Outcome of radiotherapy in T1 glottic carcinoma: A population-based study

We evaluated the radiation outcome and prognostic factors in a population-based study of early (T1N0M0) glottic carcinoma. Survival parameters and prognostic factors were evaluated by uni- and multivariate analysis in 316 consecutive irradiated patients with T1 glottic carcinoma in the Comprehensive Cancer Center West region of the western Netherlands. Median follow-up was 70 months (range 1-190 months). Five and ten-year local control was 86 and 84%. Disease specific survival was 97% at 5 and 10 years. In multivariate analysis, pre-existent laryngeal hypertrophic laryngitis was the only predictive factor for local control (relative risk = 3.0, P = 0.02). Comorbidity was prognostic for overall survival. No factor was predictive for disease specific survival. Pre-existent laryngeal hypertrophic laryngitis is a new risk factor associated with reduced local control in T1 glottic carcinoma treated with radiotherapy

Gene Transcription and Splicing of T-Type Channels Are Evolutionarily-Conserved Strategies for Regulating Channel Expression and Gating

T-type calcium channels operate within tightly regulated biophysical constraints for supporting rhythmic firing in the brain, heart and secretory organs of invertebrates and vertebrates. The snail T-type gene, LCav3 from Lymnaea stagnalis, possesses alternative, tandem donor splice sites enabling a choice of a large exon 8b (201 aa) or a short exon 25c (9 aa) in cytoplasmic linkers, similar to mammalian homologs. Inclusion of optional 25c exons in the III–IV linker of T-type channels speeds up kinetics and causes hyperpolarizing shifts in both activation and steady-state inactivation of macroscopic currents. The abundant variant lacking exon 25c is the workhorse of embryonic Cav3 channels, whose high density and right-shifted activation and availability curves are expected to increase pace-making and allow the channels to contribute more significantly to cellular excitation in prenatal tissue. Presence of brain-enriched, optional exon 8b conserved with mammalian Cav3.1 and encompassing the proximal half of the I–II linker, imparts a ∼50% reduction in total and surface-expressed LCav3 channel protein, which accounts for reduced whole-cell calcium currents of +8b variants in HEK cells. Evolutionarily conserved optional exons in cytoplasmic linkers of Cav3 channels regulate expression (exon 8b) and a battery of biophysical properties (exon 25c) for tuning specialized firing patterns in different tissues and throughout development

Open- and closed-state fast inactivation in sodium channels: Differential effects of a site-3 anemone toxin

The role of sodium channel closed-state fast inactivation in membrane excitability is not well understood. We compared open- and closed-state fast inactivation, and the gating charge immobilized during these transitions, in skeletal muscle channel hNaV1.4. A significant fraction of total charge movement and its immobilization occurred in the absence of channel opening. Simulated action potentials in skeletal muscle fibers were attenuated when pre-conditioned by subthreshold depolarization. Anthopleurin A, a site-3 toxin that inhibits gating charge associated with the movement of DIVS4, was used to assess the role of this voltage sensor in closed-state fast inactivation. Anthopleurin elicited opposing effects on the gating mode, kinetics and charge immobilized during open- versus closed-state fast inactivation. This same toxin produced identical effects on recovery of channel availability and remobilization of gating charge, irrespective of route of entry into fast inactivation. Our findings suggest that depolarization promoting entry into fast inactivation from open versus closed states provides access to the IFMT receptor via different rate-limiting conformational translocations of DIVS4

Testing of Passive Safety System Performance for Higher Power Advanced Reactors

This report describes the results of NERI research on the testing of advanced passive safety performance for the Westinghouse AP1000 design. The objectives of this research were: (a) to assess the AP1000 passive safety system core cooling performance under high decay power conditions for a spectrum of breaks located at a variety of locations, (b) to compare advanced thermal hydraulic computer code predictions to the APEX high decay power test data and (c) to develop new passive safety system concepts that could be used for Generation IV higher power reactors