There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection ...(ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi‐array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one‐by‐one analysis strategy to model the real clinical application of this test. Multiple three‐way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction.
This study of kidney transplantation describes a three‐way classifier based on global gene expression profiling of peripheral blood and the blood signatures of patients with excellent functioning grafts that can be used in the setting of acute kidney transplant dysfunction to accurately distinguish between biopsy‐proven acute rejection and acute dysfunction with no rejection.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Libraries of 16S rRNA genes cloned from methanogenic oil degrading microcosms amended with North Sea crude oil and inoculated with estuarine sediment indicated that bacteria from the genera ...Smithella (Deltaproteobacteria, Syntrophaceace) and Marinobacter sp. (Gammaproteobacteria) were enriched during degradation. Growth yields and doubling times (36 days for both Smithella and Marinobacter) were determined using qPCR and quantitative data on alkanes, which were the predominant hydrocarbons degraded. The growth yield of the Smithella sp. 0.020 g(cell‐C)/g(alkane‐C), assuming it utilized all alkanes removed was consistent with yields of bacteria that degrade hydrocarbons and other organic compounds in methanogenic consortia. Over 450 days of incubation predominance and exponential growth of Smithella was coincident with alkane removal and exponential accumulation of methane. This growth is consistent with Smithella's occurrence in near surface anoxic hydrocarbon degrading systems and their complete oxidation of crude oil alkanes to acetate and/or hydrogen in syntrophic partnership with methanogens in such systems. The calculated growth yield of the Marinobacter sp., assuming it grew on alkanes, was 0.0005 g(cell‐C)/g(alkane‐C) suggesting that it played a minor role in alkane degradation. The dominant methanogens were hydrogenotrophs (Methanocalculus spp. from the Methanomicrobiales). Enrichment of hydrogen‐oxidizing methanogens relative to acetoclastic methanogens was consistent with syntrophic acetate oxidation measured in methanogenic crude oil degrading enrichment cultures. qPCR of the Methanomicrobiales indicated growth characteristics consistent with measured rates of methane production and growth in partnership with Smithella.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1‐year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological ...evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long‐term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty‐one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune‐mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.
In this multicenter study featuring gene expression profiles with matching demographic and long‐term follow‐ up data, the authors demonstrate that biopsies with interstitial fibrosis and tubular atrophy without alternative explanations for pathogenesis and regardless of histological reads with or without inflammation, have significantly worse graft survival than those with biopsy‐proven normal transplant histology and differential gene expression changes that indicate ongoing cellular immune‐mediated injury that correlate with worse long‐term outcomes. See Maluf et al's editorial on page 1947.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Biodegradation of crude oil in subsurface petroleum reservoirs has adversely affected the majority of the world's oil, making recovery and refining of that oil more costly. The prevalent occurrence ...of biodegradation in shallow subsurface petroleum reservoirs has been attributed to aerobic bacterial hydrocarbon degradation stimulated by surface recharge of oxygen-bearing meteoric waters. This hypothesis is empirically supported by the likelihood of encountering biodegraded oils at higher levels of degradation in reservoirs near the surface. More recent findings, however, suggest that anaerobic degradation processes dominate subsurface sedimentary environments, despite slow reaction kinetics and uncertainty as to the actual degradation pathways occurring in oil reservoirs. Here we use laboratory experiments in microcosms monitoring the hydrocarbon composition of degraded oils and generated gases, together with the carbon isotopic compositions of gas and oil samples taken at wellheads and a Rayleigh isotope fractionation box model, to elucidate the probable mechanisms of hydrocarbon degradation in reservoirs. We find that crude-oil hydrocarbon degradation under methanogenic conditions in the laboratory mimics the characteristic sequential removal of compound classes seen in reservoir-degraded petroleum. The initial preferential removal of n-alkanes generates close to stoichiometric amounts of methane, principally by hydrogenotrophic methanogenesis. Our data imply a common methanogenic biodegradation mechanism in subsurface degraded oil reservoirs, resulting in consistent patterns of hydrocarbon alteration, and the common association of dry gas with severely degraded oils observed worldwide. Energy recovery from oilfields in the form of methane, based on accelerating natural methanogenic biodegradation, may offer a route to economic production of difficult-to-recover energy from oilfields.