Comparison of performance in a four year graduate entry medical programme and a traditional five/six year programme.

Background In 2006 the Royal College of Surgeons in Ireland, (RCSI), introduced the first four year Graduate Entry Programme (GEP) in medicine in Ireland in line with national policy to broaden access to medical education. One concern considered at the time, was whether the GEP students could be trained to the same standard as their undergraduate Direct Entry Programme (DEP, five/ six year duration) counterparts in the shorter time frame. Since students from both cohorts undertake the same examinations in the final two years, it is possible to directly compare GEP vs DEP outcomes. The primary aim of the current study was to analyse the comparative performance of GEP and DEP students undergoing these examinations between 2008 and 2013.MethodsScores from five assessments performed during the final two years were transformed to z scores for each student and 4 scores for the penultimate year were summed to create a unit weighted composite score. The resultant scores for each of the two years were used to assess the comparative performance of GEP vs DEP cohorts and to perform sub-cohort analyses of GEP outcomes.ResultsIn all cohorts/years examined, evidence demonstrated significantly better assessment outcomes for the GEP group for the final two years¿ examinations as compared with the DEP group. In all but one cohort examined, this advantage was retained when nationality factors were excluded. Further analyses showed no difference in outcomes between GEP students having science vs. non-science backgrounds and or between those from EU vs non-EU backgrounds. Finally, data suggested weak correlations between total composite scores and entry scores in American (r¿=¿0.15) and Australian (r¿=¿0.08) medical school admissions tests.ConclusionsWe have shown for the first time in Ireland, that graduate-entry students perform at least as well, or even better, than a corresponding undergraduate-entry group. Moreover, having a scientific background on entry to the GEP confers no advantage in final assessments. These data provide evidence of the viability of the graduate entry route into medical education in Ireland

AKT1 (E17K) mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection.

BACKGROUND: The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. METHODS: We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 (E17K) and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. RESULTS: Overall AKT1 (E17K) mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 (E17K) mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1 (E17K) mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 (E17K) as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 (E17K) could be associated with increased mortality. These findings warrant additional long-term follow-up. CONCLUSIONS: The data suggest that AKT1 (E17K) is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer

Colorectal tumour simulation using agent based modelling and high performance computing

450,000 European citizens are diagnosed every year with colorectal cancer (CRC) and more than 230,000 succumb to the disease annually. For this reason, significant resources are dedicated to the identification of more effective therapies for this disease. However, classical assessment techniques for these treatments are slow and costly. Consequently, systems biology researchers at the Royal College of Surgeons in Ireland (RCSI) are developing computational agent-based models simulating tumour growth and treatment responses with the objective of speeding up the therapeutic development process while, at the same time, producing a tool for adapting treatments to patient-specific characteristics. However, the model complexity and the high number of agents to be simulated require a thorough optimisation of the process in order to execute realistic simulations of tumour growth on currently available platforms. We propose to apply the most advanced HPC techniques to achieve the efficient and realistic simulation of a virtual tissue model that mimics tumour growth or regression in space and time. These techniques combine extensions of the previously developed agent-based simulation software platform (FLAME) with autotuning capabilities and optimisation strategies for the current tumour model. Development of such a platform could advance the development of novel therapeutic approaches for the treatment of CRC which can also be applied other solid tumours.This work has been partially supported by MICINN-Spain under contract TIN2011- 28689-C02-01 and TIN2014-53234-C2-1-R and GenCat-DIUiE(GRR) 2014-SGR-576. This research was also funded by the European Community’s Framework Programme Seven (FP7) Programme under contract No. 278981 680 AngioPredict and supported by the DJEI/DES/SFI/HEA Irish Centre for High- End Computing (ICHEC).Peer ReviewedPostprint (author's final draft

Supplementary data for article: O’Connor, S.; Szwej, E.; Nikodinović-Runić, J.; O’Connor, A.; Byrne, A. T.; Devocelle, M.; O’Donovan, N.; Gallagher, W. M.; Babu, R. P.; Kenny, S. T.; et al. The Anti-Cancer Activity of a Cationic Anti-Microbial Peptide Derived from Monomers of Polyhydroxyalkanoate. Biomaterials 2013, 34 (11), 2710–2718. https://doi.org/10.1016/j.biomaterials.2012.12.032

