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Opinion Statement: Soft tissue sarcomas (STS) are a rare and heterogeneous group of cancers. Treatment options have changed little in the past thirty years, and the role of neoadjuvant chemotherapy is controversial. Accurate risk stratification is crucial in STS in order to facilitate clinical discussions around peri-operative treatment. Current risk stratification tools used in clinic, such as Sarculator, use clinicopathological characteristics and may be specific to anatomical site or to histology. More recently, risk stratification tools have been developed using molecular or immunological data. Combining Sarculator with other risk stratification tools may identify novel patient groups with differential clinical outcomes. There are several considerations when translating risk stratification tools into widespread clinical use, including establishing clinical utility, health economic value, being applicable to existing clinical pathways, having strong real-world performance, and being supported by investment into infrastructure. Future work may include incorporation of novel modalities and data integration techniques. [ABSTRACT FROM AUTHOR]

Opinion statement: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need. [ABSTRACT FROM AUTHOR]

Background: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up.Methods: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint.Results: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively.Conclusions: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score. [ABSTRACT FROM AUTHOR]

Opinion statement: Advances in proteomic and metabolomic technologies have accelerated our understanding of multiple aspects of cancer biology across distinct tumour types. Here we review the current state-of-the-art in the use of proteomics and metabolomics in soft tissue sarcomas. We highlight the utility of these Omics-based methodologies to identify new drug targets, synthetic lethal interactions, candidate therapeutics and novel biomarkers to facilitate patient stratification. Due to the unbiased and global nature of these profiling methods to assess the levels of protein expression, post-translational modifications such as phosphorylation and glycosylation as well as key metabolites, many of these findings have broad applications not just in specific histotypes but across multiple STS subtypes. Specific examples of proteomic and metabolomic findings that have led to the development of early phase clinical trials of investigational agents will be discussed. While promising, the use of these technologies in the study of sarcoma is still limited, and there is a need for further research in this area. In particular, it would be important to integrate these approaches with other Omics strategies such as genomics and epigenomics as well as implement these tools alongside clinical trials in order to maximize the impact of these tools on our biological understanding and treatment of this group of rare diseases of unmet need. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas (STS) are rare and heterogeneous tumours comprising over 80 different histological subtypes. Treatment options remain limited in advanced STS with high rates of recurrence following resection of localised disease. Prognostication in clinical practice relies predominantly on histological grading systems as well as sarcoma nomograms. Rapid developments in gene expression profiling technologies presented opportunities for applications in sarcoma. Molecular profiling of sarcomas has improved our understanding of the cancer biology of these rare cancers and identified potential novel therapeutic targets. In particular, transcriptomic signatures could play a role in risk classification in sarcoma to aid prognostication. Unlike other solid and haematological malignancies, transcriptomic signatures have not yet reached routine clinical use in sarcomas. Herein, we evaluate early developments in gene expression profiling in sarcomas that laid the foundations for transcriptomic signature development. We discuss the development and clinical evaluation of key transcriptomic biomarker signatures in sarcomas, including Complexity INdex in SARComas (CINSARC), Genomic Grade Index, and hypoxia-associated signatures. Prospective validation of these transcriptomic signatures is required, and prospective trials are in progress to evaluate reliability for clinical application. We anticipate that integration of these gene expression signatures alongside existing prognosticators and other Omics methodologies, including proteomics and DNA methylation analysis, could improve the identification of 'high-risk' patients who would benefit from more aggressive or selective treatment strategies. Moving forward, the incorporation of these transcriptomic prognostication signatures in clinical practice will undoubtedly advance precision medicine in the routine clinical management of sarcoma patients. [ABSTRACT FROM AUTHOR]

A performance measure for a DART® tsunami buoy network has been developed. DART® buoys are used to detect tsunamis, but the full potential of the data they collect is realized through accurate forecasts of inundations caused by the tsunamis. The performance measure assesses how well the network achieves its full potential through a statistical analysis of simulated forecasts of wave amplitudes outside an impact site and a consideration of how much the forecasts are degraded in accuracy when one or more buoys are inoperative. The analysis uses simulated tsunami amplitude time series collected at each buoy from selected source segments in the Short-term Inundation Forecast for Tsunamis database and involves a set for 1000 forecasts for each buoy/segment pair at sites just offshore of selected impact communities. Random error-producing scatter in the time series is induced by uncertainties in the source location, addition of real oceanic noise, and imperfect tidal removal. Comparison with an error-free standard leads to root-mean-square errors (RMSEs) for DART® buoys located near a subduction zone. The RMSEs indicate which buoy provides the best forecast (lowest RMSE) for sections of the zone, under a warning-time constraint for the forecasts of 3 h. The analysis also shows how the forecasts are degraded (larger minimum RMSE among the remaining buoys) when one or more buoys become inoperative. The RMSEs provide a way to assess array augmentation or redesign such as moving buoys to more optimal locations. Examples are shown for buoys off the Aleutian Islands and off the West Coast of South America for impact sites at Hilo HI and along the US West Coast (Crescent City CA and Port San Luis CA, USA). A simple measure (coded green, yellow or red) of the current status of the network’s ability to deliver accurate forecasts is proposed to flag the urgency of buoy repair. [ABSTRACT FROM AUTHOR]

