561–8.
McEwan AJ, MacLean GD, Hooper HR, et al. MAb 170H.82: an evaluation of a novel panadenocarcinoma monoclonal antibody labeled with 99Tcm and with 111In. Nucl Med Commun 1992;13:11–9.
MacLean G, McEwan A, Noujaim A, et al. Two novel monoclonal antibodies have potential for gynecologic cancer imaging. Antibody Immunoconj Radiopharm 1991;4:297–308.
DeNardo S. Radioimmunotherapy for breast cancer: systemic tumor-targeted irradiation. Adv Oncol 1999;15:23–9.
Alexander C, Villena-Heinsen CE, Trampert L, et al. Radioimmunoscintigraphy of ovarian tumours with technetium-99m labeled monoclonal antibody-170: first clinical experiences. Eur J Nucl Med 1995;22:645–51.
Howell LP, DeNardo SJ, Levy NB, Lund J, DeNardo GL. Immunohistochemical staining of metastatic ductal carcinomas of the breast by monoclonal antibodies used in imaging and therapy: a comparative study. Int J Biol Markers 1995;10:129–35.
Kukis DL, DeNardo GL, DeNardo SJ, et al. Effect of the extent of chelate substitution on the immunoreactivity and biodistribution of 2IT-BAT-Lym-1 immunoconjugates. Cancer Res 1995;55:878–84.
Moi M, Meares C, DeNardo S. The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid and study of its yttrium (III) complex. J Am Chem Soc 2004;110:6266–7.
Li M, Meares CF. Synthesis, metal chelate stability studies, and enzyme digestion of a peptide-linked DOTA derivative and its corresponding radiolabeled immunoconjugates. Bioconjug Chem 1993;4:275–83.
DeNardo GL, Kroger LA, Meares CF, et al. Comparison of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts. Clin Cancer Res 1998;4:2483–90.
Richman CM, DeNardo SJ, O'Donnell RT, et al. Combined modality radioimmunotherapy (RIT) in metastatic prostate (PC) and breast cancer (BC) using paclitaxel (PT) and a MUC-1 monoclonal antibody, m170, linked to yttrium-90 (Y-90): a phase I trial [abstract 2554]. Proc Am Soc Clin Oncol 2004;23:176.
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109–22.
DeNardo SJ, Kroger LA, Lamborn KR, et al. Importance of temporal relationships in combined modality radioimmunotherapy of breast carcinoma. Cancer 1997;80:2583–90.
Horwitz S. Mechanism of action of taxol. Trends Pharmacol Sci 1992;13:134–6.
DeNardo SJ, Kukis DL, Miers LA, et al. Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts. J Nucl Med 1998;39:842–9.
Wahl AF, Donaldson KL, Fairchild C, et al. Loss of normal p53 function confers sensitization to Taxol by increasing G2-M arrest and apoptosis. Nat Med 1996;2:72–9.
Shi XB, Gumerlock PH, deVere White RW. Molecular biology of prostate cancer. World J Urol 1996;14:318–28.
Meredith R, Alvarez R, Khazaeli M, et al. Intraperitoneal radioimmunotherapy for refractory epithelial ovarian cancer with 177Lu-CC49. Minerva Biotechnol 1998;10:100–7.
Miers L, Lamborn K, Yuan A, et al. Does paclitaxel given after 111In labeled monoclonal antibodies increase tumor cumulated activity in epithelial cancers? Clin Cancer Res. In press 2005.
Meredith RF, Khazaeli MB, Liu T, et al. Dose fractionation of radiolabeled antibodies in patients with metastatic colon cancer. J Nucl Med 1992;33:1648–53.
Schlom J, Molinolo A, Simpson JF, et al. Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy. J Natl Cancer Inst 1990;82:763–71.
DeNardo S, DeNardo G, O'Grady L, et al. Pilot studies of radioimmunotherapy of B-cell lymphoma and leukemia using I-131 Lym-1 monoclonal antibody. Antibody Immunoconj Radiopharm 1988;1:17–33.
Liu SY, Eary JF, Petersdorf SH, et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol 1998;16:3270–8.
Ledermann JA, Begent RH, Massof C, et al. A phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response. Int J Cancer 1991;47:659–64.
Weiden PL, Wolf SB, Breitz HB, et al. Human anti-mouse antibody suppression with cyclosporin A. Cancer 1994;73:1093–7.
Appelbaum FR, Matthews DC, Eary JF, et al. The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia. Transplantation 1992;54:829–33.
Matthews DC, Appelbaum FR, Eary JF, et al. Phase I study of 131I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 1999;94:1237–47.
Pagel JM, Matthews DC, Appelbaum FR, Bernstein ID, Press OW. The use of radioimmunoconjugates in stem cell transplantation. Bone Marrow Transplant 2002;29:807–16.
Yokota T, Milenic DE, Whitlow M, Schlom J. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res 1992;52:3402–8.
Hu S, Shively L, Raubitschek A, Sherman M, et al. Minibody: a novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res 1996;56:3055–61.
Axworthy DB, Reno JM, Hylarides MD, et al. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity. Proc Natl Acad Sci U S A 2000;97:1802–7.
Weiden PL, Breitz HB, Press O, et al. Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results. Cancer 2000;15:15–29.
You are going to email the following High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, m170, Linked to Indium-111/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human…
Clin Cancer Res August 15 2005 (11) (16) 5920-5927; DOI: 10.1158/1078-0432.CCR-05-0211
Biomarker Analysis from the BERIL-1 Study
Radiation and TGFβ Blockade in Metastatic Breast Cancer
Guadecitabine and Carboplatin in Ovarian Cancer
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text:
Wawa planning a standalone drive-thru convenience store
Wawa, Inc.
A depiction of what a drive-thru, standalone, Wawa convenience store could look like.
By: Sam Cohen
There is no question the coronavirus pandemic is changing how Americans shop, with an increase in delivery, drive thru and curbside pick-up.
Later this year, fans of Wawa will be able to get their favorite convenience store items in a drive thru. The east coast-based company announced they are building a freestanding drive-thru at an intersection in Lower Bucks County Pennsylvania. They are also adding drive-thru features to a Wawa under construction in Westhampton, New Jersey.
In a press release, Wawa says the standalone store, not attached to a gas station, will feature "state-of-the-art technology to quickly order Wawa's most popular food and beverages, including value meals, combo meals along with coffee and specialty beverages." If the drive-thru line gets too long, customers will be able to pull into curbside parking and wait for their order.
Construction will start this month, with an opening planned for December.
"We are hoping to learn from the layout, workflow and traffic flow at this location, as we continue to explore alternatives for longer term application to our stores post-COVID-19," said Terri Micklin, Director of Construction, Wawa.

