Adrenergic stimulation adversely affects tumor growth and metastasis, but the underlying mechanisms are not well understood. Here, we uncovered a novel mechanism by which catecholamines induce ...inflammation by increasing prostaglandin E2 (PGE2) levels in ovarian cancer cells. Metabolic changes in tumors isolated from patients with depression and mice subjected to restraint stress showed elevated PGE2 levels. Increased metabolites, PTGS2 and PTGES protein levels were found in Skov3-ip1 and HeyA8 cells treated with norepinephrine (NE), and these changes were shown to be mediated by ADRB2 receptor signaling. Silencing PTGS2 resulted in significantly decreased migration and invasion in ovarian cancer cells in the presence of NE and decreased tumor burden and metastasis in restraint stress orthotopic models. In human ovarian cancer samples, concurrent increased ADRB2, PTGS2 and PTGES expression was associated with reduced overall and progression-free patient survival. In conclusion, increased adrenergic stimulation results in increased PGE2 synthesis via ADRB2-Nf-kB-PTGS2 axis, which drives tumor growth and metastasis.
Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management ...by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti‐inflammatory signaling and membrane‐stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF‐κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live‐imaging and pathology through both preventive and post‐onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.
Through studying the molecular mechanisms of glucocorticoids in Duchenne Muscular Dystrophy, the authors developed VBP15 as a novel oral drug with great therapeutic potentials in mdx mice.VBP15 acts like steroids, yet lacks their side effects.
Objectives
In HIV‐uninfected populations, obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease, metabolic syndrome, and cognitive impairment. These comorbidities are ...common in HIV‐infected patients, but there are scarce data regarding OSA in HIV‐infected patients. Therefore, we examined the prevalence and correlates of OSA in a cohort of HIV‐infected and uninfected patients.
Methods
An observational cohort study was carried out. Electronic medical record and self‐report data were examined in patients enrolled in the Veterans Aging Cohort Study (VACS) between 2002 and 2008 and followed until 2010. The primary outcome was OSA diagnosis, determined using International Classification of Diseases, 9th edition (ICD‐9) codes, in HIV‐infected compared with uninfected individuals. We used regression analyses to determine the association between OSA diagnosis, symptoms and comorbidities in adjusted models.
Results
Of 3683 HIV‐infected and 3641 uninfected patients, 143 (3.9%) and 453 (12.4%) had a diagnosis of OSA (p < 0.0001), respectively. HIV‐infected patients were more likely to report symptoms associated with OSA such as tiredness and fatigue. Compared with uninfected patients with OSA, HIV‐infected patients with OSA were younger, had lower body mass indexes (BMIs), and were less likely to have hypertension. In models adjusting for these traditional OSA risk factors, HIV infection was associated with markedly reduced odds of OSA diagnosis (odds ratio 0.48; 95% confidence interval 0.39‐0.60).
Conclusions
HIV‐infected patients are less likely to receive a diagnosis of OSA. Future studies are needed to determine whether the lower prevalence of OSA diagnoses in HIV‐infected patients is attributable to decreased screening and detection or to a truly decreased likelihood of OSA in the setting of HIV infection.
MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA ...biogenesis, causing a decreased pool of miRNAs in cancer and resulting in increased tumor growth and metastasis. Here we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanoliposomes resulted in increased tumor growth and metastasis, and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line-based overexpression of sense or antisense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer.
We examine whether pregnancy weight (pre-pregnancy body mass index (BMI) and/or weight gain) is related to core symptoms of attention deficit hyperactivity disorder (ADHD) in school-age offspring.
...Follow-up of prospective pregnancy cohorts from Sweden, Denmark and Finland within the Nordic Network on ADHD.
Maternal pregnancy and delivery data were collected prospectively. Teachers rated inattention and hyperactivity symptoms in offspring. High scores were defined as at least one core symptom rated as 'severe' and two as 'present' (approximately 10% of children scored in this range). Logistic regression and latent class analyses were used to examine maternal pregnancy weight in relation to children's ADHD core symptoms.
Teacher rated 12 556 school-aged children. Gestational weight gain outside of the Institute of Medicine guidelines was not related to ADHD symptoms (below recommendations: odds ratio (OR): 0.96; 95% confidence interval (CI): 0.81, 1.14; above recommendations: OR: 0.98; 95% CI: 0.82, 1.16). To examine various patterns of pre-pregnancy BMI and weight gain, we used latent class analysis and found significant associations between classes that included pre-pregnancy overweight or obesity and a high ADHD symptom score in offspring, ORs ranged between 1.37 (95% CI: 1.07, 1.75) and 1.89 (95% CI: 1.13, 3.15) adjusted for gestational age, birth weight, weight gain, pregnancy smoking, maternal age, maternal education, child gender, family structure and cohort country of origin. Children of women who were both overweight and gained a large amount of weight during gestation had a 2-fold risk of ADHD symptoms (OR: 2.10, 95% CI: 1.19, 3.72) compared to normal-weight women.
We show for the first time that pre-pregnancy BMI is associated with ADHD symptoms in children. Our results are of public health significance if the associations are causal and will then add ADHD symptoms in offspring to the list of deleterious outcomes related to overweight and obesity in the prenatal period.