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polycyclic aromatic compounds (PACs) are ubiquitous in the environment. Wildlife (including fish) are chronically exposed to PACs through air, water, sediment, soil, and/or dietary routes. Exposures ...are highest near industrial or urban sites, such as aluminum smelters and oil sands mines, or near natural sources such as forest fires. This review assesses the exposure and toxicity of PACs to wildlife, with a focus on the Canadian environment. Most published field studies measured PAC concentrations in tissues of invertebrates, fish, and birds, with fewer studies of amphibians and mammals. In general, PAC concentrations measured in Canadian wildlife tissues were under the benzoapyrene (BaP) guideline for human consumption. Health effects of PAC exposure include embryotoxicity, deformities, cardiotoxicity, DNA damage, changes to DNA methylation, oxidative stress, endocrine disruption, and impaired reproduction. Much of the toxicity of PACs can be attributed to their bioavailability, and the extent to which certain PACs are transformed into more toxic metabolites by cytochrome P450 enzymes. As most mechanistic studies are limited to individual polycyclic aromatic hydrocarbons (PAHs), particularly BaP, research on other PACs and PAC-containing complex mixtures is required to understand the environmental significance of PAC exposure and toxicity. Additional work on responses to PACs in amphibians, reptiles, and semi-aquatic mammals, and development of molecular markers for early detection of biological responses to PACs would provide a stronger biological and ecological justification for regulating PAC emissions to protect Canadian wildlife.
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•Most studies measured polycyclic aromatic compounds (PAC) in invertebrates and fish.•In general, PAC concentrations in Canadian wildlife tissue were below guidelines.•Mechanisms of PAC toxicity are similar among species but some unique effects exist.•Best to measure biological effects with environmental and tissue PAC exposure.
This paper reviews literature on the exposure and effects of PACs on wildlife and ecosystems, with a special focus on Canadian invertebrates, fish, amphibians, reptiles, birds, and small mammals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This prospective study is, to our knowledge, the first report of daily adaptive radiation therapy (ART) for head and neck cancer (HNC) using a 1.5T magnetic resonance imaging-linear accelerator ...(MR-linac) with particular focus on safety and feasibility and dosimetric results of an online rigid registration-based adapt to position (ATP) workflow.
Ten patients with HNC received daily ART on a 1.5T/7MV MR-linac, 6 using ATP only and 4 using ATP with 1 offline adapt-to-shape replan. Setup variability with custom immobilization masks was assessed by calculating the mean systematic error (M), standard deviation of the systematic error (Σ), and standard deviation of the random error (σ) of the isocenter shifts. Quality assurance was performed with a cylindrical diode array using 3%/3 mm γ criteria. Adaptive treatment plans were summed for each patient to compare the delivered dose with the planned dose from the reference plan. The impact of dosimetric variability between adaptive fractions on the summation plan doses was assessed by tracking the number of optimization constraint violations at each individual fraction.
The random errors (mm) for the x, y, and z isocenter shifts, respectively, were M = –0.3, 0.7, 0.1; Σ = 3.3, 2.6, 1.4; and σ = 1.7, 2.9, 1.0. The median (range) γ pass rate was 99.9% (90.9%-100%). The differences between the reference and summation plan doses were –0.61% to 1.78% for the clinical target volume and –11.74% to 8.11% for organs at risk (OARs), although an increase greater than 2% in OAR dose only occurred in 3 cases, each for a single OAR. All cases had at least 2 fractions with 1 or more constraint violations. However, in nearly all instances, constraints were still met in the summation plan despite multiple single-fraction violations.