redpajama_set_name: RedPajamaCommonCrawl


Girl Rising: Stories of 9 young girls from developing countries overcoming great obstacles to obtain an education and change their fates.
Now playing at UA Emery Bay Stadium 10, 6330 Christie Avenue, Emeryville. If you enjoy films or documentaries without car chases, explosions, or Dolby sound so loud it hurts your ears, support Emery Bay Stadium, the city's first movie house.


Hi, and welcome to my stop on the tour!! Thanks for stopping in today! You will find info on the book, the author, Jennifer M. Eaton, My Thoughts (cause I love to share!!), links to pick up your copy (a must have for both books in this series), and a giveaway. Oh, and make sure you check out other stops on the tour for author interviews, guest posts, and lots more fun!
The Cover: Even prettier than that of Fire in the Woods, Book 1 in this series, Ashes in the Sky shows the silhouette of a man against a backdrop of trees and bright green light. This cover peaked my interest just as much as the first one.
The Plot: Ashes in the Sky picks up a couple months after Jessica and David save the human race from extermination. David has gone on to terra form Mars while Jessica is a celebrity just trying to get back to normal and stay out of the news. That is until she gets invited on board to photograph the aliens' spaceship. That's where things start to get complicated, kids.
I was very impressed with the amazing plot line of this book. It took off very quickly and didn't slow down until the end. I loved learning more about the aliens and the ways they lived, but Jessica and David's adventure was filled with intrigue and even more heart stopping moments. A new planet and new scary and wonderful species mixed in with gunfights and steamy romance round out this fantastic return to Jessica and David's story.
The Characters: As in our first book, our characters were just as awesome. Jessica was a bit more sure of herself and I liked David a heck of a lot more this time around. There were a lot of new characters and I was never sure who was an friend or foe. But all were well developed and fit into the story line nicely.
Is it Worth Reading?: Yes! Ashes in the Sky was an intense return to a great story. I loved exploring the new planet with Jessica and even though I am terrified of spiders, her new creepy friend grew on me. I look forward the another book in the out of this world series, recommend it to readers of YA sci-fi, drama and romance and give it 4 out of 5 crossbows.


