Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation.

Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.

Neural mechanisms of response priming do not support veridical unconscious processing.

Studies using the priming paradigm often infer that unconscious processes have more veridical access to the world than conscious processes. These interpretations are based on a standard reasoning that erroneously infers good sensitivity of indirect measures from a clear priming effect. To correct for this fallacy, researchers should explicitly compute the sensitivities from indirect measures and compare them against the sensitivities of direct measures. Recent results suggest that indirect behavioral measures are not more sensitive than direct measures and challenge interpretations about veridical unconscious processing. We add to these behavioral results by focusing on neurophysiological indirect measures. In two EEG experiments, we investigate whether event related potentials (ERPs) are more sensitive to different visual stimuli than direct measures. The results show the opposite effect: higher sensitivities for direct than indirect measures. Therefore-contrasting commonly held belief-we find no evidence for more veridical unconscious than conscious processes in ERP measures.

Stability of conventional and machine learning-based tumor auto-segmentation techniques using undersampled dynamic radial bSSFP acquisitions on a 0.35 T hybrid MR-linac system.

PURPOSE: Hybrid MRI-linear accelerator systems (MR-linacs) allow for the incorporation of MR images with high soft-tissue contrast into the radiation therapy procedure prior to, during, or post irradiation. This allows not only for the optimization of the treatment planning, but also for real-time monitoring of the tumor position using cine MRI, from which intrafractional motion can be compensated. Fast imaging and accurate tumor tracking are crucial for effective compensation. This study investigates the application of cine MRI with a radial acquisition scheme on a low-field MR-linac to accelerate the acquisition rate and evaluates the effect on tracking accuracy. METHODS: An MR sequence using tiny golden-angle radial k-space sampling was developed and applied to cine imaging on patients with liver tumors on a 0.35 T MR-linac. Tumor tracking was assessed for accuracy and stability from the cine images with increasing k-space undersampling factors. Tracking was achieved using two different auto-segmentation algorithms: a deformable image registration B-spline similar to that implemented on the MR-linac and a convolutional neural network approach known as U-Net. RESULTS: Radial imaging allows for increased temporal resolution with reliable tumor tracking, although tracking robustness decreases as temporal resolution increases. Additional acquisition-based artifacts can be avoided by reducing the angle increment using tiny golden-angles. The U-net algorithm was found to have superior auto-segmentation metrics compared to B-spline. U-net was able to track two well-defined tumors, imaged with just 30 spokes per image (10.6 frames per second), with an average Dice coefficient ≥ 83%, Hausdorff distance ≤ 1.4 pixel, and mean contour distance ≤ 0.5 pixel. CONCLUSIONS: Radial acquisitions are commonplace in dynamic imaging; however, in MR-guided radiotherapy, robust tumor tracking is also required. This study demonstrates the in vivo feasibility of tumor tracking from radially acquired images on a low-field MR-linac. Radial imaging allows for decreased image acquisition times while maintaining robust tracking. The U-net algorithm can track a tumor with higher accuracy in images with undersampling artifacts than a conventional deformable B-spline algorithm and is a promising tool for tracking in MR-guided radiation therapy.

Beyond T2 and 3T: New MRI techniques for clinicians.

Technological advances in Magnetic Resonance Imaging (MRI) in terms of field strength and hybrid MR systems have led to improvements in tumor imaging in terms of anatomy and functionality. This review paper discusses the applications of such advances in the field of radiation oncology with regards to treatment planning, therapy guidance and monitoring tumor response and predicting outcome.

Laparoscopic versus open appendectomy--quality of life 7 years after surgery.

BACKGROUND: In spite of the widespread use of laparoscopic appendectomy, there is an ongoing debate on the advantages of this method when compared to open appendectomy. In the evaluation of a postoperative procedure, long-term quality of life is essential. PATIENTS AND METHODS: From 1999 to 2001, 493 patients diagnosed with acute appendicitis were operated in a German general district hospital and included in an observational study. In a median postoperative interval of 7 years, these patients were re-evaluated regarding their quality of life after surgery. A Short-Form 36 Health Survey (SF-36) questionnaire was applied to evaluate the general parameters of quality of life after surgery. This questionnaire was supplemented by an additional self-developed module referring to the appendectomy. The primary outcome was the recommendation of the experienced operating procedure to relatives and friends. RESULTS: A total of 243 patients underwent a laparoscopic procedure: 132 patients were re-evaluated (recovery rate 54%). In the open group, 250 patients were operated: 121 patients were re-evaluated (recovery rate 48%). The median interval from operation to evaluation was 7 years in the laparoscopic group and 7.7 years in the open group. For the primary outcome, patients with laparoscopic appendectomy would significantly more often recommend the procedure than patients with the open operation method. For secondary outcomes, the cosmetic results were judged significantly more favourably in the laparoscopic group. The eight scaled scores of the SF-36 questionnaire did not differ significantly between the two groups. Four patients of the open group and nine patients of the laparoscopic group (including one converted procedure) needed a reoperation because of incisional hernia, adhesions and late infections. CONCLUSION: Patients after laparoscopic appendectomy show a higher degree of satisfaction with their body and their scar than patients after open appendectomy.