Accumulation of anthropogenic litter (i.e. garbage; AL) and its ecosystem effects in marine environments are well documented. Rivers receive AL from terrestrial habitats and represent a major source ...of AL to marine environments, but AL is rarely studied within freshwater ecosystems. Our objectives were to 1) quantify AL density in urban freshwaters, 2) compare AL abundance among freshwater, terrestrial, and marine ecosystems, and 3) characterize the activity and composition of AL biofilms in freshwater habitats. We quantified AL from the Chicago River and Chicago's Lake Michigan shoreline, and found that AL abundance in Chicago freshwater ecosystems was comparable to previously reported data for marine and terrestrial ecosystems, although AL density and composition differed among habitats. To assess microbial interactions with AL, we incubated AL and natural substrates in 3 freshwater ecosystems, quantified biofilm metabolism as gross primary production (GPP) and community respiration (CR), and characterized biofilm bacterial community composition via high-throughput sequencing of 16S rRNA genes. The main driver of biofilm community composition was incubation location (e.g., river vs pond), but there were some significant differences in biofilm composition and metabolism among substrates. For example, biofilms on organic substrates (cardboard and leaves) had lower GPP than hard substrates (glass, plastic, aluminum and tiles). In addition, bacterial communities on organic substrates were distinct in composition from those on hard substrates, with higher relative abundances of bacteria associated with cellulose decomposition. Finally, we used our results to develop a conceptual diagram designed to unite the study of AL in terrestrial and freshwater environments with the well-established field of marine debris research. We suggest this broad perspective will be useful for future studies which synthesize AL sources, ecosystem effects, and fate across multiple ecosystem types, and will benefit management and reduction of global AL accumulations.
Kawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate ...gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment.
Deep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD.
T lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis.
The immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies.
We hypothesized that cardiovascular miRNAs might be diagnostic biomarkers for Kawasaki disease (KD). We identified dysregulated miRNAs in KD coronary arteries, and tested sera from KD patients and ...febrile controls for cardiovascular miRNAs using 2 methods. We did not identify cardiovascular miRNAs diagnostic for KD; our results may help guide future studies of potential miRNA biomarkers for KD.
Abstract
Background
Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is ...closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses.
Methods
Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation.
Results
Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation.
Conclusions
Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.
Background
The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over ...32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator’s Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16.
Objective
This post hoc analysis investigated the impact of tralokinumab plus TCS on atopic dermatitis (AD) severity, symptoms, and health-related quality of life (QoL) over the entire 32-week treatment period of ECZTRA 3, including all patients initiated on tralokinumab irrespective of the response achieved at Week 16.
Methods
Patients were randomized 2:1 to receive subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) with TCS as needed for an initial 16 weeks. At Week 16, patients who achieved the clinical response criteria (IGA 0/1 and/or EASI-75) with tralokinumab were re-randomized 1:1 to tralokinumab q2w or every 4 weeks (q4w), with TCS as needed, for another 16 weeks. Patients not achieving the clinical response criteria with tralokinumab received tralokinumab q2w plus TCS from Week 16. All patients randomized to tralokinumab in the initial treatment period were pooled for this analysis, irrespective of response at Week 16 or dosing regimen beyond Week 16.
Results
Continued tralokinumab (q2w,
N
= 164; q4w,
N
= 69) plus TCS treatment provided progressive improvements from Week 16 onwards in AD signs, with 70.2% (177/252) of patients achieving EASI-75 and 50.4% (127/252) achieving EASI-90 at Week 32. Improvements in patient-reported outcomes were observed within the first few weeks of tralokinumab q2w plus TCS treatment and were sustained throughout the 32-week period. At Week 32, patients initiated on tralokinumab q2w plus TCS achieved a relative improvement versus baseline of 70.8% (standard error (SE), 2.4) in eczema-related sleep interference numeric rating scale (NRS) and 66.8% (SE, 3.1) in Dermatology Life Quality Index (DLQI). Mean TCS use during Weeks 16–32 ranged from 9.2 to 13.6 g (SE, 1.2–2.0) q2w. Most patients (89.9% (222/247)) initiated on tralokinumab q2w plus TCS achieved a meaningful improvement in at least one of the three disease domains, including AD signs (EASI-50), symptoms (pruritus NRS improvement ≥ 3), and QoL (DLQI improvement ≥ 4) at Week 16. Of patients initiated on tralokinumab q2w plus TCS, 53.4% (132/247) achieved a clinically meaningful improvement in all three domains at Week 16 (vs. placebo, 28.5% (35/123);
p
< 0.001).
