Simultaneous gene silencing of Bcl-2, XIAP and Survivin re-sensitizes pancreatic cancer cells towards apoptosis

Abstract Background Pancreatic ductal adenocarcinoma shows a distinct apoptosis resistance, which contributes significantly to the aggressive nature of this tumor and constrains the effectiveness of new therapeutic strategies. Apoptosis resistance is determined by the net balance of the cells pro-and anti-apoptotic "control mechanisms". Numerous dysregulated anti-apoptotic genes have been identified in pancreatic cancer and seem to contribute to the high anti-apoptotic buffering capacity. We aimed to compare the benefit of simultaneous gene silencing (SGS) of several candidate genes with conventional gene silencing of single genes. Methods From literature search we identified the anti-apoptotic genes XIAP, Survivin and Bcl-2 as commonly upregulated in pancreatic cancer. We performed SGS and silencing of single candidate genes using siRNA molecules in two pancreatic cancer cell lines. Effectiveness of SGS was assessed by qRT-PCR and western blotting. Apoptosis induction was measured by flow cytometry and caspase activation. Results Simultaneous gene silencing reduced expression of the three target genes effectively. Compared to silencing of a single target or control, SGS of these genes resulted in a significant higher induction of apoptosis in pancreatic cancer cells. Conclusions In the present study we performed a subliminal silencing of different anti-apoptotic target genes simultaneously. Compared to silencing of single target genes, SGS had a significant higher impact on apoptosis induction in pancreatic cancer cells. Thereby, we give further evidence for the concept of an anti-apoptotic buffering capacity of pancreatic cancer cells.</p

Acoustic signal analysis of instrument-tissue interaction for minimally invasive interventions

PURPOSE Minimally invasive surgery (MIS) has become the standard for many surgical procedures as it minimizes trauma, reduces infection rates and shortens hospitalization. However, the manipulation of objects in the surgical workspace can be difficult due to the unintuitive handling of instruments and limited range of motion. Apart from the advantages of robot-assisted systems such as augmented view or improved dexterity, both robotic and MIS techniques introduce drawbacks such as limited haptic perception and their major reliance on visual perception. METHODS In order to address the above-mentioned limitations, a perception study was conducted to investigate whether the transmission of intra-abdominal acoustic signals can potentially improve the perception during MIS. To investigate whether these acoustic signals can be used as a basis for further automated analysis, a large audio data set capturing the application of electrosurgery on different types of porcine tissue was acquired. A sliding window technique was applied to compute log-mel-spectrograms, which were fed to a pre-trained convolutional neural network for feature extraction. A fully connected layer was trained on the intermediate feature representation to classify instrument-tissue interaction. RESULTS The perception study revealed that acoustic feedback has potential to improve the perception during MIS and to serve as a basis for further automated analysis. The proposed classification pipeline yielded excellent performance for four types of instrument-tissue interaction (muscle, fascia, liver and fatty tissue) and achieved top-1 accuracies of up to 89.9%. Moreover, our model is able to distinguish electrosurgical operation modes with an overall classification accuracy of 86.40%. CONCLUSION Our proof-of-principle indicates great application potential for guidance systems in MIS, such as controlled tissue resection. Supported by a pilot perception study with surgeons, we believe that utilizing audio signals as an additional information channel has great potential to improve the surgical performance and to partly compensate the loss of haptic feedback

The Role of Apoptosis in the Pathology of Pancreatic Cancer

Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as well as an intrinsic pathway linked to the mitochondria. Defects in apoptotic pathways and the deregulation of apoptotic proteins, such as Survivin, Bcl-2, Bcl-xL and Mcl-1, play decisive roles in the development of pancreatic cancer. Investigation of the molecular mechanism allowing tumors to resist apoptotic cell death would lead to an improved understanding of the physiology and the development of new molecular strategies in pancreatic cancer