812 research outputs found
Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1
Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions
b-Initiated processes at the LHC: a reappraisal
Several key processes at the LHC in the standard model and beyond that
involve quarks, such as single-top, Higgs, and weak vector boson associated
production, can be described in QCD either in a 4-flavor or 5-flavor scheme. In
the former, quarks appear only in the final state and are typically
considered massive. In 5-flavor schemes, calculations include quarks in the
initial state, are simpler and allow the resummation of possibly large initial
state logarithms of the type into the
parton distribution function (PDF), being the typical scale of the
hard process. In this work we critically reconsider the rationale for using
5-flavor improved schemes at the LHC. Our motivation stems from the observation
that the effects of initial state logs are rarely very large in hadron
collisions: 4-flavor computations are pertubatively well behaved and a
substantial agreement between predictions in the two schemes is found. We
identify two distinct reasons that explain this behaviour, i.e., the
resummation of the initial state logarithms into the -PDF is relevant only
at large Bjorken and the possibly large ratios 's are
always accompanied by universal phase space suppression factors. Our study
paves the way to using both schemes for the same process so to exploit their
complementary advantages for different observables, such as employing a
5-flavor scheme to accurately predict the total cross section at NNLO and the
corresponding 4-flavor computation at NLO for fully exclusive studies.Comment: Fixed typo in Eq. (A.10) and few typos in Eq. (C.2) and (C.3
Safety and efficacy of the hybrid approach in coronary chronic total occlusion percutaneous coronary intervention: The Hybrid Video Registry
Objectives
The aim of the Hybrid Video Registry (HVR) is to assess the acute safety and efficacy of the Hybrid Approach in comparison to other contemporary methods of CTO‐PCI. Background: Recently, multiple techniques in Percutaneous Coronary Intervention (PCI) for coronary Chronic Total Occlusions (CTO) have been synthesized into a method referred to as the “Hybrid Approach”.
Methods
About 194 video‐taped timed live cases from CTO‐PCI training workshops were analyzed by independent data abstractors and compared to three contemporary CTO‐PCI registries stratified by case complexity based on the J‐CTO score.
Results
Overall procedural success was 95% of all cases attempted with an excellent safety profile. In the most complex lesion subset, which made up 45% of all HVR cases, success was 92.8%, which was significantly higher than either the Royal Bromptom (78.9%), or Japanese‐CTO (73.3%) registries, P = 0.04 Hybrid vs. Royal Brompton, P = 0.006 Hybrid vs. Japanese‐CTO). The Hybrid Approach was also associated with shorter procedure times and lower contrast utilization.
Conclusions
In a real world angiographic registry of complex CTOs, the Hybrid Approach to CTO‐PCI is safe, and may be superior to other contemporary approaches to CTO intervention with respect to procedural success and efficiency among a diverse group of operators and lesion complexity
First Detection of Mycobacterium ulcerans DNA in Environmental Samples from South America
The occurrences of many environmentally-persistent and zoonotic infections are driven by ecosystem changes, which in turn are underpinned by land-use modifications that alter the governance of pathogen, biodiversity and human interactions. Our current understanding of these ecological changes on disease emergence however remains limited. Buruli ulcer is an emerging human skin disease caused by the mycobacterium, Mycobacterium ulcerans, for which the exact route of infection remains unclear. It can have a devastating impact on its human host, causing extensive necrosis of the skin and underlying tissue, often leading to permanent disability. The mycobacterium is associated with tropical aquatic environments and incidences of the disease are significantly higher on floodplains and where there is an increase of human aquatic activities. Although the disease has been previously diagnosed in South America, until now the presence of M. ulcerans DNA in the wild has only been identified in Australia where there have been significant outbreaks and in western and central regions of Africa where the disease is persistent. Here for the first time, we have identified the presence of the aetiological agent's DNA in environmental samples from South America. The DNA was positively identified using Real-time Polymerase Chain Reaction (PCR) on 163 environmental samples, taken from 23 freshwater bodies in French Guiana (Southern America), using primers for both IS2404 and for the ketoreductase-B domain of the M. ulcerans mycolactone polyketide synthase genes (KR). Five samples out of 163 were positive for both primers from three different water bodies. A further nine sites had low levels of IS2404 close to a standard CT of 35 and could potentially harbour M. ulcerans. The majority of our positive samples (8/14) came from filtered water. These results also reveal the Sinnamary River as a potential source of infection to humans. © 2014 Morris et al
The developmental dynamics of terrorist organizations
We identify robust statistical patterns in the frequency and severity of
violent attacks by terrorist organizations as they grow and age. Using
group-level static and dynamic analyses of terrorist events worldwide from
1968-2008 and a simulation model of organizational dynamics, we show that the
production of violent events tends to accelerate with increasing size and
experience. This coupling of frequency, experience and size arises from a
fundamental positive feedback loop in which attacks lead to growth which leads
to increased production of new attacks. In contrast, event severity is
independent of both size and experience. Thus larger, more experienced
organizations are more deadly because they attack more frequently, not because
their attacks are more deadly, and large events are equally likely to come from
large and small organizations. These results hold across political ideologies
and time, suggesting that the frequency and severity of terrorism may be
constrained by fundamental processes.Comment: 28 pages, 8 figures, 4 tables, supplementary materia
Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction
Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin
Pelvic tenderness is not limited to the prostate in chronic prostatitis/chronic pelvic pain syndrome (CPPS) type IIIA and IIIB: comparison of men with and without CP/CPPS
Background: We wished to determine if there were differences in pelvic and non-pelvic tenderness between men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) Type III and men without pelvic pain.
