The complex MR imaging appearance of glioblastoma is a function of underlying histopathologic heterogeneity. A better understanding of these correlations, particularly the influence of infiltrating ...glioma cells and vasogenic edema on T2 and diffusivity signal in nonenhancing areas, has important implications in the management of these patients. With localized biopsies, the objective of this study was to generate a model capable of predicting cellularity at each voxel within an entire tumor volume as a function of signal intensity, thus providing a means of quantifying tumor infiltration into surrounding brain tissue.
Ninety-one localized biopsies were obtained from 36 patients with glioblastoma. Signal intensities corresponding to these samples were derived from T1-postcontrast subtraction, T2-FLAIR, and ADC sequences by using an automated coregistration algorithm. Cell density was calculated for each specimen by using an automated cell-counting algorithm. Signal intensity was plotted against cell density for each MR image.
T2-FLAIR (
= -0.61) and ADC (
= -0.63) sequences were inversely correlated with cell density. T1-postcontrast (
= 0.69) subtraction was directly correlated with cell density. Combining these relationships yielded a multiparametric model with improved correlation (
= 0.74), suggesting that each sequence offers different and complementary information.
Using localized biopsies, we have generated a model that illustrates a quantitative and significant relationship between MR signal and cell density. Projecting this relationship over the entire tumor volume allows mapping of the intratumoral heterogeneity in both the contrast-enhancing tumor core and nonenhancing margins of glioblastoma and may be used to guide extended surgical resection, localized biopsies, and radiation field mapping.
Very little is currently known about the effects of acute hamstring injury on over-ground sprinting mechanics. The aim of this research was to describe changes in power-force-velocity properties of ...sprinting in two injury case studies related to hamstring strain management: Case 1: during a repeated sprint task (10 sprints of 40 m) when an injury occurred (5th sprint) in a professional rugby player; and Case 2: prior to (8 days) and after (33 days) an acute hamstring injury in a professional soccer player. A sports radar system was used to measure instantaneous velocity-time data, from which individual mechanical profiles were derived using a recently validated method based on a macroscopic biomechanical model. Variables of interest included: maximum theoretical velocity (V
0
) and horizontal force (F
H0
), slope of the force-velocity (F-v) relationship, maximal power, and split times over 5 and 20 m. For Case 1, during the injury sprint (sprint 5), there was a clear change in the F-v profile with a 14% greater value of F
H0
(7.6-8.7 N/kg) and a 6% decrease in V
0
(10.1 to 9.5 m/s). For Case 2, at return to sport, the F-v profile clearly changed with a 20.5% lower value of F
H0
(8.3 vs. 6.6 N/kg) and no change in V
0.
The results suggest that the capability to produce horizontal force at low speed (F
H0
) (i.e. first metres of the acceleration phase) is altered both before and after return to sport from a hamstring injury in these two elite athletes with little or no change of maximal velocity capabilities (V
0
), as evidenced in on-field conditions. Practitioners should consider regularly monitoring horizontal force production during sprint running both from a performance and injury prevention perspective.
Moa eggshell fragments from 13 North Island sites (New Zealand), were 0.54-1.74 mm thick (n = 6036). Thicknesses with published DNA-identifications overlapped greatly between the four North Island ...species, but median thicknesses were separate: Pachyornis geranoides thinnest, Dinornis novaezealandiae thickest, and Euryapteryx curtus and Anomalopteryx didiformis in the middle, but with the former slightly thinner. Thickness histograms for regional samples of unidentified moa eggshell fragments, each had one of four thickness patterns: Type A (thin eggshell only), Type B (thick eggshell only), Type C (medium-thickness eggshell only), and Type D (all thicknesses present). The Gisborne site, poorly-known from moa bones, had a similar thickness profile (Type D, skewed towards thin shell) to North Cape and Tokerau Beach implying a similar moa fauna. Eggshell thicknesses suggested that D. novaezealandiae was absent at Port Jackson (Type A histogram) and that P. geranoides was absent at Whananaki (Type B pattern) and rare at Herbertville (Type D, skewed towards thick shell). Thickness analysis for eggshell from a Lake Taupo archaeological site suggested that few eggs of just one species were involved, whereas a wide spread of shell thicknesses for a Great Mercury Island site implied a contribution from several species.