Opinion Statement: Two recently reported phase III randomised control trials (RCTs) have resulted in the registration of two new systemic therapies for advanced soft tissue sarcoma. Both of these trials' designs were informed by phase II data that guided the selection of sensitive STS diagnoses, enabling the demonstration of benefit in certain subtypes. A number of other phase III trials reported in the last 18 months have seemingly fit into a recurrent pattern of failure-promising efficacy signals in earlier phase studies being lost in the survival follow-up of large, highly heterogeneous cohorts. Greater effort is needed to identify histological and molecularly defined subgroups associated with differential treatment response in order to avoid the tremendous disappointment and loss of resources associated with a failed phase III trial. Additionally, improvements in available treatment of advanced STS have underpinned a prolongation in overall survival (OS). Consequently, surrogate efficacy endpoints are of increasing importance to STS drug trials. Whilst progression-free survival (PFS) should arguably replace overall survival as the primary endpoint of choice in first-line studies, more work is required to provide definitive validation of surrogacy, as well as developing more sophisticated techniques of assessing radiological response and expanding the inclusion of quality-of-life-related endpoints. [ABSTRACT FROM AUTHOR]

US Tsunami Warning Centers use real-time bottom pressure (BP) data transmitted from a network of buoys deployed in the Pacific and Atlantic Oceans to tune source coefficients of tsunami forecast models. For accurate coefficients and therefore forecasts, tides and background noise at the buoys must be accounted for through detiding. In this study, five methods for coefficient estimation are compared, each of which handles detiding differently. The first three subtract off a tidal prediction based on (1) a localized harmonic analysis involving 29 days of data immediately preceding the tsunami event, (2) 68 preexisting harmonic constituents specific to each buoy, and (3) an empirical orthogonal function fit to the previous 25 h of data. Method (4) is a Kalman smoother that uses method (1) as its input. These four methods estimate source coefficients after detiding. Method (5) estimates the coefficients simultaneously with a two-component harmonic model that accounts for the tides. The five methods are evaluated using archived data from 11 DART buoys, to which selected artificial tsunami signals are superimposed. These buoys represent a full range of observed tidal conditions and background BP noise in the Pacific and Atlantic, and the artificial signals have a variety of patterns and induce varying signal-to-noise ratios. The root-mean-square errors (RMSEs) of least squares estimates of source coefficients using varying amounts of data are used to compare the five detiding methods. The RMSE varies over two orders of magnitude among detiding methods, generally decreasing in the order listed, with method (5) yielding the most accurate estimate of the source coefficient. The RMSE is substantially reduced by waiting for the first full wave of the tsunami signal to arrive. As a case study, the five methods are compared using data recorded from the devastating 2011 Japan tsunami. [ABSTRACT FROM AUTHOR]

The destructive Pacific Ocean tsunami generated off the east coast of Honshu, Japan, on 11 March 2011 prompted the West Coast and Alaska Tsunami Warning Center (WCATWC) to issue a tsunami warning and advisory for the coastal regions of Alaska, British Columbia, Washington, Oregon, and California. Estimating the length of time the warning or advisory would remain in effect proved difficult. To address this problem, the WCATWC developed a technique to estimate the amplitude decay of a tsunami recorded at tide stations within the Warning Center's Area of Responsibly (AOR). At many sites along the West Coast of North America, the tsunami wave amplitudes will decay exponentially following the arrival of the maximum wave ( Mofjeld et al., Nat Hazards 22:71-89, ). To estimate the time it will take before wave amplitudes drop to safe levels, the real-time tide gauge data are filtered to remove the effects of tidal variations. The analytic envelope is computed and a 2 h sequence of amplitude values following the tsunami peak is used to obtain a least squares fit to an exponential function. This yields a decay curve which is then combined with an average West Coast decay function to provide an initial tsunami amplitude-duration forecast. This information may then be provided to emergency managers to assist with response planning. [ABSTRACT FROM AUTHOR]

To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography, with their limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400-900 nm) is an alternative, but at present it requires craniotomy, cranial windows and skull-thinning techniques, and the penetration depth is limited to 1-2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy, utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3-1.4 μm near-infrared window (NIR-IIa window). Reduced photon scattering in this spectral region allows fluorescence imaging to a depth of >2 mm in mouse brain with sub-10-μm resolution. An imaging rate of ∼5.3 frames per second allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of a blood flow anomaly in a mouse middle cerebral artery occlusion stroke model. [ABSTRACT FROM AUTHOR]