Our current understanding of ocean-atmosphere-cryosphere interactions at ice-age terminations relies largely on assessments of the most recent (last) glacial-interglacial transition, Termination I ...(T-I). But the extent to which T-I is representative of previous terminations remains unclear. Testing the consistency of termination processes requires comparison of time series of critical climate parameters with detailed absolute and relative age control. However, such age control has been lacking for even the penultimate glacial termination (T-II), which culminated in a sea-level highstand during the last interglacial period that was several metres above present. Here we show that Heinrich Stadial 11 (HS11), a prominent North Atlantic cold episode, occurred between 135 ± 1 and 130 ± 2 thousand years ago and was linked with rapid sea-level rise during T-II. Our conclusions are based on new and existing data for T-II and the last interglacial that we collate onto a single, radiometrically constrained chronology. The HS11 cold episode punctuated T-II and coincided directly with a major deglacial meltwater pulse, which predominantly entered the North Atlantic Ocean and accounted for about 70 per cent of the glacial-interglacial sea-level rise. We conclude that, possibly in response to stronger insolation and CO2 forcing earlier in T-II, the relationship between climate and ice-volume changes differed fundamentally from that of T-I. In T-I, the major sea-level rise clearly post-dates Heinrich Stadial 1. We also find that HS11 coincided with sustained Antarctic warming, probably through a bipolar seesaw temperature response, and propose that this heat gain at high southern latitudes promoted Antarctic ice-sheet melting that fuelled the last interglacial sea-level peak.
Grasslands provide grass and fodder to sustain the growing need for ruminant meat and milk. Soil nutrients in grasslands are removed through withdrawal in these livestock products and through animal ...manure that originates from grasslands and is spread in croplands. This leads to loss of soil fertility, because globally most grasslands receive no mineral fertilizer. Here we show that phosphorus (P) inputs (mineral and organic) in global grasslands will have to increase more than fourfold in 2050 relative to 2005 to achieve an anticipated 80% increase in grass production (for milk and meat), while maintaining the soil P status. Combined with requirements for cropland, we estimate that mineral P fertilizer use must double by 2050 to sustain future crop and grassland production. Our findings point to the need to better understand the role of grasslands and their soil P status and their importance for global food security.
Context.
Fan-shaped jets sometimes form above light bridges and are believed to be driven by the reconnection of the vertical umbral field with the more horizontal field above the light bridges. ...Because these jets are not fully opaque in the wings of most chromospheric lines, it is not possible to study their spectra without highly complex considerations of radiative transfer in spectral lines from the atmosphere behind the fan.
Aims.
We take advantage of a unique set of observations of the H
α
line along with the Ca
II
8542 Å and Ca
II
K lines obtained with the CRISP and CHROMIS instrument of the Swedish 1-m Solar Telescope to study the physical properties of a fan-shaped jet that was backlit by an X9.3 flare. For what we believe to be the first time, we report an observationally derived estimate of the mass and density of material in a fan-shaped jet.
Methods.
The H
α
flare ribbon emission profiles from behind the fan are highly broadened and flattened, allowing us to investigate the fan with a single slab via Beckers’ cloud model, as if it were backlit by a flat spectral profile of continuum emission. Using this model we derived the opacity and velocity of the material in the jet. Using inversions of Ca
II
8542 Å emission via the STockholm inversion Code, we were also able to estimate the temperature and to cross-check the velocity of the material in the jet. Finally, we used the masses and the plane-of-sky and line-of-sight velocities as functions of time to investigate the downward supply of energy and momentum to the photosphere in the collapse of this jet, and evaluated it as a potential driver for a sunquake beneath.
Results.
We find that the physical properties of the fan material are reasonably chromospheric in nature, with a temperature of 7050 ± 250 K and a mean density of 2 ± 0.3 × 10
−11
g cm
−3
.
Conclusions.
The total mass observed in H
α
was found to be 3.9 ± 0.7 × 10
13
g and the kinetic energy delivered to the base of the fan in its collapse was nearly two orders of magnitude below typical sunquake energies. We therefore rule out this jet as the sunquake driver, but cannot completely rule out larger fan jets as potential drivers.
Summary
Background
Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and ...scratching behaviour in these patients.
Objectives
We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD.
Methods
The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off‐site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes).
Results
In patients with AD, stress induced by TSST caused a significant reduction of cowhage‐evoked itch but significantly increased off‐site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema.
Conclusions
We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress‐related exacerbation of itch in patients with AD.
What's already known about this topic?
An imbalance of immune function is associated with stress‐induced exacerbation of itch in patients with atopic dermatitis (AD).
No study has investigated if and how acute stress influences itch sensation and scratching behaviour in patients with AD.
What does this study add?
Acute stress increases spontaneous scratching behaviour in patients with AD.
Acute stress reduces itch sensation in patients with AD.
Patients with AD who are more sensitive to acute stress display more severe skin eczema.
What is the translational message?
Stress‐related increase of spontaneous scratching may be an important target for treatment for AD.
Linked Editorial: Stander. Br J Dermatol 2019; 180:689–690.
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Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in ...peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation‐03 study using a panel of 100 hypothesis‐driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome‐related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long‐term implications of these gene expression differences on the outcome of the allograft.
In this multicenter observational cohort study, Diamond et al demonstrate significant early overexpression of innate immune/inflammasome‐related gene expression and underexpression of T cell and adaptive immunity‐related genes in the peripheral blood of lung transplant recipients with primary graft dysfunction.
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