Consumers’ evaluation of allocation policies for scarce health care services: Vested interest activation trumps spatial and temporal distance

The allocation of scarce health care service resources often requires trade-offs between individual and collective outcomes (e.g., when some individuals benefit more strongly from a given policy th

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

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

Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer

BACKGROUND: Integrin-linked kinase (ILK) promotes tumor growth and invasion. Increased ILK expression is correlated with progression of several tumor types, but the expression of ILK has not been investigated in patients with non-small cell lung cancers (NSCLCs). METHODS: We investigated ILK expression in patients with NSCLC by means of immunohistochemistry. RESULTS: ILK expression was significantly associated with tumor grade, T status, lymph node metastasis and stage. (p = 0.0169 for tumor grade; p = 0.0006 for T status; p = 0.0002 for lymph node metastasis; p < 0.0001 for stage). The 5-year survival rates for patients with strong and weak or no ILK expression levels were 20% and 59%, respectively: the difference was statistically significant (p < 0.0001). A multivariate analysis of survival revealed that ILK expression, T status, N status and vascular invasion were statistically significant prognostic factors (p = 0.0218 for ILK; p = 0.0046 for T status; p < 0.0001 for N status; p < 0.0001 for vascular invasion). CONCLUSIONS: Our study demonstrates that increased expression of ILK is a poor prognostic factor in patients with NSCLC

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors

Urinary volatile organic compounds for the detection of prostate cancer

© 2015 Khalid et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The aim of this work was to investigate volatile organic compounds (VOCs) emanating from urine samples to determine whether they can be used to classify samples into those from prostate cancer and non-cancer groups. Participants were men referred for a trans-rectal ultrasound-guided prostate biopsy because of an elevated prostate specific antigen (PSA) level or abnormal findings on digital rectal examination. Urine samples were collected from patients with prostate cancer (n = 59) and cancer-free controls (n = 43), on the day of their biopsy, prior to their procedure. VOCs from the headspace of basified urine samples were extracted using solid-phase micro-extraction and analysed by gas chromatography/mass spectrometry. Classifiers were developed using Random Forest (RF) and Linear Discriminant Analysis (LDA) classification techniques. PSA alone had an accuracy of 62-64% in these samples. A model based on 4 VOCs, 2,6-dimethyl-7-octen-2-ol, pentanal, 3-octanone, and 2-octanone, was marginally more accurate 63-65%. When combined, PSA level and these four VOCs had mean accuracies of 74% and 65%, using RF and LDA, respectively. With repeated double cross-validation, the mean accuracies fell to 71% and 65%, using RF and LDA, respectively. Results from VOC profiling of urine headspace are encouraging and suggest that there are other metabolomic avenues worth exploring which could help improve the stratification of men at risk of prostate cancer. This study also adds to our knowledge on the profile of compounds found in basified urine, from controls and cancer patients, which is useful information for future studies comparing the urine from patients with other disease states

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

The use of Raman spectroscopy to differentiate between different prostatic adenocarcinoma cell lines

Raman spectroscopy (RS) is an optical technique that provides an objective method of pathological diagnosis based on the molecular composition of tissue. Studies have shown that the technique can accurately identify and grade prostatic adenocarcinoma (CaP) in vitro. This study aimed to determine whether RS was able to differentiate between CaP cell lines of varying degrees of biological aggressiveness. Raman spectra were measured from two well-differentiated, androgen-sensitive cell lines (LNCaP and PCa 2b) and two poorly differentiated, androgen-insensitive cell lines (DU145 and PC 3). Principal component analysis was used to study the molecular differences that exist between cell lines and, in conjunction with linear discriminant analysis, was applied to 200 spectra to construct a diagnostic algorithm capable of differentiating between the different cell lines. The algorithm was able to identify the cell line of each individual cell with an overall sensitivity of 98% and a specificity of 99%. The results further demonstrate the ability of RS to differentiate between CaP samples of varying biological aggressiveness. RS shows promise for application in the diagnosis and grading of CaP in clinical practise as well as providing molecular information on CaP samples in a research setting

Unsupervised Learning of Category-Specific Symmetric 3D Keypoints from Point Sets

Automatic discovery of category-specific 3D keypoints from a collection of objects of a category is a challenging problem. The difficulty is added when objects are represented by 3D point clouds, with variations in shape and semantic parts and unknown coordinate frames. We define keypoints to be category-specific, if they meaningfully represent objects’ shape and their correspondences can be simply established order-wise across all objects. This paper aims at learning such 3D keypoints, in an unsupervised manner, using a collection of misaligned 3D point clouds of objects from an unknown category. In order to do so, we model shapes defined by the keypoints, within a category, using the symmetric linear basis shapes without assuming the plane of symmetry to be known. The usage of symmetry prior leads us to learn stable keypoints suitable for higher misalignments. To the best of our knowledge, this is the first work on learning such keypoints directly from 3D point clouds for a general category. Using objects from four benchmark datasets, we demonstrate the quality of our learned keypoints by quantitative and qualitative evaluations. Our experiments also show that the keypoints discovered by our method are geometrically and semantically consistent