59 research outputs found

    Chemokine receptors coordinately regulate macrophage dynamics and mammary gland development

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    Macrophages are key regulators of developmental processes, including those involved in mammary gland development. We previously demonstrated that the atypical chemokine receptor, ACKR2, contributes to control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor, which mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here we reveal reciprocal regulation of branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition, estrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets

    Milk yield, milk composition, and milk metabolomics of dairy goats intramammary-challenged with lipopolysaccharide under heat stress conditions

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    Heat stress and mastitis are major economic issues in dairy production. The objective was to test whether goat's mammary gland immune response to E. coli lipopolysaccharide (LPS) could be conditioned by heat stress (HS). Changes in milk composition and milk metabolomics were evaluated after the administration of LPS in mammary glands of dairy goats under thermal-neutral (TN; n = 4; 15 to 20 °C; 40 to 45% humidity) or HS (n = 4; 35 °C day, 28 °C night; 40% humidity) conditions. Milk metabolomics were evaluated using 1H nuclear magnetic resonance spectroscopy, and multivariate analyses were carried out. Heat stress reduced feed intake and milk yield by 28 and 21%, respectively. Mammary treatment with LPS resulted in febrile response that was detectable in TN goats, but was masked by elevated body temperature due to heat load in HS goats. Additionally, LPS increased milk protein and decreased milk lactose, with more marked changes in HS goats. The recruitment of somatic cells in milk after LPS treatment was delayed by HS. Milk metabolomics revealed that citrate increased by HS, whereas choline, phosphocholine, N-acetylcarbohydrates, lactate, and ß-hydroxybutyrate could be considered as putative markers of inflammation with different pattern according to the ambient temperature (i.e. TN vs. HS). In conclusion, changes in milk somatic cells and milk metabolomics indicated that heat stress affected the mammary immune response to simulated infection, which could make dairy animals more vulnerable to mastitis

    Optimising triage of urgent referrals for suspected IBD: results from the Birmingham IBD inception study

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    Objective: Diagnostic delays in inflammatory bowel disease (IBD) result in adverse outcomes. We report a bespoke diagnostic pathway to assess how best to combine clinical history and faecal calprotectin (FCP) for early diagnosis and efficient resource utilisation. Methods: A rapid-access pathway was implemented for suspected IBD patients referred outside urgent ‘two-week wait’ criteria. Patients were triaged using symptoms and FCP. A 13-point symptom history was taken prediagnosis and clinical indices, including repeat FCP, collected prospectively. Results: Of 767 patients (January 2021–August 2023), 423 were diagnosed with IBD (208 Crohn’s disease (CD), 215 ulcerative colitis (UC)). Most common symptoms in CD were abdominal pain (84%), looser stools (84%) and fatigue (79%) and in UC per-rectal bleeding (94%), urgency (82%) and looser stools (81%). Strongest IBD predictors were blood mixed with stools (CD OR 4.38; 95% CI 2.40–7.98, UC OR 33.68; 15.47–73.33) and weight loss (CD OR 3.39; 2.14–5.38, UC OR 2.33; 1.37–4.00). Repeat FCP testing showed reduction from baseline in non-IBD. Both measurements >100 µg/g (area under the curve (AUC) 0.800) and >200 µg/g (AUC 0.834) collectively predicted IBD. However, a second value ≥220 µg/g considered alone, regardless of the first result, was more accurate (Youden’s index 0.735, AUC 0.923). Modelling symptoms with FCP increased AUC to 0.947. Conclusion: Serial FCP measurement prevents unnecessary colonoscopy. Two FCPs >200 µg/g could stream patients direct to colonoscopy, with two >100 µg/g prompting clinic review. A second result ≥220 µg/g was more accurate than dual-result thresholds. Coupling home FCP testing with key symptoms may form the basis of effective self-referral pathways

    Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study.

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    To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.We aimed to quantify the risk of major adverse cardiovascular events (MACE) among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis without known PsA compared with the general population after adjusting for traditional cardiovascular risk factors.A population-based longitudinal cohort study from 1994 to 2010 was performed in The Health Improvement Network (THIN), a primary care medical record database in the UK. Patients aged 18-89 years of age with PsA, RA or psoriasis were included. Up to 10 unexposed controls matched on practice and index date were selected for each patient with PsA. Outcomes included cardiovascular death, myocardial infarction, cerebrovascular accidents and the composite outcome (MACE). Cox proportional hazards models were used to calculate the HRs for each outcome adjusted for traditional risk factors. A priori, we hypothesised an interaction between disease status and disease-modifying antirheumatic drug (DMARD) use.Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=81 573) were identified. After adjustment for traditional risk factors, the risk of MACE was higher in patients with PsA not prescribed a DMARD (HR 1.24, 95% CI 1.03 to 1.49), patients with RA (No DMARD: HR 1.39, 95% CI 1.28 to 1.50, DMARD: HR 1.58, 95% CI 1.46 to 1.70), patients with psoriasis not prescribed a DMARD (HR 1.08, 95% CI 1.02 to 1.15) and patients with severe psoriasis (DMARD users: HR 1.42, 95% CI 1.17 to 1.73).Cardiovascular risk should be addressed with all patients affected by psoriasis, PsA or RA.American College of Rheumatology R01HL089744 K24AR064310 Clinical and Translational Science Award at the University of Pennsylvania from the National Center for Research Resources 8UL1TR000003 American College of Rheumatology Research and Education Foundation NIH K23AR063764 Doris Duke Charitable Foundation Center for Clinical Epidemiology and Biostatistics Icelandic Research Fund 120433021 R01AG025152 K23HL097151-0