text:
Showing posts with label Abbey Ettal. Show all posts
'Welt' Accuses Cardinal Marx of Covering up Abuse-- Archdiocese Threatens Lawsuit
Editor: as kreuz.net earlier reported, Regensburg Diocese has already sued 'Spiegel'.
A serious accusation: Cardinal Marx is said to have covered up a suspected sexual abuse, in order to use this "politically" -- The Archdiocese of Munich is taking legal steps.
Munich (kath.net) "Cardinal Marx covers suspected abuse". With this headline on late Wednesday afternoon the newspaper "Die Welt" has aroused the concern of the Archdiocese of Munich. "There was an impression that Marx himself was the one who was aware of the abuse at first. Actually, he held back the information of a suspicion of sexual abuse, in order to use it later for political reasons.", wrote the paper. It is maintained in a report that the Munich Archbishop Cardinal Reinhard Marx, according to information from "Welt Online", is suspected of allegedly covering up an abuse for over three months and through that he could allegedly permit a man exposed as a pedophile to continue working as an educator at Cloister Ettal.
The "Welt" declared that it should have been the case that the victim of the educator who had informed the Diocese at first on 5. April 2010 was brought to the attention of the abuse delegate of the Archdiocese. Supposedly this was reported three months later to the State Prosecutor of Munich. The Cloister in Ettal, where the educator was active, should have been the first to have been informed, actually.
According to information from "Welt Online" Archbishop Marx is supposed to have been personally aware of the accusations against the Ettal teacher. Corresponding guidelines of the German Bishops Conference for the handling of sexual abuse require that the abuse delegate is "immediately" informed over these events. Otherwise the suspected victim according to "Welt" is supposed to have spoken later to Marx personally.
The paper reported that there was a conflict in the background between the Archdiocese of Munich and Cloister Ettal. In February 2010 Archbishop Marx had demanded the resignation of the then Abbott and the director of the Ettal Dormitory, both of whom were later rehabilitated by the Pope. The Diocese then directed, according to "Welt", the suspicion against the Ettal Educator to after a month of inactivity in the same week in which the rehabilitation of the Ettal Abbott was made public. "Possibly, these recent negative allegations could draw a cloud over the positive media-echo for Ettal", writes Welt.
The Archdiocese of Munich and Freising has condemend the report from "Welt" as untrue. "The "Welt" is called to retract and omit the untrue and damaging information. We plan on taking legal steps to obtain retraction and omission." they said in an official statement.
From kath.net...
Posted by Tancred at 12:49 PM No comments:
Labels: Abbey Ettal, Cardinal Marx, Munich, Sex Abuse
Vatican Rebuke for Munich Archbishop Marx: Ettal Abbot and Prior Exonerated
The Vatican exonerated the earlier Abbot of Ettal and rebukes the Diocese of Munich: Abbot Barnabas has done everything, what was required by the situation. The naming of a successor is not to happen.
Berlin/Munich (kath.net/KNA) A Vatican Investigative Commission has, says the newspapers "Die Welt" and "Muenchner Merkur", (Friday)that the resigned management of the Benedictine Cloister Ettal has been exonerated of the abuse scandal. Both papers refer to a corresponding letter of the Roman Cardinal Prefect Franc Rode, who directs for the Monks the competent section in the Vatican. As the papers report, there had been an Apostolic visitation in the Cloister, that resigned order members had made no error in their handling of the Ettal sexual and physical abuse.
Neither Abbot Barnabas Bögle nor Prior Maurus Krass would have neglected a prescribed requirement to report. The Abbot did everything, "which was required by the situation". A renewed election of both ministers from their earlier offices is not required.
The Abbot and the Prior had been accused, that they had not reported to the competent Archdiocese of Muenchen-Freising in 2005 when they became aware of a new sexual abuse. According to the information the papers have the expert opinion of the Vatican is not associated with that of the view of the Archdiocese of Munich.
The letter from Rome had been delivered by Wednesday to the Cloister of Ettal, reported "Muenchner Merkur" further. Otherwise it would have been necessary to select a name Abbot by 31 July. The Monastic Congregation has appointed this directive. From the Cloister no one has wanted till now to discuss any of the new developments. There should be a press release on Friday.
The report brings a new rebuke for the ambitious Archbishop Marx at the same time in "Die Welt". There have been for a long while already critics of the administration of the Archiepiscopal Chair. So it was already made known in March, that the resignation of Barnabas and Maurus was to take place on the ground of a false accusation.
Report from Die Welt...
Posted by Tancred at 1:04 AM No comments:
Labels: Abbey Ettal, Archbishop Marx, Sex Abuse


