The dismal outlook for patients with the most aggressive and common form of adult brain cancer, glioblastoma (GBM), motivates a search for new therapeutic strategies and targets for this aggressive ...disease. Here we review the findings to date on the role of Eph family receptor tyrosine kinases and their ephrin ligands in brain cancer. Expression of the Eph family of cell surface proteins is generally downregulated to very low levels in normal adult tissues making them particularly attractive for directed therapeutic targeting. Recent Eph targeting studies in pre-clinical models of GBM have been very encouraging and may provide an avenue to treat these highly refractory aggressive tumours.
Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts and ...perivascular stromal cells including endothelial cells, CXCL12-abundant reticular cells, leptin-receptor-positive stromal cells, and nestin-green fluorescent protein (GFP)-positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C-X-C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1-cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.
Background, & Aims Studies of primary biliary cirrhosis (PBC) phenotypes largely have been performed using small and selected populations. Study size has precluded investigation of important disease ...subgroups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. Methods We performed a cross-sectional study using the United Kingdom-PBC, patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). Results Seventy-nine percent of the patients reported current UDCA, therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response rate; P < .05); male sex was an independent predictor of nonresponse on multivariate analysis. Age at diagnosis was associated strongly and independently with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than age 70, to less than 50% for those younger than age 30 ( P < .0001). Patients who presented at younger ages also were significantly more likely not to respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's ( P < .0001). The increase in fatigue severity in women was related strongly (r = 0.58; P < .0001) to higher levels of autonomic symptoms ( P < .0001). Conclusions Among patients with PBC, response to UDCA, treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at younger than age 50. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.
More than 90% of the world's population lives in areas where outdoor air pollution levels exceed health-based limits. In these areas, individuals may use indoor air filtration, often on a sporadic ...basis, in their residences to reduce exposure to respirable particles (PM2.5). Whether this intervention can lead to improvements in health outcomes has not been evaluated.
Seventy non-smoking healthy adults, aged 19 to 26 years, received both true and sham indoor air filtration in a double-blinded randomized crossover study. Each filtration session was approximately 13 h long. True and sham filtration sessions were separated by a two-week washout interval. The study was carried out in a suburb of Shanghai.
During the study period, outdoor PM2.5 concentrations ranged from 18.6 to 106.9 μg/m3, which overlapped with levels measured in Western Europe and North America. Compared to sham filtration, true filtration on average decreased indoor PM2.5 concentration by 72.4% to 10.0 μg/m3 and particle number concentration by 59.2% to 2316/cm3. For lung function measured immediately after the end of filtration, true filtration significantly lowered airway impedance at 5 Hz (Z5) by 7.1% 95% CI: 2.4%, 11.9%, airway resistance at 5 Hz (R5) by 7.4% 95% CI: 2.4%, 12.5%, and small airway resistance (R5-R20) by 20.3% 95% CI: 0.1%, 40.5%, reflecting improved airway mechanics especially for the small airways. However, no significant improvements for spirometry indicators (FEV1, FVC) were observed. True filtration also significantly lowered von Willebrand factor (VWF) by 26.9% 95% CI: 7.3%, 46.4% 24 h after the end of filtration, indicating reduced risk for thrombosis. Stratified analysis in male and female participants showed that true filtration significantly decreased pulse pressure by 3.3% 95% CI: 0.8%, 7.4% in females, and significantly reduced VWF by 42.4% 95% CI: 17.4%, 67.4% and interleukin-6 by 22.6% 95% CI: 0.4%, 44.9% in males. Effect modification analyses indicated that filtration effects in male and female participants were not significantly different.
A single overnight residential air filtration, capable of reducing indoor particle concentrations substantially, can lead to improved airway mechanics and reduced thrombosis risk.
•Air filtration reduced indoor PM2·5 by 72.4% and particle number concentrations by 59.2%.•An overnight filtration improved airway mechanics but not spirometric lung function.•It also reduced levels of von Willebrand factor, an indicator of thrombosis risk.•Impulse oscillometry provided sensitive measurements of airway mechanics.
