63 research outputs found
Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors
PURPOSE: To assess the maximum-tolerated dose, toxicity, and
pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase
I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors.
EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once
every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0
mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life
exceeding the 2 weeks administration interval, the protocol was amended to
a 6-week interval between administrations also based on available
information from a parallel trial using an every 4 weeks schedule.
Conjugated DX-8951 (the carrier-linked molecule), and the metabolites
DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days
post first and second dose. RESULTS: Twenty-seven patients were enrolled
into the study and received a total of 86 administrations. Neutropenia and
grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive
disease, were dose-limiting toxicities. Other hematologic and
nonhematologic toxicities were mild to moderate and reversible. The
apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was
13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951
was 600. No drug concentration was detectable in erythrocytes, skin, and
saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable
in tumor biopsies. One patient with metastatic adenocarcinoma of unknown
primary achieved a histologically proven complete remission. One confirmed
partial remission was observed in a patient with metastatic pancreatic
cancer and disease stabilization was noted in 14 additional patients.
CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given
once every 6 weeks. The active moiety DX-8951 is released slowly from
DE-310 and over an extended period, achieving the desired prolonged
exposure to this topoisomerase I inhibitor
Nonprofit governance: Improving performance in troubled economic times
Nonprofit management is currently pressured to perform effectively in a weak economy. Yet, nonprofit governance continues to suffer from unclear conceptions of the division of labor between board of directors and executive directors. This online survey of 114 executive directors aims to provide clarification and recommendations for social administration
Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials
Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs
Signatures of a globally optimal searching strategy in the three-dimensional foraging flights of bumblebees
Simulated annealing is a powerful stochastic search algorithm for locating a global maximum that is hidden among many poorer local maxima in a search space. It is frequently implemented in computers working on complex optimization problems but until now has not been directly observed in nature as a searching strategy adopted by foraging animals. We analysed high-speed video recordings of the three-dimensional searching flights of bumblebees (Bombus terrestris) made in the presence of large or small artificial flowers within a 0.5 m3 enclosed arena. Analyses of the three-dimensional flight patterns in both conditions reveal signatures of simulated annealing searches. After leaving a flower, bees tend to scan back-and forth past that flower before making prospecting flights (loops), whose length increases over time. The search pattern becomes gradually more expansive and culminates when another rewarding flower is found. Bees then scan back and forth in the vicinity of the newly discovered flower and the process repeats. This looping search pattern, in which flight step lengths are typically power-law distributed, provides a relatively simple yet highly efficient strategy for pollinators such as bees to find best quality resources in complex environments made of multiple ephemeral feeding sites with nutritionally variable rewards
How and why do nectar-foraging bumblebees initiate movements between inflorescences of wild bergamot Monarda fistulosa (Lamiaceae)?
By experimental manipulation of the nectar in flowers, I characterized the decision-making process used by nectar-gathering bumblebees for initiating movements between inflorescences of wild bergamot. The decision-making process has these characteristics: departure from an inflorescence is less likely as nectar rewards increase; departure decisions are based on the amount of nectar in the last flower probed and are not influenced by the nectar rewards in either the previously probed flower or the previously visited inflorescence; the number of flowers already probed at an inflorescence influences departure decisions weakly; a bees' response (to stay or to depart) to a given size of nectar reward is variable. Since previously proposed foraging rules do not accord with this description, I propose a new rule. I show by experiment that the movements made by bumblebees enhance foraging success.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47784/1/442_2004_Article_BF00319785.pd
Deletion of toxin–antitoxin systems in the evolution of Shigella sonnei as a host-adapted pathogen
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Oak Ridge National Laboratory Report CF-61-1-42
A listing and description is given of the experiments associated with the HFIR Critical Experiment-2. The primary experiments concern the reactivity of the bare core, reactivity worth of "gray" control plates, core-power distribution, reactivity. The secondary experiments concern the reactivity of the fuel, and the reactivity worth of a "partial" gray plate
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