This is a wonderful program, very user friendly, excellent and precise. I will continue to use it and recommend it to my other friend and business associates. Thanks Celeste C.
Nice service. Would be desirable to add custom paragraph.
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text:
Marie C. Wilson
Marie C. Wilson President, The White House Project / Women's Leadership Fund.
"An advocate of women's issues for more than 30 years, Marie Wilson is founder and president of The White House Project, co-creator of Take Our Daughters to Work Day and author of Closing the Leadership Gap: Why Women Can and Must Help Run the World (Viking 2004). Wilson founded The White House Project in 1998 in recognition of the need to build a truly representative democracy - one where women lead alongside men in all spheres.
"Wilson started The White House Project while she was still president of the Ms. Foundation for Women, a position she has held since 1984. She stepped down as president of the Ms. Foundation on June 30th, 2004 to devote her full energy to The White House Project. She was president of both organizations for six years. In honor of her work, the Ms. Foundation has created The Marie C. Wilson Leadership Fund, which will be under her sole advisement...
"Over the last thirty years, Wilson's accomplishments span becoming the first woman elected to the Des Moines City Council as a member-at-large in 1983, co-authoring the critically acclaimed Mother Daughter Revolution (1993, Bantam Books), and serving as an official government delegate to the United Nations Fourth World Conference on Women held in Beijing, China in 1995. And in the year 2000, in conjunction with Mattel, Wilson brought the world President Barbie.
"As president of the Ms. Foundation for Women, Wilson increased the Foundation's budget from $400,000 to $8.6 million, established an endowment fund, which now stands at $22 million and created innovative and sustainable programming...
"Marie Wilson, was recognized in September 2006 by Civic Ventures, a think tank that works to reframe the debate about aging in America and redefine the second half of life as a source of social and individual renewal." [1]
Director, State of Change
Winner of the 2002 Robert W. Scrivner Award for Creative Grantmaking [1]
"Biography", Accessed January 2007.
↑ Robert W. Scrivner Award for Creative Grantmaking, Council on Foundations, accessed September 4, 2009.
Retrieved from "https://www.sourcewatch.org/index.php?title=Marie_C._Wilson&oldid=437658"


In the event you hear a ringing or humming noise constantly https://www.quora.com/How-can-you-relieve-ear-infection-pain-at-night, you possess Ear Infections. Fortunately, there are numerous techniques you can use to get respite from those irritating noises in your thoughts. This short article will provide with a few different methods for handling Ear Infections.
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text:
Q: Is this set of curves discrete? Let $\alpha_1, \dots, \alpha_n$ be complex numbers whose sum is zero and $u_1, \dots, u_{2g-2+n}$ be pariwise distinct nonzero complex numbers. Consider the the set of smooth genus g curves with n+1 marked points $P_0, x_1\dots, x_n$ and a marked canonical homology basis, with the following properties:

*

*Take the unique Abelian differential of the third kind $\omega$ on the curve having a simple pole at $x_i$ with residue $\alpha_i$, $i=1, \dots, n$ and zero a-periods. Then all b-periods of $\omega$ are zero.

*Let $P_1, \dots, P_{2g-2+n}$ be the zeroes of $\omega$. Then there exist paths $\gamma_i$ on the curve connecting $P_0$ and $P_i$ such that $\exp(\int_{\gamma_i}\omega)=u_i, i=1, \dots, 2g-2+n$.

