Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here, we found that histone deacetylase inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type but not mutant HDAC8 leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Due to the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.

The number of procedures performed with robotic surgery may exceed one million globally in 2018. The continual lack of haptic feedback, however, forces surgeons to rely on visual cues in order to avoid breaking sutures due to excessive applied force. To mitigate this problem, the authors developed and validated a novel grasper-integrated system with biaxial shear sensing and haptic feedback to warn the operator prior to anticipated suture breakage. Furthermore, the design enables facile suture manipulation without a degradation in efficacy, as determined via measured tightness of resulting suture knots. Biaxial shear sensors were integrated with a da Vinci robotic surgical system. Novice subjects (n =17) were instructed to tighten 10 knots, five times with the Haptic Feedback System (HFS) enabled, five times with the system disabled. Seven suture failures occurred in trials with HFS enabled while seventeen occurred in trials without feedback. The biaxial shear sensing system reduced the incidence of suture failure by 59% (p = 0.0371). It also resulted in 25% lower average applied force in comparison to trials without feedback (p = 0.00034), which is relevant because average force was observed to play a role in suture breakage (p = 0.03925). An observed 55% decrease in standard deviation of knot quality when using the HFS also indicates an improvement in consistency when using the feedback system. These results suggest this system may improve outcomes related to knot tying tasks in robotic surgery and reduce instances of suture failure while not degrading the quality of knots produced.

RNA interference (RNAi) represents a powerful, new tool for scientific investigation as well as a promising new form of targeted gene therapy, with applications currently in clinical trials. Bifunctional short hairpin RNA (shRNA) are synthetic RNAi molecules, engineered to utilize multiple endogenous RNAi pathways to specifically silence target genes. Pancreatic and duodenal homeobox 1 (PDX1) is a key regulator of pancreatic development, β-cell differentiation, normal β-cell function and pancreatic cancer. Our aim is to review the process of identifying PDX1 as a specific, potential RNAi target in pancreatic cancer, as well as the underlying mechanisms and various forms of RNAi, with subsequent testing and development of PDX1-targeted bifunctional shRNA therapy.

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