Daily ART on a 1.5T MR-linac using an online ATP workflow is safe and clinically feasible for HNC and results in delivered doses consistent with planned doses.
Rodent models of hypertension Jama, Hamdi A.; Muralitharan, Rikeish R.; Xu, Chudan ...
British journal of pharmacology,
March 2022, 2022-03-00, 20220301, Volume:
179, Issue:
5
Journal Article
Peer reviewed
Open access
Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension ...remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive‐pregnancy disorders, providing an important resource for researchers.
LINKED ARTICLES
This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
At temperatures up to about 80 degrees C, petroleum in subsurface reservoirs is often biologically degraded, over geological timescales, by microorganisms that destroy hydrocarbons and other ...components to produce altered, denser 'heavy oils'. This temperature threshold for hydrocarbon biodegradation might represent the maximum temperature boundary for life in the deep nutrient-depleted Earth. Most of the world's oil was biodegraded under anaerobic conditions, with methane, a valuable commodity, often being a major by-product, which suggests alternative approaches to recovering the world's vast heavy oil resource that otherwise will remain largely unproduced.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To automate the estimation of swallowing motion from 2D MR cine images using deformable registration for future applications of personalized margin reduction in head and neck radiotherapy and outcome ...assessment of radiation-associated dysphagia.
Twenty-one patients with serial 2D FSPGR-MR cine scans of the head and neck conducted through the course of definitive radiotherapy for oropharyngeal cancer. Included patients had at least one cine scan before, during, or after radiotherapy, with a total of 52 cine scans. Contours of 7 swallowing related regions-of-interest (ROIs), including pharyngeal constrictor, epiglottis, base of tongue, geniohyoid, hyoid, soft palate, and larynx, were manually delineated from consecutive frames of the cine scan covering at least one swallowing cycle. We applied a modified thin-plate-spline robust-point-matching algorithm to register the point sets of each ROI automatically over frames. The deformation vector fields from the registration were then used to estimate the motion during swallowing for each ROI. Registration errors were estimated by comparing the deformed contours with the manual contours.
On average 22 frames of each cine scan were contoured. The registration for one cine scan (7 ROIs over 22 frames) on average took roughly 22 minutes. A number of 8018 registrations were successfully batch processed without human interaction after the contours were drawn. The average registration error for all ROIs and all patients was 0.36 mm (range: 0.06 mm- 2.06 mm). Larynx had the average largest motion in superior direction of all structures under consideration (range: 0.0 mm- 58.7 mm). Geniohyoid had the smallest overall motion of all ROIs under consideration and the superior-inferior motion was larger than the anterior-posterior motion for all ROIs.
We developed and validated a deformable registration framework to automate the estimation of swallowing motion from 2D MR cine scans.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Radiomics is one such "big data" approach that applies advanced image refining/data characterization algorithms to generate imaging features that can quantitatively classify tumor phenotypes in a ...non-invasive manner. We hypothesize that certain textural features of oropharyngeal cancer (OPC) primary tumors will have statistically significant correlations to patient outcomes such as local control. Patients from an IRB-approved database dispositioned to (chemo)radiotherapy for locally advanced OPC were included in this retrospective series. Pretreatment contrast CT scans were extracted and radiomics-based analysis of gross tumor volume of the primary disease (GTVp) were performed using imaging biomarker explorer (IBEX) software that runs in Matlab platform. Data set was randomly divided into a training dataset and test and tuning holdback dataset. Machine learning methods were applied to yield a radiomic signature consisting of features with minimal overlap and maximum prognostic significance. The radiomic signature was adapted to discriminate patients, in concordance with other key clinical prognosticators. 465 patients were available for analysis. A signature composed of 2 radiomic features from pre-therapy imaging was derived, based on the Intensity Direct and Neighbor Intensity Difference methods. Analysis of resultant groupings showed robust discrimination of recurrence probability and Kaplan-Meier-estimated local control rate (LCR) differences between "favorable" and "unfavorable" clusters were noted.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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