Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development.

Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions

Spatially resolved ultrafast precessional magnetization reversal

Spatially resolved measurements of quasi-ballistic precessional magnetic switching in a microstructure are presented. Crossing current wires allow detailed study of the precessional switching induced by coincident longitudinal and transverse magnetic field pulses. Though the response is initially spatially uniform, dephasing occurs leading to nonuniformity and transient demagnetization. This nonuniformity comes in spite of a novel method for suppression of end domains in remanence. The results have implications for the reliability of ballistic precessional switching in magnetic devices.Comment: 17 pages (including 4 figures), submitted to Phys. Rev. Let

Impaired planning in Parkinson's disease is reflected by reduced brain activation and connectivity

Contains fulltext : 159315.pdf (publisher's version ) (Open Access)13 p

Broadband quadrature-squeezed vacuum and nonclassical photon number correlations from a nanophotonic device

We report the first demonstrations of both quadrature squeezed vacuum and photon number difference squeezing generated in an integrated nanophotonic device. Squeezed light is generated via strongly driven spontaneous four-wave mixing below threshold in silicon nitride microring resonators. The generated light is characterized with both homodyne detection and direct measurements of photon statistics using photon number-resolving transition edge sensors. We measure $1.0(1)$~dB of broadband quadrature squeezing (${\sim}4$~dB inferred on-chip) and $1.5(3)$~dB of photon number difference squeezing (${\sim}7$~dB inferred on-chip). Nearly-single temporal mode operation is achieved, with raw unheralded second-order correlations $g^{(2)}$ as high as $1.87(1)$ measured (${\sim}1.9$~when corrected for noise). Multi-photon events of over 10 photons are directly detected with rates exceeding any previous quantum optical demonstration using integrated nanophotonics. These results will have an enabling impact on scaling continuous variable quantum technology.Comment: Significant improvements and updates to photon number squeezing results and discussions, including results on single temporal mode operatio

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

Health-related quality of life following surgical attenuation of congenital portosystemic shunts versus a healthy control population of dogs

OBJECTIVES: To design a health-related quality of life questionnaire for dogs with congenital portosystemic shunts, use it in a cohort of dogs treated with suture attenuation and compare results with those obtained from a healthy control cohort. MATERIALS AND METHODS: Data were collected from the hospital records of dogs treated with suture ligation of an intrahepatic or extrahepatic congenital portosystemic shunt at two referral centres. Owners were asked to complete a questionnaire assessing their dog's health-related quality of life preoperatively (retrospectively) and at the time of follow-up. Owners of control dogs also completed the questionnaire. RESULTS: One hundred and twenty-eight dogs with congenital portosystemic shunts and 131 control dogs were recruited. Median follow-up time was 64 months (range 19.7 to 157.2). The median long-term health-related quality of life score was excellent for both intrahepatic and extrahepatic shunt cases and similar to that of control dogs. The long-term portosystemic shunt clinical sign scores for both intrahepatic and extrahepatic congenital portosystemic shunt dogs were significantly worse than the those of the control group. CLINICAL SIGNIFICANCE: Suture attenuation of congenitial portosystemic shunts is associated with an excellent health-related quality of life score at long-term follow-up

Transverse optical plasmons in layered superconductors

We discuss the possible existance of transverse optical plasma modes in superlattices consisting of Josephson coupled superconducting layers. These modes appear as resonances in the current-current correlation function, as opposed to the usual plasmons which are poles in the density-density channel. We consider both bilayer superlattices, and single layer lattices with a spread of interlayer Josephson couplings. We show that our model is in quantitative agreement with the recent experimental observation by a number of groups of a peak at the Josephson plasma frequency in the optical conductivity of La$_{1.85}$Sr$_{0.15}$CuO$_4$Comment: Proceedings of LT21, in press, 4 pages, Latex with LTpaper.sty and epsfig.sty, 2 postscript figure