Conclusions
Continued tralokinumab treatment plus TCS as needed provides progressive and sustained improvements in AD signs, symptoms, and health-related QoL over 32 weeks.
Clinical trial registration
NCT03363854; study start date: 22 February 2018; primary completion date: 8 March 2019; study completion date: 26 September 2019.
Infographic
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Video abstract:
What is the impact of tralokinumab plus topical corticosteroids in adults with moderate-to-severe atopic dermatitis over 32 weeks? (MP4 216,988 KB)
Plain Language Summary: Treatment with tralokinumab plus topical corticosteroids provided continued improvements over a 32-week study period
Atopic dermatitis (AD) is a chronic inflammatory disease that causes excessively dry and itchy skin that can negatively impact sleep and overall quality of life for patients. Topical corticosteroids (TCS) are the most common medication used for AD, but they are not able to control the most severe cases. Tralokinumab is a treatment injected under the skin that targets an immune messenger protein called interleukin 13, which plays a key role in driving the signs and symptoms of AD. The ECZTRA 3 clinical trial, funded by LEO Pharma, compared the use of TCS as needed with either tralokinumab or placebo in over 350 adult patients with moderate-to-severe AD over a 32-week period. After 16 weeks, more patients taking tralokinumab plus TCS had clear or almost clear skin compared with patients taking placebo plus TCS. Patients taking tralokinumab also used less TCS than patients taking placebo. In new analyses presented here, we found that the proportion of patients with clear or almost clear skin continued to increase with on-going treatment from Week 16 to Week 32. Tralokinumab plus TCS treatment also led to clinically meaningful improvements in outcomes important to patients, including itch, sleep, and quality of life. Improvements occurred early, within the first few weeks of therapy, and lasted through Week 32. Our assessment of multiple outcomes over time clearly demonstrates the positive impact of tralokinumab on different aspects of AD.
In 2017, in addition to the traditional, old, and more recently established political parties, a new formation – the Czech Pirate Party – espousing more participative principles, including the use of ...online platforms for discussions – arrived on the political scene in the Czech Republic. This newcomer to the parliamentary ecosystem, shortly after achieving success at the national level, also managed to attract significant support in local elections. For this reason, there is currently a Pirate Party parliamentary group present in the Chamber of Deputies (the lower chamber of the Czech parliament), while simultaneously the mayor of Prague and members of the ruling coalition in Brno – the second biggest city in the Czech Republic – also represent the Pirate Party. Furthermore, recent opinion polls show support for the Pirates running at about 14%. This is coupled with another new feature: the young age of the party’s elected parliamentarians and local councilors, which brings new challenges to politics. After the elections, a number of commentators immediately dubbed the Pirate Party a ‘youth party.’ But is this really the case? What forms of participation do the party and/or its members use and encourage? This article offers answers to these questions. In particular, it presents the electoral base of this new political party through interpretative analysis. The data are based on election results triangulated with other sources – specifically, a Czech election study is juxtaposed against a quantitative survey carried out by three academic institutions in the Czech Republic (the Faculty of Social Studies at Masaryk University, Brno; Palacký University, Olomouc; and the Institute of Sociology at the Czech Academy of Sciences, Prague). These statistical tools enable us to identify in great detail the demographic and socio-economic characteristics of Pirate Party voters (for instance: age, education, their views about contemporary democracy, and the timing of their decision to vote) and map their attitudes towards other parties and their leaders. The article reveals how popular the Czech Pirate Party is among the younger generation of voters, where the latter come from, and what political preferences they had previously.