I would like to show that this set is discrete, and possibly to find some explicit description of it. For integers values of $\alpha_i$ this is essentially Riemann's existence theorem.
Thanks

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Any ideas if the portable browser plugin still works with v3.x? When I follow SYSTEM's extraction instructions above, I don't get npPdfViewer.dll but two other dlls, PdfFilter and PdfPreview. Without nPdfViewer the plugin does not work, with it opera:plugins (good ole Opera 12) says the plugin is still at v2.5.2, the version of said dll.
SumatraPDF would be great if it didn't support DRM. It prevents you from copying or printing PDFs that are "protected", and the author refuses to make it optional. Hypocritical for Free Software to support DRM if you ask me.
Actually, the installer of Sumatra PDF 2.3 can be extracted by running it with the /x command line switch. :) Extracting the installer requires admin rights, though.
Download the installer. Extract it by running it with the /x command line switch.
Exit the web browser and copy the files libmupdf.dll, npPdfViewer.dll, SumatraPDF.exe and optionally DroidSansFallback.ttf to the plugin directory of the browser.
Finally, restart the browser. The plugin is ready for use.
This version will once again run on older (non-SSE2) CPUs. Checkout the advanced settings: Settings - Advanced Options. The link for help with the settings is found at the top of the text file.
The good - a new 'SumatraPDF-settings.txt' file.
The bad - wont run on non-SSE2 processors.
Re portable browser plugin: It seems that extracting the installer no longer works on v2.3.
the background color persists (stored in sumatrapdfprefs.dat).
So, the next time you start with sumatra.exe the background will be white.
@Midas : Thanks for the hint!
There are more parameters possible. See the manual.
Finally I got rid of Adobe Reader and switched to Sumatra, the browser plugin works just as well.
Unfortunately, version 1.7 no longer runs under WinXP-sp1 or Win2000.
v1.5 has bulked up almost 2 megs! Whoa!
@SYSTEM: I tried this version but you need npPdfViewer.dll and SumatraPDF.exe portable in the plugins dir: from 1.56K to 3.56K!
Sadly, the GIF-bug still exists. (See my comment on 2011-03-13). Too bad, because I'm looking forward to replacing my Foxit with Sumatra!!
First, download the INSTALLER and extract it with Universal Extractor ( http://www.portablefreeware.com/?id=641 ). When prompted, answer that the installer is not InstallShield.
After that, exit the web browser and copy the files npPdfViewer.dll and SumatraPDF.exe to the plugin directory of the browser. Optionally you can copy DroidSansFallback.ttf as well.
Finally, restart the browser and enjoy the plugin.
I'm wondering whether it is possible to use the browser plugin with the portable version?
@linuxx...Alot of people don't realize this. Thanks for posting the facts.
The error i described on 2011-02-04 still exists. Too bad, because I really like this program, and look forward to the day I can replace my old Foxit with Sumatra. The error is: PDF's I make from B/W GIF's show up blank in Sumatra!!
Jami, you can usually get an app directly from most developers. That will alleviate much of the exaggeration problem. 'They're so small' is the same argument often used to fill your system with tons of language files and the like. The direct plan would also soothe the 'just waiting for missed or lagging updates to become available' problems. Choice is good.
@Jami Categorizing 230k as 'hefty' is an exaggeration to say the least, especially considering the majority of those files are source code and help files you can delete if you don't want em.
Singularity@ - Good call! Takes you from 2 lone files up to 29 files & 11 folders. A hefty price to pay just to remember the last file viewed. Especially if you use lots of portable apps.
@Singularity - You'll find that your recently opened files in Sumatra PDF's zip version will fail to open as you move PCs and your drive letter changes. The PortableApps.com release of Sumatra fixes that issue. And if you don't like it, you can disable the splash with a quick INI change.
Tried Sumatra recently, and I really like it. But when I create a PDF file from black-and-white GIF files (2 colors) using eg. Faststone Viewer (using "Create/ Multipage file/ PDF"), they show up blank in Sumatra.
Many apps around are already portable, or they usually have a zip counterpart without installer. I tell this to avoid you installing those so called "portable" versions, doing nothing more than loading useless spashscreen and adding space to your drive. The zip version of Sumatra pdf, downloaded from author page, it's many times faster then the other so called "portable" version you find on other websites like Portableapps and so on.
Sumatra is great - about a million times faster than Adobe Reader plus, if you need to copy text from a document, you can bring it up in Adobe Reader in the same place in the document as Sumatra. I got Sumatra for the way it saves your place in a given PDF, stuck with it for it's speed, portability and size.
Place it somewhere else and it should be ok!
Is it just me or does SumatraPDF still store it settings Application Data folder?
@dianoga. Sumatra 1.1 does not show comments added with PDF-XChange Viewer.
I would like to see in the toolbar 2 icons: copy text and copy figure (As in Foxit Reader).
I know this may be done by some keys(that sometimes I can't remember when more I need).
Updated comment from me for version 1.0: I have no issues with this app anymore. It no longer writes settings outside the app folder, remembers viewing-settings correctly, doesn\\'t crash anymore here, and just basically does anything i\\'d want of a simple lightweight PDF-Viewer.
Can Sumatra 0.9.3 show sticky notes and other annotations to the original PDF? For some reason they do not show up.
Although it has simplicity and reliability on its side (have been using constantly for months), Foxit (http://www.portablefreeware.com/?id=1041) handles printing of dramatically better, has more features, and is more intuitive, though it is mild nagware.
This would be a wonderful replacement for other PDF-Viewers, if it weren't that the app is missing one feature which almost any other app has by default: Remembering your viewing-settings. Well yes, 0.8.1 now remembers SOME of those settings, but still not all - for example, i want my PDFs to open in a maximized window, but sumatry wont remember that - it will always open files in a small window and i therefore always have to maximize the window manually. This may sound trivial, but its the kind of features which you normally dont notice anymore because you asume them to be normal - you only miss then when you get an app which lacks them.
friendly. I'm so glad to be free of Adobe. I've haved Foxit in the past too, but I like this much better.
Regarding some old posts above: The new version 0.8 is as fast as it probably can get - and supports searching, selecting and copying text to the clipboard (no "select all" function, though). It's a bit tricky to find, however: To mark text, left-click and drag while keeping CTRL pressed.
It copies everything covered by the yellow area, regardless of words or lines, so you'll have to carefully avoid getting to close to characters you don't want to be copied.
Also, when you paste the copied text, there's always a line-break at the end. (I don't know if this is a bug or intended behavior.) Quite rarely, search won't find text even though it's there.
Other than that, everything works fine. It has never crashed for me, either.
Fast, simple, usefull, but missing search option.
A Word doc I converted to pdf with PDF995 crashes Sumatra if I open it from Explorer, but opens fine if I use Sumatra's menu File Open. Another larger doc converted the same way gives no problems at all.
The problem doc when converted with OpenOffice gives no problems at all.
Possibly something to do with using GhostScript in PDF995 ???
Hope they get the bugs out, its wonderfully small.
If I put it in my Program Files folder, it'll create a SumatraPDF folder in My Documents and Settings folder.
If I put it in My Documents folder it will not.
nice and simple, wish it has basic features such as select, select all, copy, ect and a mdi interface or tabs or multiple viewing. i havent seen any other opensource, and really small pdf viewers.