Methods: We performed the Manual Tender Point Survey (MTPS) as described by the American College of Rheumatology on 62 men with CP/CPPS Type IIIA and IIIB and 98 men without pelvic pain. We also assessed tenderness of 10 external pelvic tender points (EPTP) and of 7 internal
pelvic tender points (IPTP). All study participants completed the National Institutes of Health Chronic Prostatitis Symptom Inventory (NIH CPSI).
Results: We found that men with CPPS were significantly more tender in the MTPS, the EPTPS and the IPTPS. CPSI scores correlated with EPTP scale but not with IPTP scale or prostate tenderness. Prostatic tenderness was present in 75% of men with CPPS and in 50% of men without
CPPS. Expressed prostatic fluid leukocytosis was not associated with prostatic tenderness.
Conclusion: Men with CP/CPPS have more tenderness compared to men without CPPS. Tenderness in men with CPPS is distributed throughout the pelvis and not specific to the prostate
The remnants of galaxy formation from a panoramic survey of the region around M31
In hierarchical cosmological models, galaxies grow in mass through the
continual accretion of smaller ones. The tidal disruption of these systems is
expected to result in loosely bound stars surrounding the galaxy, at distances
that reach times the radius of the central disk. The number,
luminosity and morphology of the relics of this process provide significant
clues to galaxy formation history, but obtaining a comprehensive survey of
these components is difficult because of their intrinsic faintness and vast
extent. Here we report a panoramic survey of the Andromeda galaxy (M31). We
detect stars and coherent structures that are almost certainly remnants of
dwarf galaxies destroyed by the tidal field of M31. An improved census of their
surviving counterparts implies that three-quarters of M31's satellites brighter
than await discovery. The brightest companion, Triangulum (M33), is
surrounded by a stellar structure that provides persuasive evidence for a
recent encounter with M31. This panorama of galaxy structure directly confirms
the basic tenets of the hierarchical galaxy formation model and reveals the
shared history of M31 and M33 in the unceasing build-up of galaxies.Comment: Published in Nature. Supplementary movie available at
https://www.astrosci.ca/users/alan/PANDAS/Latest%20news%3A%20movie%20of%20orbit.htm
Partitioning of Minimotifs Based on Function with Improved Prediction Accuracy
Background: Minimotifs are short contiguous peptide sequences in proteins that are known to have a function in at least one other protein. One of the principal limitations in minimotif prediction is that false positives limit the usefulness of this approach. As a step toward resolving this problem we have built, implemented, and tested a new data-driven algorithm that reduces false-positive predictions. Methodology/Principal Findings: Certain domains and minimotifs are known to be strongly associated with a known cellular process or molecular function. Therefore, we hypothesized that by restricting minimotif predictions to those where the minimotif containing protein and target protein have a related cellular or molecular function, the prediction is more likely to be accurate. This filter was implemented in Minimotif Miner using function annotations from the Gene Ontology. We have also combined two filters that are based on entirely different principles and this combined filter has a better predictability than the individual components. Conclusions/Significance: Testing these functional filters on known and random minimotifs has revealed that they are capable of separating true motifs from false positives. In particular, for the cellular function filter, the percentage of known minimotifs that are not removed by the filter is,4.6 times that of random minimotifs. For the molecular function filter this ratio is,2.9. These results, together with the comparison with the published frequency score filter, strongly suggest tha
Clinical prediction models to support the diagnosis of asthma in primary care: a systematic review protocol
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