Regulation of circulating free fatty acid (FFA) levels and delivery is crucial to maintain tissue homeostasis. Exosomes are nanomembranous vesicles that are released from diverse cell types and ...mediate intercellular communication by delivering bioactive molecules. Here, we sought to investigate the uptake of FFAs by circulating exosomes, the delivery of FFA-loaded exosomes to cardiac cells and the possible role of the FFA transporter CD36 in these processes. Circulating exosomes were purified from the serum of healthy donors after an overnight fast (F) or 20 minutes after a high caloric breakfast (postprandial, PP). Western blotting, Immunogold Electron Microscopy and FACS analysis of circulating exosomes showed that CD36 was expressed under both states, but was higher in postprandial-derived exosomes. Flow cytometry analysis showed that circulating exosomes were able to take-up FFA directly from serum. Importantly, preincubation of exosomes with a blocking CD36 antibody significantly impeded uptake of the FFA analogue BODIPY, pointing to the role of CD36 in FFA exosomal uptake. Finally, we found that circulating exosomes could delivery FFA analogue BODIPY into cardiac cells ex vivo and in vivo in a mice model. Overall, our results suggest a novel mechanism in which circulating exosomes can delivery FFAs from the bloodstream to cardiac tissue. Further studies will be necessary to understand this mechanism and, in particular, its potential involvement in metabolic pathologies such as obesity, diabetes and atherosclerosis.
Summary
Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data ...retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long‐term outlook. Median follow‐up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse‐free survival was 16 years. After relapse (n = 79) or non‐response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse‐free survival was 11 years. After third‐line therapy (n = 23), 50% achieved CR and median relapse‐free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third‐line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 109/l before treatment had the longest relapse‐free survival (P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL‐related causes. Patients achieving a CR can expect a normal lifespan.
Muscle strength is sex-related and declines with advancing age; yet, a comprehensive comparative evaluation of age-related strength loss in human females and males has not been undertaken. To do so, ...segmented piecewise regression analysis was performed on aggregated data from studies published from 1990 to 2018 and are available in CINAHL, EMBASE, MEDLINE, and PsycINFO databases. The search identified 5613 articles that were reviewed for physical assessment results stratified by sex and age. Maximal isometric and isokinetic 60°·s
−1
knee extension (KE) and knee flexion (KF) contractions from 57 studies and 15 283 subjects (N = 7918 females) had sufficient data reported on females and males for meaningful statistical evaluation to be undertaken. The analysis revealed that isometric KE and KF strength undergo similar rapid declines in both sexes late in the sixth decade of life. Yet, there is an abrupt age-related decline in KE 60°·s
−1
peak torque earlier in females (aged 41.8 years) than males (aged 66.7 years). In the assessment of KF peak torque, an age-related acceleration in strength loss was only identified in males (aged 49.3 years). The results suggest that age-related isometric strength loss is similar between sexes while the characteristics of KE and KF peak torque decline are sex-related, which likely explains the differential rate of age-related functional decline.
Novelty
Inclusion of muscle strength and torque of KE and KF data from >15 000 subjects.
Isometric KE and KF strength loss are similar between sexes.
Isokinetic 60°·s
−1
KE torque decline accelerates 25 years earlier in females and female age-related KF peak torque decline does not accelerate with age.
Adeno-associated virus (AAV) has been used to direct gene transfer to a variety of tissues, including heart, liver, skeletal muscle, brain, kidney and lung, but it has not previously been shown to ...effectively target fibroblasts in vivo, including cardiac fibroblasts. We constructed expression cassettes using a modified periostin promoter to drive gene expression in a cardiac myofibroblast-like lineage, with only occasional spillover into cardiomyocyte-like cells. We compared AAV serotypes 6 and 9 and found robust gene expression when the vectors were delivered by systemic injection after myocardial infarction (MI), with little expression in healthy, non-infarcted mice. AAV9 provided expression in a greater number of cells than AAV6, with reporter gene expression visible in the cardiac infarct and border zones from 5 to 62 days post MI, as assessed by luciferase and Cre-activated green fluorescent protein expression. Although common myofibroblast markers were expressed in low abundance, most of the targeted cells expressed myosin IIb, an embryonic form of smooth muscle myosin heavy chain that has previously been associated with myofibroblasts after reperfused MI. This study is the first to demonstrate AAV-mediated expression in a potentially novel myofibroblast-like lineage in mouse hearts post MI and may open new avenues of gene therapy to treat patients surviving MI.