text:
California mulls how to regulate driverless cars
JUSTIN PRITCHARD
Associated Press March 12, 2014
FILE - In this Sept. 25, 2012 file photo, Google co-founder Sergey Brin gestures after riding in a driverless car with California Gov. Edmund G Brown Jr., left, and state Senator Alex Padilla, second from left, to a bill signing for driverless cars at Google headquarters in Mountain View, Calif. The California Department of Motor Vehicles on Tuesday, March 11, 2014, held a public hearing to solicit ideas on how to integrate driverless cars, sometimes called "autonomous vehicles," onto public roads. (AP Photo/Eric Risberg, File)
LOS ANGELES (AP) — Sooner or later, consumers will be able to buy cars that rely on computers — not the owner — to do the driving.
Though the technology is still being tested, the day it rolls out into broad public use can now be measured in years, not decades.
With that timeframe in mind, California's Department of Motor Vehicles on Tuesday began puzzling through how to regulate the vehicles that haven't been fully developed yet.
Among the complex questions officials sought to unravel at the initial public hearing on regulations in Sacramento:
How will the state know the cars are safe?
Does a driver even need to be behind the wheel?
Can manufacturers mine data from onboard computers to make product pitches based on where the car goes or set insurance rates based on how it is driven?
Do owners get docked points on their license if they send a car to park itself and it slams into another vehicle?
Once the stuff of science fiction, driverless cars could be commercially available by decade's end. Under a California law passed in 2012, the DMV must decide by the end of this year how to integrate the cars — often called autonomous vehicles — onto public roads.
Three other states have passed driverless car laws, but those rules mostly focus on testing. California has mandated rules on testing and public operation, and the DMV expects within weeks to finalize regulations dictating what companies must do to test the technology on public roads.
Those rules came after Google Inc. had already sent its fleet of Priuses and Lexuses, fitted with an array of sensors including radar and lasers, hundreds of thousands of miles in California. Major automakers also have tested their own models.
Now, the DMV is scrambling to regulate the broader use of the cars. With the federal government apparently years away from developing regulations, California's rules could effectively become the national standard.
Much of the initial discussion Tuesday focused on privacy concerns.
California's law requires autonomous vehicles to log records of operation so the data can be used to reconstruct an accident.
But the cars "must not become another way to track us in our daily lives," John M. Simpson of the nonprofit Consumer Watchdog said at the hearing. Simpson called out Google, saying the Internet giant rebuffed attempts to add privacy guarantees when it pushed the 2012 legislation mandating rules on testing and public operation.
Seated across from Simpson at the hearing's head tables was a representative from Google, who offered no comment on the data privacy issue.
Discussion also touched on how to know a car is safe, and whether an owner knows how to properly operate it.
Ron Medford, Google's director of safety for its "self-driving car" project, suggested that manufacturers should be able to self-certify that their cars are safe. He cautioned that it would get complicated, fast, if the state tried to assume that role.
In initial iterations, human drivers would be expected to take control in an instant if the computer systems fail. Unlike current technology — which can help park a car or keep it in its freeway lane — owners might eventually be able to read, daydream or even sleep while the car did the work.
Responding to a question received over Twitter, DMV attorney Brian Soublet acknowledged that the department is still grappling with the most fundamental question of whether a person will need to be in the driver's seat.
Maybe not, by the time the technology is safe and reliable, he said.
Soublet asked who would ensure that owners know how to use the new technology. Should the onus be on dealers, manufacturers, owners?
Representatives of automakers suggested they shouldn't be asked to guarantee the capability of owners. John Tillman of Mercedes-Benz said the DMV could test owners on basics such as starting and stopping the automated driving function.
Automaker representatives also expressed concerns that other states could pass regulations that were substantially different from California, creating the kind of patchwork rules that businesses hate.
States outside California have been in touch and are following California's rule-making process closely, said Bernard Soriano, a deputy director at the DMV.
Other discussion centered on how vulnerable the cars could be to hackers, who might wrest control of the vehicles.
Industry representatives said that while that's a concern, they would vigilantly guard against such vulnerability because it would be disastrous.
DMV regulation writers will post draft language regulations around June, then alter the rules in response to public comment by fall in order to get them finalized by year's end, Soublet said.
Contact Justin Pritchard: https://twitter.com/lalanewsman
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text:
Herine igre bile su starogrčki festival u kojem su se mlade djevojke natjecale u trčanju. Herine igre su se održavale svakih četiri godina u Olimpiji i vjerojatno su se održavale u isto vrijeme kao i Olimpijske igre.