African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African ...American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Linking foraging and breeding habitats is key to the understanding of behaviour, ecology and demography of migratory species. Establishing such connections has long been hampered by the logistical ...problems of following individuals between foraging and breeding areas, especially in the marine realm. We used variation in nitrogen stable isotope patterns between 2 foraging regions of loggerhead sea turtlesCaretta carettadetermined from samples of satellite-tracked individuals to assign untracked turtles to a foraging region. We sought to enhance determination of the relative importance of geographically separated foraging regions and to investigate the relationship between fitness correlates and inferred migratory strategies. Of 18 turtles followed by satellite tracking from Zakynthos (Greece), 10 moved north to foraging areas in the Adriatic Sea and the Gulf of Amvrakikos and 8 moved south to foraging areas off the coast of North Africa. Of 51 untracked individuals sampled for stable isotope analysis, we considered the stable isotope signature of 47 to qualify for assignment to foraging areas in the north (n = 22) and south (n = 25). Females foraging north were significantly larger (curved carapace length), and the former group laid larger clutches (even after correction for body length) than turtles foraging south, a fact that can be interpreted as a carry-over effect. Combining satellite tracking with stable isotope signatures in marine turtles opens new perspectives into how forensic tracking methodologies may be used to scale up knowledge from electronic tracking of a limited number of individuals to sample sizes that are more meaningful from a population perspective.
The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of ...compounds that selectively inhibit mTORC1 and not mTORC2. These ‘bi-steric inhibitors’ comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.Design of a bivalent inhibitor containing an ATP-competitive moiety and rapamycin-modified FRB binding ligand that selectively inhibits mTORC1 results in potent and durable inhibition of 4EBP1 phosphorylation and cell proliferation in vitro and in vivo.
Malignant glioma is a highly infiltrative malignancy that causes variable disruptions to the structure and function of the cerebrovasculature. While many of these structural disruptions have known ...correlative histopathologic alterations, the mechanisms underlying vascular dysfunction identified by resting-state blood oxygen level-dependent imaging are not yet known. The purpose of this study was to characterize the alterations that correlate with a blood oxygen level-dependent biomarker of vascular dysregulation.
Thirty-two stereotactically localized biopsies were obtained from contrast-enhancing (
= 16) and nonenhancing (
= 16) regions during open surgical resection of malignant glioma in 17 patients. Preoperative resting-state blood oxygen level-dependent fMRI was used to evaluate the relationships between radiographic and histopathologic characteristics. Signal intensity for a blood oxygen level-dependent biomarker was compared with scores of tumor infiltration and microvascular proliferation as well as total cell and neuronal density.
Biopsies corresponded to a range of blood oxygen level-dependent signals, ranging from relatively normal (
= -4.79) to markedly abnormal (
= 8.84). Total cell density was directly related to blood oxygen level-dependent signal abnormality (
= .013,
= 0.19), while the neuronal labeling index was inversely related to blood oxygen level-dependent signal abnormality (
= .016,
= 0.21). The blood oxygen level-dependent signal abnormality was also related to tumor infiltration (
= .014) and microvascular proliferation (
= .045).
The relationship between local, neoplastic characteristics and a blood oxygen level-dependent biomarker of vascular function suggests that local effects of glioma cell infiltration contribute to vascular dysregulation.
Food systems are associated with severe and persistent problems worldwide. Governance approaches aiming to foster sustainable transformation of food systems face several challenges due to the complex ...nature of food systems.
In this commentary we argue that addressing these governance challenges requires the development and adoption of novel research and innovation (R&I) approaches that will provide evidence to inform food system transformation and will serve as catalysts for change. We first elaborate on the complexity of food systems (transformation) and stress the need to move beyond traditional linear R&I approaches to be able to respond to persistent problems that affect food systems. Though integrated transdisciplinary approaches are promising, current R&I systems do not sufficiently support such endeavors. As such, we argue, we need strategies that trigger a double transformation – of food systems and of their R&I systems.