    Association of DCIS Size and Margin Status With Risk of Developing Breast Cancer Post-Treatment: Multinational, Pooled Cohort Study

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    OBJECTIVE: To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer. DESIGN: Multinational, pooled cohort study. SETTING: Four large international cohorts. PARTICIPANTS: Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both. MAIN OUTCOME MEASURES: The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data RESULTS: The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS(hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCISfound. CONCLUSIONS: The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS

    Plant mitochondrial introns as genetic markers - conservation and variation

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    Plant genomes are comprised of nuclear, plastid and mitochondrial components characterized by different patterns of inheritance and evolution. Genetic markers from the three genomes provide complementary tools for investigations of inheritance, genetic relationships and phenotypic contributions. Plant mitochondrial genomes are challenging for universal marker development because they are highly variable in terms of size, gene order and intergenic sequences and highly conserved with respect to protein-coding sequences. PCR amplification of introns with primers that anneal to conserved, flanking exons is effective for the development of polymorphic nuclear genome markers. The potential for plant mitochondrial intron polymorphisms to distinguish between congeneric species or intraspecific varieties has not been systematically investigated and is possibly constrained by requirements for intron secondary structure and interactions with co-evolved organelle intron splicing factors. To explore the potential for broadly applicable plant mitochondrial intron markers, PCR primer sets based upon conserved sequences flanking 11 introns common to seven angiosperm species were tested across a range of plant orders. PCR-amplified introns were screened for indel polymorphisms among a group of cross-compatible Citrus species and relatives; two Raphanus sativus mitotypes; representatives of the two Phaseolus vulgaris gene pools; and congeneric pairs of Cynodon, Cenchrus, Solanum, and Vaccinium species. All introns were successfully amplified from each plant entry. Length polymorphisms distinguishable by gel electrophoresis were common among genera but infrequent within genera. Sequencing of three introns amplified from 16 entries identified additional short indel polymorphisms and nucleotide substitutions that separated Citrus, Cynodon, Cenchrus and Vaccinium congeners, but failed to distinguish Solanum congeners or representatives of the Phaseolus vulgaris major gene pools. The ability of primer sets to amplify a wider range of plant species’ introns and the presence of intron polymorphisms that distinguish congeners was confirmed by in silico analysis. While mitochondrial intron variation is limited in comparison to nuclear introns, these exon-based primer sets provide robust tools for the amplification of mitochondrial introns across a wide range of plant species wherein useful polymorphisms can be identified

    Development of a statistical crop model to explain the relationship between seed yield and phenotypic diversity within the Brassica napus Genepool

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    Plants are extremely versatile organisms that respond to the environment in which they find themselves, but a large part of their development is under genetic regulation. The links between developmental parameters and yield are poorly understood in oilseed rape; understanding this relationship will help growers to predict their yields more accurately and breeders to focus on traits that may lead to yield improvements. To determine the relationship between seed yield and other agronomic traits, we investigated the natural variation that already exists with regards to resource allocation in 37 lines of the crop species Brassica napus. Over 130 different traits were assessed; they included seed yield parameters, seed composition, leaf mineral analysis, rates of pod and leaf senescence and plant architecture traits. A stepwise regression analysis was used to model statistically the measured traits with seed yield per plant. Above-ground biomass and protein content together accounted for 94.36% of the recorded variation. The primary raceme area, which was highly correlated with yield parameters (0.65), provides an early indicator of potential yield. The pod and leaf photosynthetic and senescence parameters measured had only a limited influence on seed yield and were not correlated with each other, indicating that reproductive development is not necessarily driving the senescence process within field-grown B. napus. Assessing the diversity that exists within the B. napus gene pool has highlighted architectural, seed and mineral composition traits that should be targeted in breeding programmes through the development of linked markers to improve crop yields

    Enhanced CCR2 expression by ACKR2-deficient NK cells enhances increases tumoricidal cell therapy efficacy

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    Chemokines regulate leukocyte navigation to inflamed sites and specific tissue locales and may therefore be useful for ensuring accurate homing of cell therapeutic products. We, and others, have shown that atypical chemokine receptor 2 (ACKR2)-deficient mice (ACKR2−/−) are protected from metastasis development in cell line and spontaneous mouse models. We have shown that this relates to enhanced CCR2 expression on ACKR2−/− natural killer cells, allowing them to home more effectively to CCR2 ligand-expressing metastatic deposits. Here we demonstrate that the metastatic-suppression phenotype in ACKR2−/− mice is not a direct effect of the absence of ACKR2. Instead, enhanced natural killer cell CCR2 expression is caused by passenger mutations that originate from the creation of the ACKR2−/− mouse strain in 129 embryonic stem cells. We further demonstrate that simple selection of CCR2+ natural killer cells enriches for a population of cells with enhanced antimetastatic capabilities. Given the widespread expression of CCR2 ligands by tumors, our study highlights CCR2 as a potentially important contributor to natural killer cell tumoricidal cell therapy
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