Supplementary material for: [https://doi.org/10.1016/j.biomaterials.2012.12.032]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1609

The Hydroxylase Inhibitor Dimethyloxallyl Glycine Attenuates Endotoxic Shock Via Alternative Activation of Macrophages and IL-10 Production by B1 Cells

Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors HIF-1α and NF-κB via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of HIF-1 and NF-κB. We have demonstrated in vivo that pre-treatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. DMOG treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of pro-inflammatory cytokines such as TNFα. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B-1 cell population. This study demonstrates cell type specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock

Mechanistic interrogation of combination Bevacizumab/dual PI3K/mTOR inhibitor response in Glioblastoma implementing novel MR and PET imaging biomarkers.

Purpose: Resistance to bevacizumab (BEV) in glioblastoma (GBM) is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Implementing an MRI/PET molecular imaging biomarker approach, we sought to interrogate response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Methods: Tumors were established by orthotopically implanting U87MG-luc2 in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion weighted-MRI, T2 weighted (T2w), and T2* weighted (T2*w) before and following delivery of superparamagnetic iron oxide (SPIO) contrast. Maps for changes in relaxation rates: ΔR2, ΔR2* and apparent diffusion coefficient (ADC) were calculated. Vessel Size Index (VSI) and micro vessel density index (MDI) were derived. 3´-deoxy-3´-[18F]fluorothymidine ([18F]FLT)- and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET was further performed and tumor endothelium/proliferation markers assessed by immunohistochemistry. Results: Treatment with BEV resulted in a pronounced decrease in tumor volume (T2w MRI). No additive effect on tumour volume was observed in BEV/BEZ235 combination compared with BEV monotherapy. Ki67 proliferation index staining and [18F]FLT uptake studies were used to support observations. Using ΔR2* and ΔR2 values respectively, BEZ235 + BEV combination significantly reduced tumor microvessel volume in comparison to BEV alone. Decreased MDI was further observed in the combination group; supported by von Willebrand Factor (vWF) immunohistochemistry. We observed decreased [18F]FET uptake following BEV, but failed to observe further reduced [18F]FET uptake in the combination cohort. vWF IHC analysis showed mean tumor vessel size increased in all cohorts. Conclusions: Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET, informed drug combination mechanism of action and provided clues as to potential clinical response. Translation of a BEZ35/BEV combination regimen could support reduction of peritumoral edemaobviating the requirement for steroids. Implementing hypothesis driven molecular imaging studies facilitates the interrogation of drug response in the pre-clinic. These data may more accurately predict the clinical potential of novel therapeutic approaches in oncology

Supplementary data for article: O’Connor, S.; Szwej, E.; Nikodinović-Runić, J.; O’Connor, A.; Byrne, A. T.; Devocelle, M.; O’Donovan, N.; Gallagher, W. M.; Babu, R. P.; Kenny, S. T.; et al. The Anti-Cancer Activity of a Cationic Anti-Microbial Peptide Derived from Monomers of Polyhydroxyalkanoate. Biomaterials 2013, 34 (11), 2710–2718. https://doi.org/10.1016/j.biomaterials.2012.12.032

Supplementary material for: [https://doi.org/10.1016/j.biomaterials.2012.12.032]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1609

Genomic Exploration of Distinct Molecular Phenotypes Steering Temozolomide Resistance Development in Patient-Derived Glioblastoma Cells

Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells’ molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell RNA sequencing on four of the cell cultures to track the evolution of temozolomide resistance. The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as “adaptive” (ADA) or “non-adaptive” (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable. The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor’s ability to survive. Depending on the tumor’s adaptability potential, subpopulations with acquired resistance mechanisms may arise.</p

Quality of life of adult retinoblastoma survivors in the Netherlands

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Implementing patient-derived xenografts to assess the effectiveness of cyclin-dependent kinase inhibitors in glioblastoma

Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. A reduction in viability and significant levels of apoptosis were observed in vitro in human GBM neurospheres following treatment with seliciclib plus drozitumab. While the co-treatment strategy induced a similar effect in PDX models, the dosing regimen required to observe seliciclib-targeted responses in the brain, resulted in lethal toxicity in 45% of animals. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models.Irish Health Research BoardEuropean Commissio