Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Acetabular reconstruction in oncological surgery: A systematic review and meta-analysis of implant survivorship and patient outcomes

Background: Reconstruction of the hip for peri-acetabular oncological disease remains a challenge. The objective of this study was to summarize the evidence and identify techniques utilized for primary and metastatic tumors of the acetabulum and hemipelvis. Methods: A systematic review of the published literature was carried out in accordance with PRISMA guidelines. MEDLINE, EMBASE and Cochrane databases identified relevant articles. Quality was assessed using the Newcastle-Ottawa Scale. The study was registered on PROSPERO. Results: 53 papers were included, 16 were suitable for meta-analysis. 909 patients had primary and 1140 metastatic disease. 1094 patients underwent reconstruction with conventional total hip arthroplasty (with or without cup-cage or cement augmentation) or modifications of the Harrington procedure, collectively termed ‘noncomplex’. 928 patients underwent ‘complex’ reconstructions with either a modular hemipelvic, saddle, reverse snow-cone, custom-made or 3D-printed endoprosthesis. The most common complication was deep infection (11%) followed by dislocation (5%). Mean MSTS scores were 61.9% for ‘non-complex’ versus 63.2% for ‘complex’ reconstruction. Meta-analysis suggested increased mortality for primary (OR 3.14; 95% CI 1.15-8.54) and trends toward reduced mortality for metastatic disease (OR 0.93; 95% CI 0.26-3.29) following ‘complex’ versus ‘non-complex’ reconstruction. Reoperation rates were higher following ‘complex’ reconstruction for metastatic disease (OR 1.90; 95% CI 0.66-5.46) and similar for primary disease (OR 0.98; 95% CI 0.45-2.14). Conclusions: Peri-acetabular tumors are associated with high rates of morbidity and mortality. Decisions regarding implant selection are multi-factorial with recent increase in the use of custom-made and 3D-printing technologies. Multiple factors contribute to the oncological outcome and patient function. Further research is required in order to guide optimal practice

The development of cisplatin resistance in neuroblastoma is accompanied by epithelial to mesenchymal transition in vitro

AbstractNeuroblastoma is a challenging childhood malignancy, with a very high percentage of patients relapsing following acquisition of drug resistance, thereby necessitating the identification of mechanisms of drug resistance as well as new biological targets contributing to the aggressive pathogenicity of the disease. In order to investigate the molecular pathways that are involved with drug resistance in neuroblastoma, we have developed and characterised cisplatin resistant sublines SK-N-ASCis24, KellyCis83 and CHP-212Cis100, integrating data of cell behaviour, cytotoxicity, genomic alterations and modulation of protein expression. All three cisplatin resistant cell lines demonstrated cross resistance to temozolomide, etoposide and irinotecan, all of which are drugs in re-initiation therapy. Array CGH analysis indicated that resistant lines have acquired additional genomic imbalances. Differentially expressed proteins were identified by mass spectrometry and classified by bioinformatics tools according to their molecular and cellular functions and their involvement into biological pathways. Significant changes in the expression of proteins involved with pathways such as actin cytoskeletal signalling (p = 9.28E−10), integrin linked kinase (ILK) signalling (p = 4.01E−8), epithelial adherens junctions signalling (p = 5.49E−8) and remodelling of epithelial adherens junctions (p = 5.87E−8) pointed towards a mesenchymal phenotype developed by cisplatin resistant SK-N-ASCis24. Western blotting and confocal microscopy of MYH9, ACTN4 and ROCK1 coupled with invasion assays provide evidence that elevated levels of MYH9 and ACTN4 and reduced levels of ROCK1 contribute to the increased ROCK1-independent migratory potential of SK-N-ASCis24. Therefore, our results suggest that epithelial-to-mesenchymal transition is a feature during the development of drug resistance in neuroblastoma

Translating digital healthcare to enhance clinical management: a protocol for an observational study using a digital health technology system to monitor medication adherence and its effect on mobility in people with Parkinson’s

Introduction In people with Parkinson’s (PwP) impaired mobility is associated with an increased falls risk. To improve mobility, dopaminergic medication is typically prescribed, but complex medication regimens result in suboptimal adherence. Exploring medication adherence and its impact on mobility in PwP will provide essential insights to optimise medication regimens and improve mobility. However, this is typically assessed in controlled environments, during one-off clinical assessments. Digital health technology (DHT) presents a means to overcome this, by continuously and remotely monitoring mobility and medication adherence. This study aims to use a novel DHT system (DHTS) (comprising of a smartphone, smartwatch and inertial measurement unit (IMU)) to assess self-reported medication adherence, and its impact on digital mobility outcomes (DMOs) in PwP.Methods and analysis This single-centre, UK-based study, will recruit 55 participants with Parkinson’s. Participants will complete a range of clinical, and physical assessments. Participants will interact with a DHTS over 7 days, to assess self-reported medication adherence, and monitor mobility and contextual factors in the real world. Participants will complete a motor complications diary (ON-OFF-Dyskinesia) throughout the monitoring period and, at the end, a questionnaire and series of open-text questions to evaluate DHTS usability. Feasibility of the DHTS and the motor complications diary will be assessed. Validated algorithms will quantify DMOs from IMU walking activity. Time series modelling and deep learning techniques will model and predict DMO response to medication and effects of contextual factors. This study will provide essential insights into medication adherence and its effect on real-world mobility in PwP, providing insights to optimise medication regimens.Ethics and dissemination Ethical approval was granted by London—142 Westminster Research Ethics Committee (REC: 21/PR/0469), protocol V.2.4. Results will be published in peer-reviewed journals. All participants will provide written, informed consent.Trial registration number ISRCTN13156149

Polynuclear lanthanide complexes of a series of bridging ligands containing two tridentate N,N?,O-donor units: structures and luminescence properties

A set of three potentially bridging ligands containing two tridentate chelating N,N,O-donor (pyrazole–pyridine–amide) donors separated by an o, m, or p-phenylene spacer has been prepared and their coordination chemistry with lanthanide(III) ions investigated. Ligand L1 (p-phenylene spacer) forms complexes with a 2 : 3 M : L ratio according to the proportions used in the reaction mixture; the Ln2(L1)3 complexes contain two 9-coordinate Ln(III) centres with all three bridging ligands spanning both metal ions, and have a cylindrical (non-helical) mesocate architecture. The 1 : 1 complexes display a range of structural types depending on the conditions used, including a cyclic Ln4(L1)4 tetranuclear helicate, a Ln2(L1)2 dinuclear mesocate, and an infinite one-dimensional coordination polymer in which metal ions and bridging ligands alternate along the sequence. ESMS studies indicate that the 1 : 1 complexes form a mixture of oligonuclear species {Ln(L1)}n in solution (n up to 5) which are likely to be cyclic helicates. In contrast, ligands L2 and L3 (with o- and m-phenylene spacers, respectively) generally form dinuclear Ln2L2 Ln(III) complexes in which the two ligands may be arranged in a helical or non-helical architecture about the two metal ions. These complexes also contain an additional exogenous bidentate bridging ligand, either acetate or formate, which has arisen from hydrolysis of solvent molecules promoted by the Lewis-acidity of the Ln(III) ions. Luminescence studies on some of the Nd(III) complexes showed that excitation into ligand-centred –* transitions result in the characteristic near-infrared luminescence from Nd(III) at 1060 nm