Background:The precise anatomical location of pathology associated with inflammatory back pain (IBP) in early spondyloarthropathy (SpA) remains unclear.Objective:To use MRI to study the sacroiliac ...joint (SIJ) and lumbar spine (LS) and explore the relationship between sites and extent of inflammation and HLA-B27 status over 12 months.Methods:54 patients with IBP; median duration 24 weeks (54% HLA-B27 positive; median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 5.65) and 22 control subjects (11 with mechanical back pain; 11 volunteers) were recruited and 63% (n = 34) were reassessed at 1 year. Fat saturation and T1-weighted MRI was performed with images being scored for active bone marrow oedema (BMO) lesions representative of inflammation.Results:At baseline 46/54 (85%) patients had BMO (SIJs and LS) compared with 40% in the control group. The majority of affected patients had inflammation at the SIJ level (96% (n = 44); 23.5% (n = 12) LS) and 28.3% (n = 13) at both sites simultaneously. The SIJ activity score confirmed more severe inflammation (BMO grade 2 or 3: 52.2%) in the IBP group (controls = BMO grade 1: 100%; p<0.001). HLA-B27 was associated with both the severity (p = 0.009) and number of baseline SIJ lesions (p = 0.045) and with persistence (SIJ or LS) at 1 year (p = 0.02). 90% of reattenders fulfilled European Spondyloarthropathy Study Group criteria; 73.5% showed MRI inflammation despite clinical improvement (median BASDAI 5.65 to 3.05; p<0.009).Conclusion:LS and SIJ involvement may occur simultaneously in very early SpA and may be differentiated from non-inflammatory back pain by the severity of MRI lesions. HLA-B27 is associated with both the severity of osteitis and its persistence.
Abstract Ectopic adipose tissue surrounding the intra-abdominal organs (visceral fat) and located in the liver, heart, pancreas and muscle, is linked to cardio-metabolic complications commonly ...experienced in type 2 diabetes. A systematic review and meta-analysis was performed to determine the effect of exercise on ectopic fat in adults with type 2 diabetes. Relevant databases were searched to February 2016. Included were randomised controlled studies, which implemented ≥ 4 weeks of aerobic and/or resistance exercise and quantified ectopic fat via magnetic resonance imaging, computed tomography, proton magnetic resonance spectroscopy or muscle biopsy before and after intervention. Risk of bias and study quality was assessed using Egger's funnel plot test and modified Downs and Black checklist, respectively. Of the 10,750 studies retrieved, 24 were included involving 1383 participants. No studies were found assessing the interaction between exercise and cardiac or pancreas fat. One study assessed the effect of exercise on intramyocellular triglyceride concentration. There was a significant pooled effect size for the meta-analysis comparing exercise vs. control on visceral adiposity (ES = −0.21, 95% CI: −0.37 to −0.05; P = 0.010) and a near-significant pooled effect size for liver steatosis reduction with exercise (ES = −0.28, 95% CI: −0.57 to 0.01; P = 0.054). Aerobic exercise (ES = −0.23, 95% CI: −0.44 to −0.03; P = 0.025) but not resistance training exercise (ES = −0.13, 95% CI: −0.37 to 0.12; P = 0.307) was effective for reducing visceral fat in overweight/obese adults with type 2 diabetes. These data suggest that exercise effectively reduces visceral and perhaps liver adipose tissue and that aerobic exercise should be a key feature of exercise programs aimed at reducing visceral fat in obesity-related type 2 diabetes. Further studies are required to assess the relative efficacy of exercise modality on liver fat reduction and the effect of exercise on pancreas, heart, and intramyocellular fat in type 2 diabetes and to clarify the effect of exercise on ectopic fat independent of weight loss.
Abstract
Motivation
Probabilistic latent semantic analysis (pLSA) is commonly applied to describe mass spectra (MS) images. However, the method does not provide certain outputs necessary for the ...quantitative scientific interpretation of data. In particular, it lacks assessment of statistical uncertainty and the ability to perform hypothesis testing. We show how linear Poisson modelling advances pLSA, giving covariances on model parameters and supporting χ2 testing for the presence/absence of MS signal components. As an example, this is useful for the identification of pathology in MALDI biological samples. We also show potential wider applicability, beyond MS, using magnetic resonance imaging (MRI) data from colorectal xenograft models.
Results
Simulations and MALDI spectra of a stroke-damaged rat brain show MS signals from pathological tissue can be quantified. MRI diffusion data of control and radiotherapy-treated tumours further show high sensitivity hypothesis testing for treatment effects. Successful χ2 and degrees-of-freedom are computed, allowing null-hypothesis thresholding at high levels of confidence.
Availability and implementation
Open-source image analysis software available from TINA Vision, www.tina-vision.net.
Supplementary information
Supplementary data are available at Bioinformatics online.
Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist ...conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts.
In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2−) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability.
A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate 13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124, and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients.
Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.
•Lasofoxifene showed antitumor activity in patients with ESR1-mutated mBC that progressed on an AI plus a CDK4/6i.•Lasofoxifene numerically improved PFS (5.6 versus 3.7 months) and clinical benefit rate (37% versus 22%) versus fulvestrant.•Lasofoxifene was well-tolerated with no unexpected safety signals.•Lasofoxifene reduced ESR1 MAF, including Y537S MAF, in more patients than fulvestrant, exhibiting target engagement.•Lasofoxifene may be a promising endocrine therapy backbone for ESR1-mutated mBC in a post-CDK4/6i setting.
Atmospheric chemistry is driven by photolytic reactions, making their modelling a crucial component of atmospheric models. We describe the implementation and validation of Fast-JX, a state of the art ...model of interactive photolysis, into the MetUM chemistry-climate model. This allows for interactive photolysis rates to be calculated in the troposphere and augments the calculation of the rates in the stratosphere by accounting for clouds and aerosols in addition to ozone. In order to demonstrate the effectiveness of this new photolysis scheme we employ new methods of validating the model, including techniques for sampling the model to compare to flight track and satellite data.
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