Abstract Background Clear-cell renal cell carcinoma (ccRCC) exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing ...apoptosis. ccRCC resistance to therapy is driven by constitutive hypoxia-inducible factor (HIF) expression due to genetic loss of von Hippel-Lindau factor. In addition to promoting angiogenesis, HIF suppresses mitochondrial function by inducing pyruvate dehydrogenase kinase (PDK), a gatekeeping enzyme for mitochondrial glucose oxidation. Objective To reverse mitochondrial suppression of ccRCC using the PDK inhibitor dichloroacetate (DCA). Design, setting, and participants Radical nephrectomy specimens from patients with ccRCC were assessed for PDK expression. The 786-O ccRCC line and two animal models (chicken in ovo and murine xenografts) were used for mechanistic studies. Outcome measurements and statistical analysis Mitochondrial function, proliferation, apoptosis, HIF transcriptional activity, angiogenesis, and tumor size were measured in vitro and in vivo. Independent-sample t -tests and analysis of variance were used for statistical analyses. Results PDK was elevated in 786-O cells and in ccRCC compared to normal kidney tissue from the same patient. DCA reactivated mitochondrial function (increased respiration, Krebs cycle metabolites such as α-ketoglutarate cofactor of factor inhibiting HIF, and mitochondrial reactive oxygen species), increased p53 activity and apoptosis, and decreased proliferation in 786-O cells. DCA reduced HIF transcriptional activity in an FIH-dependent manner, inhibiting angiogenesis in vitro. DCA reduced tumor size and angiogenesis in vivo in both animal models. Conclusions DCA can reverse the mitochondrial suppression of ccRCC and decrease HIF transcriptional activity, bypassing its constitutive expression. Its previous clinical use in humans makes it an attractive candidate for translation to ccRCC patients. Patient summary We show that an energy-boosting drug decreases tumor growth and tumor blood vessels in animals carrying human kidney cancer cells. This generic drug has been used in patients for other conditions and thus could be tested in kidney cancer that remains incurable.
Key message
We demonstrate genetic variation for quantitative resistance against important fungal pathogens in lettuce and its wild relatives, map loci conferring resistance and predict key molecular ...mechanisms using transcriptome profiling.
Lactuca sativa
L. (lettuce) is an important leafy vegetable crop grown and consumed globally. Chemicals are routinely used to control major pathogens, including the causal agents of grey mould (
Botrytis cinerea
) and lettuce drop (
Sclerotinia sclerotiorum
)
.
With increasing prevalence of pathogen resistance to fungicides and environmental concerns, there is an urgent need to identify sources of genetic resistance to
B. cinerea
and
S. sclerotiorum
in lettuce. We demonstrated genetic variation for quantitative resistance to
B. cinerea
and
S. sclerotiorum
in a set of 97 diverse lettuce and wild relative accessions, and between the parents of lettuce mapping populations. Transcriptome profiling across multiple lettuce accessions enabled us to identify genes with expression correlated with resistance, predicting the importance of post-transcriptional gene regulation in the lettuce defence response. We identified five genetic loci influencing quantitative resistance in a
F
6
mapping population derived from a
Lactuca serriola
(wild relative) × lettuce cross, which each explained 5–10% of the variation. Differential gene expression analysis between the parent lines, and integration of data on correlation of gene expression and resistance in the diversity set, highlighted potential causal genes underlying the quantitative trait loci.
Background
There is an unmet clinical need for minimally invasive diagnostic tests to improve the detection of grade group (GG) ≥3 prostate cancer relative to prostate antigen‐specific risk ...calculators. We determined the accuracy of the blood‐based extracellular vesicle (EV) biomarker assay (EV Fingerprint test) at the point of a prostate biopsy decision to predict GG ≥3 from GG ≤2 and avoid unnecessary biopsies.
Methods
This study analyzed 415 men referred to urology clinics and scheduled for a prostate biopsy, were recruited to the APCaRI 01 prospective cohort study. The EV machine learning analysis platform was used to generate predictive EV models from microflow data. Logistic regression was then used to analyze the combined EV models and patient clinical data and generate the patients' risk score for GG ≥3 prostate cancer.
Results
The EV‐Fingerprint test was evaluated using the area under the curve (AUC) in discrimination of GG ≥3 from GG ≤2 and benign disease on initial biopsy. EV‐Fingerprint identified GG ≥3 cancer patients with high accuracy (0.81 AUC) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cutoff, 95% of men with GG ≥3 would have been recommended a biopsy while avoiding 144 unnecessary biopsies (35%) and missing four GG ≥3 cancers (5%). Conversely, a 5% cutoff would have avoided 31 unnecessary biopsies (7%), missing no GG ≥3 cancers (0%).
Conclusions
EV‐Fingerprint accurately predicted GG ≥3 prostate cancer and would have significantly reduced unnecessary prostate biopsies.
We developed an accurate diagnostic blood test for grade group (GG) ≥3 prostate cancer that comprises the generation of a microflow cytometry dataset of three prostate cancer extracellular vesicle (EV) biomarkers, analysis with a novel machine learning algorithm to generate predictive EV models, and logistic regression analysis of these models with patient clinical data to calculate the risk score for the probability of GG ≥3 prostate cancer.
Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of ...3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.
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