Seizing the opportunities to transform R&I systems has implications for how research is done – pointing to the need for competence development among researchers, policy makers and society in general – and requires specific governance interventions that stimulate a systemic approach. Such interventions should foster transdisciplinary and transformative research agendas that stimulate portfolios of projects that will reinforce one another, and stimulate innovative experiments to shape conditions for systemic change. In short, a thorough rethinking of the role of R&I as well as how it is funded is a crucial step towards the development of the integrative policies that are necessary to engender systemic change – in the food system and beyond.
•Research and Innovation (R&I) could be a catalyst for food system transformation.•This requires stimulation of transformative and transdisciplinary R&I approaches.•Current conventional R&I systems do not support such R&I approaches.•Thus, we need strategies that trigger transformation of both food and R&I systems.•This has implications for research practice and requires governance interventions.
The most common reasons for revision of unicompartmental knee arthroplasty (UKA) are loosening and pain. Cementless components may reduce the revision rate. The aim of this study was to compare the ...fixation and clinical outcome of cementless and cemented Oxford UKAs. A total of 43 patients were randomised to receive either a cemented or a cementless Oxford UKA and were followed for two years with radiostereometric analysis (RSA), radiographs aligned with the bone-implant interfaces and clinical scores. The femoral components migrated significantly during the first year (mean 0.2 mm) but not during the second. There was no significant difference in the extent of migration between cemented and cementless femoral components in either the first or the second year. In the first year the cementless tibial components subsided significantly more than the cemented components (mean 0.28 mm (sd 0.17) vs. 0.09 mm (sd 0.19 mm)). In the second year, although there was a small amount of subsidence (mean 0.05 mm) there was no significant difference (p = 0.92) between cemented and cementless tibial components. There were no femoral radiolucencies. Tibial radiolucencies were narrow (< 1 mm) and were significantly (p = 0.02) less common with cementless (6 of 21) than cemented (13 of 21) components at two years. There were no complete radiolucencies with cementless components, whereas five of 21 (24%) cemented components had complete radiolucencies. The clinical scores at two years were not significantly different (p = 0.20). As second-year migration is predictive of subsequent loosening, and as radiolucency is suggestive of reduced implant-bone contact, these data suggest that fixation of the cementless components is at least as good as, if not better than, that of cemented devices.
1. Planning for nature conservation has increasingly emphasised the concepts of resilience and spatial networks. Although the importance of habitat networks for individual species is clear, their ...significance for long-term ecological resilience and multi-species conservation strategies is less established. 2. Referencing spatial network theory, we describe the conceptual basis for defining and assessing a network of wildlife areas that supports species' resilience to multiple forms of perturbations and pressures. We explore actions that could enhance network resilience at a range of scales, based on ecological principles, with reference to four well-established strategies for intervention in a spatial network ("Better, Bigger, More and Joined") from the influential Making Space for Nature report by Lawton et al. (2010). 3. Building existing theory into useable and scalable approaches applicable to large numbers of species is challenging but tractable. We illustrate the policy context, describe the elements of a long-term adaptive management plan and provide example actions, metrics and targets for early implementation using England as a case study, where there is an opportunity to include large-scale ecological planning in a newly launched 25-year environment plan. 4. Policy implications. The concept of resilient ecological networks has attracted sc entific and political support, but there is no consensus on what a resilient network would look like, or how to assess it. Therefore, it is unclear whether existing targets for action will be sufficient to achieve network resilience. We show that the scientific principles to place resilience and network theory at the heart of largescale and long-term environmental planning are established and ready to implement in practice. Delivering a resilient network to support nature recovery is achievable and can be integrated with ongoing conservation actions and targets, by assessing their effectiveness on properties of the entire network. England's 25 Year Environment Plan promises to deliver a natural environment that is protected and enhanced for the future and so provides the ideal testbed.
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