The discoidin domain receptors (DDRs) are collagen-binding receptor tyrosine kinases that have been implicated in a number of fundamental biological processes ranging from growth and development to immunoregulation. In this review, we examine how recent proteomic technologies have enriched our understanding of DDR signaling mechanisms. We provide an overview on the use of large-scale proteomic profiling and chemical proteomics to reveal novel insights into DDR therapeutics, signaling networks, and receptor crosstalk. A perspective of how proteomics may be harnessed to answer outstanding fundamental questions including the dynamic regulation of receptor activation kinetics is presented. Collectively, these studies present an emerging molecular portrait of these unique receptors and their functional role in health and disease. [ABSTRACT FROM AUTHOR]

The ability to use computer generated high quality real-time video provides engineers/scientists/electronic game designers a powerful tool in many applications. The advent of micro-electronics further enables complicated devices to be put into smaller, inexpensive, and robust packages. During the last few years, smaller video-image-based devices have been installed in land-based vehicles to enhance driving comfort, convenience, and safety. These include navigational aids, GPS, collision avoidance devices, and many others. The proliferation of these devices is mainly due to the relatively inexpensive and short life span of land vehicles compared to that of airplanes (and submarines). This paper reports the development of a pilot/driver aid that can be used as an add-on to existing vehicles with minimal retrofit. With this device, pilots or drivers can operate the vehicles under extreme weather conditions when visual contact with the out-of-the-window view is not available. The implementation of this process is used not only for manned helicopters but also as a training aid for unmanned helicopter pilots. [ABSTRACT FROM AUTHOR]

Molecular biomarkers can be used as objective indicators of pathologic processes. Although their levels often change over time, their measurement is often constrained to a single time point. Cumulative biomarker exposure would provide a fundamentally different kind of measurement to what is available in the clinic. Magnetic resonance relaxometry can be used to noninvasively monitor changes in the relaxation properties of antibody-coated magnetic particles when they aggregate upon exposure to a biomarker of interest. We used implantable devices containing such sensors to continuously profile changes in three clinically relevant cardiac biomarkers at physiological levels for up to 72 h. Sensor response differed between experimental and control groups in a mouse model of myocardial infarction and correlated with infarct size. Our prototype for a biomarker monitoring device also detected doxorubicin-induced cardiotoxicity and can be adapted to detect other molecular biomarkers with a sensitivity as low as the pg/ml range. [ABSTRACT FROM AUTHOR]

Endothelial production of nitric oxide is critical to the regulation of vascular responses, including vascular tone and regional blood flow, leukocyte–endothelial interactions, platelet adhesion and aggregation, and vascular smooth muscle cell proliferation. A relative deficiency in the amount of bioavailable vascular NO results in endothelial dysfunction, with conditions that are conducive to the development of atherosclerosis: thrombosis, inflammation, neointimal proliferation, and vasoconstriction. This review focuses on mouse models of endothelial dysfunction caused by direct genetic modification of the endothelial nitric oxide synthase (eNOS) gene. We first describe the cardiovascular phenotypes of eNOS knockout mice, which are a model of total eNOS gene deficiency and thus the ultimate model of endothelial dysfunction. We then describe S1177A and S1177D eNOS mutant mice as mouse models with altered eNOS phosphorylation and therefore varying degrees of endothelial dysfunction. These include transgenic mice that carry the eNOS S1177A and S1177D transgenes, as well as knockin mice in which the endogenous eNOS gene has been mutated to carry the S1177A and S1177D mutations. Together, eNOS knockout mice and eNOS S1177 mutant mice are useful tools to study the effects of total genetic deficiency of eNOS as well as varying degrees of endothelial dysfunction caused by eNOS S1177 phosphorylation. [ABSTRACT FROM AUTHOR]

The generation and expansion of diverse cardiovascular cell lineages is a critical step during human cardiogenesis, with major implications for congenital heart disease. Unravelling the mechanisms for the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential. Recent studies in the mouse embryo have identified a multipotent cardiac progenitor that contributes to all of the major cell types in the murine heart. In contrast to murine development, human cardiogenesis has a much longer onset of heart cell lineage diversification and expansion, suggesting divergent pathways. Here we identify a diverse set of human fetal ISL1+ cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle and endothelial cell lineages. Using two independent transgenic and gene-targeting approaches in human embryonic stem cell lines, we show that purified ISL1+ primordial progenitors are capable of self-renewal and expansion before differentiation into the three major cell types in the heart. These results lay the foundation for the generation of human model systems for cardiovascular disease and novel approaches for human regenerative cardiovascular medicine. [ABSTRACT FROM AUTHOR]

