The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor

S-COL: A Copernican turn for the development of flexibly reusable collaboration scripts

Collaboration scripts are usually implemented as parts of a particular collaborative-learning platform. Therefore, scripts of demonstrated effectiveness are hardly used with learning platforms at other sites, and replication studies are rare. The approach of a platform-independent description language for scripts that allows for easy implementation of the same script on different platforms has not succeeded yet in making the transfer of scripts feasible. We present an alternative solution that treats the problem as a special case of providing support on top of diverse Web pages: In this case, the challenge is to trigger support based on the recognition of a Web page as belonging to a specific type of functionally equivalent pages such as the search query form or the results page of a search engine. The solution suggested has been implemented by means of a tool called S-COL (Scripting for Collaborative Online Learning) and allows for the sustainable development of scripts and scaffolds that can be used with a broad variety of content and platforms. The tool’s functions are described. In order to demonstrate the feasibility and ease of script reuse with S-COL, we describe the flexible re-implementation of a collaboration script for argumentation in S-COL and its adaptation to different learning platforms. To demonstrate that a collaboration script implemented in S-COL can actually foster learning, an empirical study about the effects of a specific script for collaborative online search on learning activities is presented. The further potentials and the limitations of the S-COL approach are discussed

Analytic frameworks for assessing dialogic argumentation in online learning environments

Over the last decade, researchers have developed sophisticated online learning environments to support students engaging in argumentation. This review first considers the range of functionalities incorporated within these online environments. The review then presents five categories of analytic frameworks focusing on (1) formal argumentation structure, (2) normative quality, (3) nature and function of contributions within the dialog, (4) epistemic nature of reasoning, and (5) patterns and trajectories of participant interaction. Example analytic frameworks from each category are presented in detail rich enough to illustrate their nature and structure. This rich detail is intended to facilitate researchers’ identification of possible frameworks to draw upon in developing or adopting analytic methods for their own work. Each framework is applied to a shared segment of student dialog to facilitate this illustration and comparison process. Synthetic discussions of each category consider the frameworks in light of the underlying theoretical perspectives on argumentation, pedagogical goals, and online environmental structures. Ultimately the review underscores the diversity of perspectives represented in this research, the importance of clearly specifying theoretical and environmental commitments throughout the process of developing or adopting an analytic framework, and the role of analytic frameworks in the future development of online learning environments for argumentation

Collaboration scripts - a conceptual analysis

This article presents a conceptual analysis of collaboration scripts used in face-to-face and computer-mediated collaborative learning. Collaboration scripts are scaffolds that aim to improve collaboration through structuring the interactive processes between two or more learning partners. Collaboration scripts consist of at least five components: (a) learning objectives, (b) type of activities, (c) sequencing, (d) role distribution, and (e) type of representation. These components serve as a basis for comparing prototypical collaboration script approaches for face-to-face vs. computer-mediated learning. As our analysis reveals, collaboration scripts for face-to-face learning often focus on supporting collaborators in engaging in activities that are specifically related to individual knowledge acquisition. Scripts for computer-mediated collaboration are typically concerned with facilitating communicative-coordinative processes that occur among group members. The two lines of research can be consolidated to facilitate the design of collaboration scripts, which both support participation and coordination, as well as induce learning activities closely related to individual knowledge acquisition and metacognition. In addition, research on collaboration scripts needs to consider the learners’ internal collaboration scripts as a further determinant of collaboration behavior. The article closes with the presentation of a conceptual framework incorporating both external and internal collaboration scripts

Номінація частин руки в говірці села Невгоди Овруцького району Житомирської області

У статті розглянуто лексеми на позначення частин руки в сучасній середньополіській говірці, зокрема проаналізовано їхню семантику та мотивацію.В статье рассматриваются лексемы, обозначающие части руки, в современном среднеполесском говоре, а именно проанализирована их семантика и мотивация.The article deals with lexemes on designations of parts of the manuscript in the middle-polissya dialect. Their semantics and motivation are also analyzed

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m−2 oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedule

Decreased expression of breast cancer resistance protein in the duodenum in patients with obstructive cholestasis

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel