Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide's anti-leukemic activity.

Parthenolide is selectively toxic to leukemia cells; however, it also activates cell protective responses that may limit its clinical application. Therefore, we sought to identify agents that synergistically enhance parthenolide's cytotoxicity. Using a high-throughput combination drug screen, we identified the anti-hyperglycemic, vildagliptin, which synergized with parthenolide to induce death of the leukemia stem cell line, TEX (combination index (CI)=0.36 and 0.16, at effective concentration (EC) 50 and 80, respectively; where CI <1 denotes statistical synergy). The combination of parthenolide and vildagliptin reduced the viability and clonogenic growth of cells from acute myeloid leukemia patients and had limited effects on the viability of normal human peripheral blood stem cells. The basis for synergy was independent of vildagliptin's primary action as an inhibitor of dipeptidyl peptidase (DPP) IV. Rather, using chemical and genetic approaches we demonstrated that the synergy was due to inhibition of the related enzymes DPP8 and DPP9. In summary, these results highlight DPP8 and DPP9 inhibition as a novel chemosensitizing strategy in leukemia cells. Moreover, these results suggest that the combination of vildagliptin and parthenolide could be useful for the treatment of leukemia.

[Non-invasive recording of the His bundle electrogram: choice of leads and reliability of the "averaging" technic]. / Riconoscimento non invasivo dell'elettrogramma hisiano: scelta delle derivazioni e attendibilità della tecnica di "averaging".

An improvement in detecting His bundle activity using a Marquette high resolution Mac unit, without pharmacologic depression of AV node conduction, was obtained with two surface lead systems, which were selected on the basis of the His bundle anatomical position and its electrostimulation axis. In 8 patients the direction of the His bundle bipolar stimulation vector was evaluated in the frontal plane, on the orthogonal leads and with map of the chest potential. In 39 patients the surface recording, using high-gain amplification, filtering between 50-300 Hz and an averaging of 256-512 cycles, was obtained by positioning the electrodes in the following sites: manubrium sterni-xiphisternum-V4. When this lead system failed, it was replaced by another one, which included V4-right sternal and right vertebral border at the level of the 3rd intercostal space. In 24 patients (PR less than 0.16" in 4 cases) intracavitary and surface H-V recording were compared. The surface interval was measured between the apex of the surface "blip" and onset of the QRS. Sensitivity was 86% with a good correlation (r = 0.94) between invasive and non-invasive measurements. The surface leads, in which the His bundle activity was best detected, were the manubrium-xiphisternum (on the midsternal line) and V4-right vertebral border at the 3rd intercostal space level. Our external measurement technique avoids subjective misinterpretations; the surface H-V interval was on an average 6 msec. shorter than the invasive one. The upper normal value of non-invasive H-V interval is therefore 50 msec in our measurement method.