Computer-generated virtual systems and virtual environments provide researchers, engineers, game/entertainment developers, designers, and many other professions with powerful tools to perform jobs that were unimaginable a few years ago. For virtual systems, visualization is only one of the five senses used by humans, so by combining sounds, motion, and other sensory stimulus, it is possible to digitally re-create objects, events and environment to completely emulate real objects, events, and environment in which they occur with high fidelity. This paper reports the research and findings on various tools, equipment, and settings that can be used to create high-fidelity virtual systems. [ABSTRACT FROM AUTHOR]

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, σ, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3σ promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3σ for proteasomal degradation. Loss of 14-3-3σ protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3σ might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3σ is unknown. Here we report a previously unknown function for 14-3-3σ as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3σ, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3σ-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3σ impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3σ-deficient cells may progress on the path to aneuploidy and tumorigenesis. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) regulates vascular tone and local blood flow, platelet aggregation and adhesion, and leukocyte-endothelial cell interactions. Abnormalities in NO production by the vascular endothelium result in endothelial dysfunction, which occurs in hypertension, diabetes, aging, and as a prelude to atherosclerosis. The common feature of endothelial dysfunction is a decrease in the amount of bioavailable NO. In this article, the physiologic roles of NO and the mechanisms of endothelial dysfunction are reviewed. Regulation of endothelial NO synthase (eNOS) activity by fatty acid modifications, intracellular localization, interactions with heat shock protein 90 (hsp90) and caveolin, substrate and cofactor dependence, and phosphorylation might all affect the level of bioavailable NO. A hypothesis is proposed that the final common pathway of diverse causes of endothelial dysfunction involves abnormalities in eNOS phosphorylation at Ser 1179 and other key phosphorylation sites [ABSTRACT FROM AUTHOR]

Investigates the role of nitric oxide synthases with effector molecules on nitric oxide signaling. Stimulation of the sarcoplasmic reticulum; Release of the ryanodine receptors; Determination of the beta-adrenergic-stimulated cardiac reserve.

Studies the role of endothelial nitric oxide synthase (ENOS) in vascular function by disrupting the gene encoding ENOS in mice. Endothelium-derived relaxing factor activity; Responses to NOS blockade in the mutant mice; Implications to blood pressure maintenance.

Abstract In brain, nitric oxide (NO) is considered as a retrograde messenger involved in synaptic plasticity. The present study was undertaken to investigate whether mice lacking the neuronal nitric oxide synthase (nNOS) gene are protected from cocaine-induced behavioral sensitization. Mice were administered, IP, either saline or cocaine (15 mg/kg) for 5 days. Sensitization was determined as an increase in cocaine-induced locomotor activity on day 5 compared with day 1 and an amplified response of cocaine-experienced mice to a challenge cocaine injection given after a 10-day drug free period (e.g., on day 15). To investigate the development of a context-dependent locomotion (conditioning), the responses of cocaine- and saline-experienced mice to a saline injection were determined on day 17. Male homozygote nNOS(-/-) mice were sensitive to the acute effect of cocaine (15 mg/kg) on day 1; however, they developed neither a sensitized response to cocaine (on day 5 and 15) nor a conditioned locomotion. Female homozygote nNOS(-/-) mice neither were responsive to 15 mg/kg cocaine on day 1, 5 and 15, nor did they develop a conditioned locomotion. In contrast, the same cocaine regimen delivered to male and female heterozygote nNOS(+/-) mice, and wild type mice (B6 J/sv129, C57BL/6 and sv129) resulted in sensitization to cocaine-induced locomotor activity and context-dependent locomotion. Investigation of [[sup 3]H]cocaine disposition in the striatum and frontal cortex of the mice revealed neither gender nor strain differences in the drug disposition. Also, no major difference in striatal dopaminergic markers between homozygote nNOS(-/-) and wild type mice was observed. The most significant distinction, however, was the finding that nNOS(-/-) mice are completely deficient in... [ABSTRACT FROM AUTHOR]

We report a case of radiation necrosis occurring 47 years after resection and radiotherapy for a juvenile pilocystic cerebellar astrocytoma, the longest yet reported. The patient presented with progressive lower cranial nerve dysfunction, and eventually died from cardiopulmonary arrest secondary to aspiration. The presentation, diagnosis, pathological features, and management of radiation necrosis are discussed. [ABSTRACT FROM AUTHOR]

This article discusses research published on a proteomics technique that is used to identify molecules regulating the behavior of melanoma cells. Melanoma is a skin cancer that becomes lethal with late prognosis, and its incidence in Western countries doubles approximately every decade. The signaling protein BRAF is a central component in melanoma, as it phosphorylates other proteins through its protein-kinase activity, thereby regulating their activity. The researchers set out to identify these proteins that are regulated by BRAF via a mass-spectrometry-based technique known as negative ion scanning. They identified phosphorylation sites within cells that expressed a mutation in BRAF and established a simulation model intended to mimic the way that melanoma cells spread through a body.