Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines.

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.

Optical performance of a burst-mode multikilowatt CO(2) laser.

A unique advancement in the flexibility of high-power lasers is presented. Operation of a 20-kW, continuous-wave, CO(2) laser with a burst excitation technique produces a broad range of optical output characteristics. A detailed discussion of the discharge excitation of this system demonstrates some unique features of the process. Control of burst frequency and duty cycle provides a convenient means to alter the time-varying nature of the output beam. Laser output can be varied from distinct, independent pulses through to a continuous wave. Optical pulse shape varies from triangular to square in profile. The primary focus of this study lies in the regime with distinct, separate pulses. Empirical relationships that summarize the dependence of optical duty cycle and peak laser power on discharge control parameters are developed. Use of these relations imparts control of the optical parameters of importance in deep penetration welding.

Toric unstable CO(2) laser resonator: an experimental study.

The output characteristics of a toric unstable resonator fitted to a multichannel stripline excitation system are presented. The resonator is shown to possess the usual advantages of a conventional unstable resonator plus the ability to modify the profile of the output beam by a simple change in the coupling aperture. Laser output parameters have been studied as a function of coupling fraction, magnification, and internal loss factors. Variations in the focal spot size as a function of the coupling aperture as well as resonator alignment sensitivity and polarization properties have been investigated.

Burst-mode gain switched technique for high peak and average optical energy extraction.

The optical performance of a cw PIE CO(2) laser has been substantially improved through the adoption of a burst-mode gain switching technique. The approach has provided a doubling of the average beam power extractable from the device. With appropriate optimization, the process could possibly permit the attainment of pulsed energy extraction in the kilohertz range, and with average optical powers within the several tens of kilowatt category.

Annular-coupled concave-convex stable resonator for large-volume high-quality energy extraction.

A theoretical investigation of a stable concave-convex resonator configuration, which appears suitable for single-mode high-power energy extraction from large volume gain media, is presented. The design features annular output coupling with a surprisingly uniform near-field intensity distribution. The computer-based analysis, supported by preliminary experimental results, suggests that acceptable alignment tolerances are provided along with an unusually small beam divergence. With proper design, a far-field divergence of 0.5 mrad, encompassing near 80% of the total laser energy, appears feasible. Operational data, recently obtained with this optical extraction approach, have revealed a further important practical advantage over an unstable resonator, being far less prone to mode degradation and hot spot formation on optical component misalignment.

Multiple pass unstable resonator for an annular gain CO2 laser.

The design, construction, and operational characteristics of an optical resonator for an annular gain media are described. The system, developed for laser power extraction investigations in a new type of coaxial discharge geometry, features a folded multipass unstable resonator concept, fabricated from lightweight uncoated diamond-turned aluminum substrates. The resulting cw CO2 device incorporates excitation aspects of the nonself-sustained PIE excitation process in addition to a new magnetic discharge stabilization technique. Laser performance and output beam characteristics are presented.