O Herinim igrama malo je poznato. Većina današnjega znanja o Herinim igrama dolazi iz Pauzanijevoga djela Vodič po Grčki. Datum početka ovoga festivala je nepoznat. Pauzanija tvrdi da su igre stare, arhaične (starogrčki: αρχαια). Postoje dokazi o djelovanju kulta u Olimpiji iz 10. stoljeća pr. Kr., no najranija kultska djelovanja pronađenih na nalazištu se vežu oko Zeusa; Herin kult u Olimpiji sigurno je postojao oko 600. pr. Kr. kada je sagrađen prvi Herin hram. Nije poznato je su li trkačke utrke bile originalno svojstvo festivala ili su kasnije dodane. Jedna priča u Pauzanijevome djelu asocira šesnaest žena odgovorne za festival sa sukobom između Elide i Pise zbog smrti pisanskoga tiranina Damofona koja se dogodila oko 580. pr. Kr. Ako je festival do tada bio utemeljen, moguće je da se u to vrijeme dogodila reorganizacija festivala, kao i kod drugih starogrčkih festivala u Arhajskome razdoblju.

Jedini događaj na Herinim igrama bio je stadion koji je bio za jednu šestinu kraći od muškoga stadiona. Samo su mlade neudane žene sudjelovale u igrama. Natjecateljice su se utrkivale u trima različitima dobnima skupinama, no nepoznato je koliko su stare natjecateljice bile. Natjecateljice su nosile distinktivnu odoru koja se sastojala od kratkoga hitona koji je bio odrezan iznad koljena koji je otkrivao desnu grud i rame. Kosa natjecateljica bila je puštena. Takva odora možda potječe od egzomisa, inačica hitona koju su nosile radnice asocirane s Hefestom.

