Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous melanoma (CM)/ocular melanoma predisposition syndrome suggests a tumor suppressor function, the ...specific role of this gene in the pathogenesis of CM is not fully understood. We thus set out to characterize BAP1 in CM and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared with nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony-forming capability, induced apoptosis, and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin, a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may have a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology, which is context and cell dependent.
Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. ...Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 rs17632542 (KLK3: I179T), each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
In this first in a series of round table meetings, the 1st World Federation of Hemophilia Gene Therapy Round Table was convened to initiate a global dialogue on the expected challenges and ...opportunities that a disruptive therapy, such as gene therapy, will bring to the haemophilia community. Perspectives from key stakeholder groups, including healthcare professionals, regulators, payors, people with hemophilia and pharmaceutical industry representatives, were sought in the identification of the key issues we expect to face. Didactic presentations and open discussion covered the clinical development of gene therapy in haemophilia; regulatory perspectives of gene therapy; making informed decisions; accessibility, affordability and pricing of gene therapy; and ethical issues of gene therapy clinical trials. These were followed by small group work. This manuscript outlines the key issues identified and the path forward.
Combining Lagrangian trajectories and satellite observations provides a novel basis for monitoring changes in water properties with high temporal and spatial resolution. In this study, a prediction ...scheme was developed for synthesizing satellite observations and Lagrangian model data for better interpretation of harmful algal bloom (HAB) risk. The algorithm can not only predict variations in chlorophyll-a concentration but also changes in spectral properties of the water, which are important for discrimination of different algal species from satellite ocean color. The prediction scheme was applied to regions along the coast of England to verify its applicability. It was shown that the Lagrangian methodology can significantly improve the coverage of satellite products, and the unique animations are effective for interpretation of the development of HABs. A comparison between chlorophyll-a predictions and satellite observations further demonstrated the effectiveness of this approach:
r
2
= 0.81 and a low mean absolute percentage error of 36.9%. Although uncertainties from modeling and the methodology affect the accuracy of predictions, this approach offers a powerful tool for monitoring the marine ecosystem and for supporting the aquaculture industry with improved early warning of potential HABs.
This study investigated the relationships of coping strategies, drinking motives, and stressful life events (major, daily positive, and daily negative) on emotional and behavioral problems, and ...academic functioning among a sample of 1251 Icelandic youth (mean age 18.9 years). Major stressful life events and negative daily events were associated with youth maladjustment across multiple domains of functioning. Coping motives for drinking predicted both alcohol use and alcohol problems. Emotion-focused coping was a strong predictor of depressed affect, and task-oriented coping was related inversely to emotional and behavioral problems. The findings with this sample of Icelandic youth were highly similar with previous findings with an American sample by Windle and Windle (
1996
), and suggest the need for more focused interventions on coping strategies and maladjustment among youth.
Measuring virus attachment to host cells is of great importance when trying to identify novel receptors. The presence of a usable receptor is a major determinant of viral host range and cell tropism. ...Furthermore, identification of appropriate receptors is central for the understanding of viral pathogenesis and gives possibilities to develop antiviral drugs. Attachment is presently measured using radiolabeled and subsequently gradient purified viruses. Traditional methods are expensive and time-consuming and not all viruses are stable during a purification procedure; hence there is room for improvement. Real-time PCR (RT-PCR) has become the standard method to detect and quantify virus infections, including enteroviruses, in clinical samples. For instance, primers directed to the highly conserved 5' untranslated region (5'UTR) of the enterovirus genome enable detection of a wide spectrum of enteroviruses. Here, we evaluate the capacity of the RT-PCR technology to study enterovirus host cell interactions at the cell surface and compare this novel implementation with an established assay using radiolabeled viruses.
Both purified and crude viral extracts of CVB5 generated comparable results in attachment studies when analyzed with RT-PCR. In addition, receptor binding studies regarding viruses with coxsackie- and adenovirus receptor (CAR) and/or decay accelerating factor (DAF) affinity, further demonstrated the possibility to use RT-PCR to measure virus attachment to host cells. Furthermore, the RT-PCR technology and crude viral extracts was used to study attachment with low multiplicity of infection (0.05 x 10(-4)TCID50/cell) and low cell numbers (250), which implies the range of potential implementations of the presented technique.
We have implemented the well-established RT-PCR technique to measure viral attachment to host cells with high accuracy and reproducibility, at low cost and with less effort than traditional methods. Furthermore, replacing traditional methods with RT-PCR offers the opportunity to use crude virus containing extracts to investigate attachment, which could be considered as a step towards viral attachment studies in a more natural state.
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 ...markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766T shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766T is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
The world has experienced phenomenal growth in data production and storage in recent years, much of which has taken the form of media files. At the same time, computing power has become abundant with ...multi-core machines, grids, and clouds. Yet it remains a challenge to harness the available power and move toward gracefully searching and retrieving from web-scale media collections. Several researchers have experimented with using automatically distributed computing frameworks, notably Hadoop and Spark, for processing multimedia material, but mostly using small collections on small computing clusters. In this article, we describe a prototype of a (near) web-scale throughput-oriented MM retrieval service using the Spark framework running on the AWS cloud service. We present retrieval results using up to 43 billion SIFT feature vectors from the public YFCC 100M collection, making this the largest high-dimensional feature vector collection reported in the literature. We also present a publicly available demonstration retrieval system, running on our own servers, where the implementation of the Spark pipelines can be observed in practice using standard image benchmarks, and downloaded for research purposes. Finally, we describe a method to evaluate retrieval quality of the ever-growing high-dimensional index of the prototype, without actually indexing a web-scale media collection.
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