Kelly McCann

Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase-telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.

cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.

Abstract Objectives: Misplaced ECG electrodes can cause changes in ECG recordings, which could have an impact on clinical decisions. We aimed to determine the inter‐rater reliability of ECG electrode placement by senior clinical staff in the ED. Methods: A prospective observational study was conducted in adult patients undergoing an ECG as part of their routine ED care. Adhesive electrodes were left in place after an ECG had been performed by the treating nurse, and subsequently each patient was assessed by two of the three investigators. Each investigator independently recorded the location of the chest electrodes relative to the recommended standard positions. Displacement of the electrodes from the standard positions was measured in the vertical and horizontal planes. The age, sex, weight, height and chest circumference was also recorded. Comparisons were made between investigators to determine variability in assessment of the standard positions. Results: Measurement of horizontal and vertical displacement for each of the six chest leads in the 77 patients resulted in 924 paired measurements. There was substantial inter‐rater variation in the measurement of both vertical (mean 13.5 mm, range 0–105 mm) and horizontal (mean 16.5 mm, range 0–120 mm) displacement. This variation was greater in the lateral chest leads and was more marked in women than in men, especially in the vertical plane (lead V6: men 14.5 mm vs women 27.0 mm, P < 0.01). Conclusion: Among clinical ‘experts’, there is wide variation in the identification of the correct location for electrode placement, particularly in the lateral leads and in women. This has significant implications when comparing ECG in which electrodes have been placed by different clinicians.