Dobitnice su nagrađene s maslinovim vijencom i porcijom teletine koja je žrtvovana Heri. Dobitnicama je dozvoljeno da posvete kipove sa svojim imenima Heri, no niti jedan od takvih kipova nije očuvan.

Herinim festivalom predsjedalo je šesnaest žena koje su bile zadužene za izvođenje igara, tkanje peplosa za Heru i priređivanje zborovskih plesova za Hipodamiju i Fusoku. Pauzonija daje dvije priče o ovim šesnaest ženama. Prema prvoj priči Herine igre osnovala je Hipodamija te su prve igre održane za slavlje njene udaje za Pelopa. Hipodamija je odabrala šesnaest žena za natjecanje. Prema drugoj priči Eliđani su odabrali jednu staru mudru ženu iz svakoga od šesnaest politisa u Elidi kako bi riješili spor između Elide i Pise. Te žene su također bile zadužene za održavanje Herinih igara.

Herine igre možda su bile pubertetski  ili predbračni obredi. Matthew Dillon tvrdi da Herine igre najvjerojatnije nisu imale veze s udajom zbog tri različitih dobnih skupina. No, utrke su asocirane s mitološkom udajom. Druge starogrčke utrke između djevojaka, poput jedne održane u Sparti u čast Dionizu koju je Pauzanija također opisao, izgledaju da su bile asocirane s predbračnima inicijacijama.

Izvori

Literatura

Vidi još
 Herin hram u Olimpiji
 Olimpija
 Žene u staroj Grčkoj

Stara Grčka

redpajama_set_name: RedPajamaWikipedia


text:
/ Asia and Africa
/ Patel, Vallabhbhai
Patel, Vallabhbhai
Patel, Vallabhbhai vŭl˝ləb-bä´ē pətĕl´ [key], 1875–1950, Indian political leader. He was admitted (1913) to the bar in England and set up a lucrative practice in India. In 1915 he met Mohandas Gandhi and within a short time became one of his closest associates, a staunch nationalist and a supporter of the Indian National Congress. A talented organizer, he successfully directed the civil-disobedience campaigns of the 1920s and 30s; several times he suffered imprisonment. He was mayor of Ahmedabad (1924–28) and was elected (1931) president of the Indian National Congress. In 1942 he was imprisoned, with other Congress leaders, for refusing to support the British war effort in World War II. After his release (1945), he initiated a purge of Communists (who had supported the war) from the Congress. Patel played an important role in the negotiations that led to independence and the partition of the subcontinent into the two states of India and Pakistan. In 1947 he was made deputy prime minister of India and minister of home affairs, minister of information, and minister of states. Holding these offices until his death, he effected the complex and difficult feat of integrating the many princely states into the new Indian political structure.
See his Correspondence, 1945–50, ed. by D. Das (Vol. I, 1971); biographies by N. D. Parikh (tr., 2 vol., 1953–56) and L. N. Sarin (1972).


A couple of other treats: around Valentine's Day this year I decided to treat myself with a couple of gorgeous fair trade, nature-themed rings from Novica (please see my Fair Trade page for more info).
In addition to other latest efforts for health, I have once again reached the bridge between doctor-prescribed antidepressants and natural products. In part due to some insights gained from my acupuncture treatments, I have decided to try 5-HTP in combination with some selected herbals for adrenal support, and turmeric for my body aches and pains. I had been back on Prozac for some time, as experience has made me comfortable with the buffer it provides (as well as the fact it is covered by my employee health benefits), however it once again feels like time to try something different, and I am glad to return to a treatment more true to the heart of this website's philosophy. (***I have safely come off Prozac several times in the past but please remember it is important to consult your physician when considering any such changes in medication***).
I have finished the first of the books and found it quite interesting. Now we'll see how successful I am at following up with the exercises! However, the books have already helped me affirm the need to return to a focus on spirit and soul in my life, and I always think anything done with intention must be good.
I have now transitioned to the 5-HTP and my first couple of weeks included some nausea and headaches which have now thankfully subsided. Of course the timing coincided with a busy time at work but somehow I managed to tough it out :) I feel like I am getting a little bit more "back on track" to living according to my beliefs, rather than finding "bandaid" solutions; living with intention, and practicing things that I feel good talking about here.
I'm looking forward to a season of gardening and starting to practice my newfound permaculture knowledge (though I will be using some traditional vegetable growing practices as well). Time to get back to nature, and all the goodness and riches that it brings to life.


text:
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