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- PublicationEvaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma(MDPI, 2022-08-19)Patients diagnosed with metastatic uveal melanoma (MUM) have a poor survival prognosis. Unfortunately for this rare disease, there is no known cure and suitable therapeutic options are limited. HDAC6 inhibitors (HDAC6i) are currently in clinical trials for other cancers and show potential beneficial effects against tumor cell survival in vitro and in vivo. In MUM cells, HDAC6i show an anti-proliferative effect in vitro and in preclinical xenograft models. The use of HDAC6 inhibitors as a treatment option for MUM should be explored further. Therefore, this review discusses (1) what is known about HDAC6i in MUM and (2) whether HDAC6 inhibitors offer a potential therapeutic option for MUM.
17 - PublicationUveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor(MDPI, 2022-02-03)Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time-and dose-dependent manner (p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.
30Scopus© Citations 5 - PublicationIn Silico Protein Motif Discovery and Structural Analysis(Springer, 2011-06-30)A wealth of in silico tools is available for protein motif discovery and structural analysis. The aim of this chapter is to collect some of the most common and useful tools and to guide the biologist in their use. A detailed explanation is provided for the use of Distill, a suite of web servers for the prediction of protein structural features and the prediction of full-atom 3D models from a protein sequence. Besides this, we also provide pointers to many other tools available for motif discovery and secondary and tertiary structure prediction from a primary amino acid sequence. The prediction of protein intrinsic disorder and the prediction of functional sites and SLiMs are also briefly discussed. Given that user queries vary greatly in size, scope and character, the trade-offs in speed, accuracy and scale need to be considered when choosing which methods to adopt.
25Scopus© Citations 1 - PublicationAerosols, airflow, and airspace contamination during laparoscopy(Oxford University Press, 2021-09-27)Laparoscopic surgery has been undermined throughout the COVID-19 pandemic by concerns that it may generate an infectious risk to the operating team through aerosolization of peritoneal particles. There is anyway a need for increased awareness and understanding of the occupational hazard for surgical teams regarding unfiltered escape of pollutants generated by surgical smoke and other microbials. Here, the aerosol-generating nature of this access modality was confirmed through repeatable real-time methodology both qualitatively and quantitively to inform best practice and additional engineering solutions to optimize the operating room environment.
20Scopus© Citations 5 - PublicationA CFD Analysis of Gas Leaks and Aerosol Transport in Laparoscopic Surgery(AIP, 2022-07-20)Gas used to distend the abdomen during laparoscopic surgery is released to the external environment when trocar internal valves are opened during instrumentation. Particulate matter, including smoke pollutants and both biological and microbial materials, may be transported within the leakage gas. Here, we quantify the percentage of particulate matter that escape to the airspace and put surgical staff at risk of inhalation using a high-fidelity computational fluid dynamics model, validated with direct Schlieren observation of surgery on a porcine cadaver, to model the gas leak occurring due to the opening of 12 mm trocar valves around insertion/extraction of a 5 mm laparoscopic instrument. Fluid flow was modeled through the internal double-valved geometry of the trocar to a large external region representing the operating room (OR) space. Aerosol particles in the range 0.3–10  μm were injected into the simulation. A range of intra-abdominal pressures (IAPs) and leakage durations were studied. For gas leak durations of 0.5–1 s, at least 65% of particles reach the surgical team's breathing zone across all IAPs. A typical leak had an estimated volume of 0.476 l of CO2 meaning for a typical laparoscopic operation (averaging 51 instrument exchanges), and 24.3 l escapes via this mechanism alone. Trocar gas-leak emissions propel considerable gas and particle volumes into the OR. Reducing the IAP does not mitigate their long-range travel. This work indicates the potential for powerful computational tools like large eddy simulation to play an impactful role in the design of medical devices such as surgical trocars where complex gas dynamics occur.
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