Notes

Lane-Hamilton malady * Is it a legitimate pin in a haystack?
Oncogenic KRAS mutations are encountered in more than 90% of pancreatic ductal adenocarcinomas. MEK inhibition has failed to procure any clinical benefits in mutant RAS-driven cancers including pancreatic ductal adenocarcinoma (PDAC). To identify potential resistance mechanisms underlying MEK inhibitor (MEKi) resistance in PDAC, we investigated lysosomal drug accumulation in PDAC models both in vitro and in vivo. Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. A time-dependent, increase in lysosomal content was observed upon MEK inhibition. Strikingly, there was a strong activation of lysosomal biogenesis in cell lines of the classical compared to the basal-like molecular subtype. Increase in lysosomal content was associated with nuclear translocation of the Transcription Factor EB (TFEB) and upregulation of TFEB target genes. siRNA-mediated depletion of TFEB led to a decreased lysosomal biogenesis upon MEK inhibition and potentiated sensitivity. Using LC-MS, we show accumulation of MEKi in the lysosomes of treated cells. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC. © The Author(s) 2020.Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogateion prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients. © The Author(s) 2020.Cardiopoietic stem cells have reached advanced clinical testing for ischemic heart failure. To profile their molecular influence on recipient hearts, systems proteomics was here applied in a chronic model of infarction randomized with and without human cardiopoietic stem cell treatment. Multidimensional label-free tandem mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease. Systems proteomics thus offers utility to delineate and interpret complex molecular regenerative outcomes. © The Author(s) 2020.Successful drug discovery is ultimately contingent on the availability of workable, relevant, predictive model systems. Conversely, for cardiac muscle, the lack of human preclinical models to inform target validation and compound development has likely contributed to the perennial problem of clinical trial failures, despite encouraging non-human results. By contrast, human cardiomyocytes produced from pluripotent stem cell models have recently been applied to safety pharmacology, phenotypic screening, target validation and high-throughput assays, facilitating cardiac drug discovery. Here, we review the impact of human pluripotent stem cell models in cardiac drug discovery, discussing the range of applications, readouts, and disease models employed, along with the challenges and prospects to advance this fruitful mode of research further. © The Author(s) 2020.With the expansion of proton radiotherapy for cancer treatments, it has become important to explore proton-based imaging technologies to increase the accuracy of proton treatment planning, alignment, and verification. The purpose of this study is to demonstrate the feasibility of using a volumetric liquid scintillator to generate proton radiographs at a clinically relevant energy (180 MeV) using an integrating detector approach. The volumetric scintillator detector is capable of capturing a wide distribution of residual proton beam energies from a single beam irradiation. It has the potential to reduce acquisition time and imaging dose compared to other proton radiography methods. The imaging system design is comprised of a volumetric (20 × 20 × 20 cm3) organic liquid scintillator working as a residual-range detector and a charge-coupled device (CCD) placed along the beams'-eye-view for capturing radiographic projections. The scintillation light produced within the scintillator volume in response to a 3-dimenintillator detector and at a clinically-relevant energy was demonstrated.Aims and objectives To describe a study protocol of a randomised control trial (RCT) assessing the effectiveness, in reducing dental anxiety, of an acclimatising nitrous oxide sedation (N2O) session prior to actual dental treatment with N2O. Materials and methods A single-centre investigator-blinded parallel-group RCT conducted in a postgraduate dental hospital in Dubai, United Arab Emirates (UAE). Anxious children requiring N2O (aged 5-15 years) will be randomly assigned to; a study group children who will have a preparatory N2O trial experience or; a control group children who will only have N2O explained to them. Treatment with N2O for both groups will start at the second visit. The following outcomes will be recorded completion of dental treatment, anxiety scores at baseline and after treatment (using the Modified Child Dental Anxiety Scale faces), behaviour of the child (using Frankl Rating Behaviour Scale) and the acquisition of real-time physiological anxiety-related parameters (using E4® electronic wrist devices). Results The data will be analysed statistically. Discussion There is a paucity of research regarding dental N2O acclimatising appointments. This RCT will supplement existing literature. Conclusions This RCT will report whether prior acclimatising of a child to N2O sedation is effective, or not, in improving dental treatment behaviour. © The Author(s) 2020.Background Calcium hydroxide is the most commonly used material in indirect pulp treatment (IPT). However, its drawbacks required its replacement by other materials. Aim This study aims to estimate clinically and radiographically the success of indirect pulp treatment of young permanent molars with either photo-activated oral disinfection (PAD) or calcium hydroxide. Design This Randomized Controlled Pilot Trial included 32 vital first permanent molars with deep caries that were treated by indirect pulp treatment with either PAD (group 1) or calcium hydroxide (group 2). Clinical and radiographic success in addition to newly-formed dentin thickness were evaluated regularly at 2, 6, 9, and 12 months. Results The success for both groups was 100% clinically and radiographically at all follow-up periods. Regarding the mean thickness of newly-formed dentin for both groups at different follow-up periods, there was no statistically significant difference between both groups at 2, 6, 9, and 12 months, with P values = 0.825, 0.146, 0.280, and 0.400, respectively. Conclusions The clinical and radiographic success for indirect pulp treatment of young permanent molars with both PAD and calcium hydroxide were comparable. © The Author(s) 2020.The development of Fast Healthcare Interoperability Resources (FHIR) Genomics, a feasible and efficient method for exchanging complex clinical genomic data and interpretations, is described. FHIR Genomics is a subset of the emerging Health Level 7 FHIR standard and targets data from increasingly available technologies such as next-generation sequencing. Much care and integration of feedback have been taken to ease implementation, facilitate wide-scale interoperability, and enable modern app development toward a complete precision medicine standard. A new use case, the integration of the Variant Interpretation for Cancer Consortium (VICC) "meta-knowledgebase" into a third-party application, is described. © The Author(s) 2020.DNA methylation is an important epigenetic mechanism regulating gene expression and its role in carcinogenesis has been extensively studied. High-throughput DNA methylation assays have been used broadly in cancer research. read more Histopathology images are commonly obtained in cancer treatment, given that tissue sampling remains the clinical gold-standard for diagnosis. In this work, we investigate the interaction between cancer histopathology images and DNA methylation profiles to provide a better understanding of tumor pathobiology at the epigenetic level. We demonstrate that classical machine learning algorithms can associate the DNA methylation profiles of cancer samples with morphometric features extracted from whole slide images. Furthermore, grouping the genes into methylation clusters greatly improves the performance of the models. The well-predicted genes are enriched in key pathways in carcinogenesis including hypoxia in glioma and angiogenesis in renal cell carcinoma. Our results provide new insights into the link between histopathological and molecular data. © The Author(s) 2020.The genomic inter-individual heterogeneity remains a significant challenge for both clinical decision-making and the design of clinical trials. Although next-generation sequencing (NGS) is increasingly implemented in drug development and clinical trials, translation of the obtained genomic information into actionable clinical advice lags behind. Major reasons are the paucity of sufficiently powered trials that can quantify the added value of pharmacogenetic testing, and the considerable pharmacogenetic complexity with millions of rare variants with unclear functional consequences. The resulting uncertainty is reflected in inconsistencies of pharmacogenomic drug labels in Europe and the United States. In this review, we discuss how the knowledge gap for bridging pharmacogenomics into the clinics can be reduced. First, emerging methods that allow the high-throughput experimental characterization of pharmacogenomic variants combined with novel computational tools hold promise to improve the accuracy of drug response predictions.
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