There is a pressing need for transitional care that prepares rural dwelling medical patients to identify and respond to the signs of worsening health conditions. An evidence-based warning signs ...intervention has the potential to address this need. While the intervention is predominantly delivered by nurses, other healthcare providers may be required to deliver it in rural communities where human health resources are typically limited. Understanding the perspectives of other healthcare providers likely to be involved in delivering the intervention is a necessary first step to avert consequences of low acceptability, such as poor intervention implementation, uptake, and effectiveness. This study examined and compared nurses' and other healthcare providers' perceived acceptability of an evidence-based warning signs intervention proposed for rural transitional care.
A cross-sectional design was used. The convenience sample included 45 nurses and 32 other healthcare providers (e.g., physical and occupational therapists, physicians) who self-identified as delivering transitional care to patients in rural Ontario, Canada. In an online survey, participants were presented with a description of the warning signs intervention and completed established measures of intervention acceptability. The measures captured 10 intervention acceptability attributes (effectiveness, appropriateness, risk, convenience, relevance, applicability, usefulness, frequency of current use, likelihood of future use, and confidence in ability to deliver the intervention). Ratings ≥ 2 indicated acceptability. Data analysis included descriptive statistics, independent samples t-tests, as well as effect sizes to quantify the magnitude of any differences in acceptability ratings between nurses and other healthcare providers.
Nurses and other healthcare providers rated all intervention attributes > 2, except the attributes of convenience and frequency of current use. Differences between the two groups were found for only three attributes: nurses' ratings were significantly higher than other healthcare providers on perceived applicability, frequency of current use, and the likelihood of future use of the intervention (all p's < .007; effect sizes .58 - .68, respectively).
The results indicate that both participant groups had positive perspectives of the intervention on most of the attributes and suggest that initiatives to enhance the convenience of the intervention's implementation are warranted to support its widespread adoption in rural transitional care. However, the results also suggest that other healthcare providers may be less receptive to the intervention in practice. Future research is needed to explore and mitigate the possible reasons for low ratings on perceived convenience and frequency of current use of the intervention, as well as the between group differences on perceived applicability, frequency of current use, and the likelihood of future use of the intervention.
The intervention represents a tenable option for rural transitional care in Ontario, Canada, and possibly other jurisdictions emphasizing transitional care.
The mechanisms that mediate the shift from lymphopoiesis to myelopoiesis in response to infectious stress are largely unknown. We show that treatment with granulocyte colony-stimulating factor ...(G-CSF), which is often induced during infection, results in marked suppression of B lymphopoiesis at multiple stages of B-cell development. Mesenchymal-lineage stromal cells in the bone marrow, including CXCL12-abundant reticular (CAR) cells and osteoblasts, constitutively support B lymphopoiesis through the production of multiple B trophic factors. G-CSF acting through a monocytic cell intermediate reprograms these stromal cells, altering their capacity to support B lymphopoiesis. G-CSF treatment is associated with an expansion of CAR cells and a shift toward osteogenic lineage commitment. It markedly suppresses the production of multiple B-cell trophic factors by CAR cells and osteoblasts, including CXCL12, kit ligand, interleukin-6, interleukin-7, and insulin-like growth factor-1. Targeting bone marrow stromal cells is one mechanism by which inflammatory cytokines such as G-CSF actively suppress lymphopoiesis.
•G-CSF suppresses B lymphopoiesis at multiple stages of development.•G-CSF reprograms bone marrow stromal cells to inhibit their production of B-cell trophic factors.
The role of astrocytes is becoming increasingly important to understanding how glioblastoma (GBM) tumor cells diffusely invade the brain. Yet, little is known of the contribution of extracellular ...vesicle (EV) signaling in GBM/astrocyte interactions. We modeled GBM-EV signaling to normal astrocytes in vitro to assess whether this mode of intercellular communication could support GBM progression. EVs were isolated and characterized from three patient-derived GBM
stem
cells (NES
+
/CD133
+
) and their differentiated (
diff
) progeny cells (NES
−
/CD133
−
). Uptake of GBM-EVs by normal primary astrocytes was confirmed by fluorescence microscopy, and changes in astrocyte podosome formation and gelatin degradation were measured. Quantitative mass spectrometry-based proteomics was performed on GBM-EV stimulated astrocytes. Interaction networks were generated from common, differentially abundant proteins using Ingenuity® (Qiagen Bioinformatics) and predicted upstream regulators were tested by qPCR assays. Podosome formation and Cy3-gelatin degradation were induced in astrocytes following 24-h exposure to GBM-
stem
and -
diff
EVs, with EVs released by GBM-
stem
cells eliciting a greater effect. More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFβ1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR. Further qPCR studies identified significantly decreased Δ133p53 and increased p53
β
in astrocytes exposed to GBM-EVs that might indicate the acquisition of a pro-inflammatory, tumor-promoting senescence-associated secretory phenotype (SASP). Inhibition of TP53 and activation of MYC signaling pathways in normal astrocytes exposed to GBM-EVs may be a mechanism by which GBM manipulates astrocytes to acquire a phenotype that promotes tumor progression.
•Maternal gestational phthalate mixtures were associated with child behavior.•Early pregnancy phthalates were associated with autistic traits in both sexes.•Early pregnancy phthalates were associated ...with worse adaptive skills in girls.•Late pregnancy phthalates were associated with higher externalizing behavior in boys.•MBzP and MCPP were important phthalates in almost all mixture associations.
Prenatal exposure to multiple phthalates is ubiquitous, and yet few studies have evaluated these exposures as a mixture in relation to child autistic traits and behavioral problems.
To assess cumulative associations between prenatal phthalate mixtures and child behaviors, including effect modification by exposure timing and child sex.
Analyses included 501 mother/child pairs from the multicenter pregnancy cohort The Infant Development and Environment Study (TIDES). Nine maternal urinary phthalate metabolites were measured in early and late pregnancy, and behavior was assessed at ages 4–5 years using composite T scores for the Behavioral Assessment System for Children (BASC-2), which measures several dimensions of child behavior, and the Social Responsiveness Scale (SRS-2), which measures social impairment consistent with autistic traits. We utilized weighted quantile sum (WQS) regressions to examine pregnancy period-specific associations between phthalate mixtures and behavioral outcomes. Full-sample 95% WQS confidence intervals are known to be anti-conservative, so we calculated a confirmatory p-value using a permutation test. Effect modification by sex was examined with stratified analyses.
A one-quintile increase in the early pregnancy phthalate mixture was associated with increased SRS-2 total score (coefficient = 1.0, confirmatory p = 0.01) and worse adaptive skills (coefficient = −1.0, confirmatory p = 0.06) in both sexes. In sex-stratified analyses, the early pregnancy phthalate mixture was associated with increased SRS-2 total score in boys (coefficient = 1.2, confirmatory p = 0.04) and girls (coefficient = 1.0, confirmatory p = 0.10) and worse BASC-2 adaptive skills score in girls (coefficient = −1.5, confirmatory p = 0.06), while the late pregnancy phthalate mixture was associated with increased BASC-2 externalizing score in boys (coefficient = 1.3, confirmatory p = 0.03).
Our results suggest cumulative adverse associations between prenatal phthalate mixtures and multiple facets of childhood behavior.
Wildlife populations often exhibit unequal catchability between subgroups such as males and females. This heterogeneity of capture probabilities can bias both population size and sex ratio estimates. ...Several authors have suggested that this problem can be overcome by treating males and females as separate populations and calculating a population estimate for each of them. However, this suggestion has received little testing, and many researchers do not implement it. Therefore, we used two simulations to test the utility of this method. One simulated a closed population, while the other simulated an open population and used the robust design to calculate population sizes. We tested both simulations with multiple levels of heterogeneity, and we used a third simulation to test several methods for detecting heterogeneity of capture probabilities. We found that treating males and females as separate populations produced more accurate population and sex ratio estimates. The benefits of this method were particularly pronounced for sex ratio estimates. When males and females were included as a single population, the sex ratio estimates became inaccurate when even slight heterogeneity was present, but when males and females were treated separately, the estimates were accurate even when large biases were present. Nevertheless, treating males and females separately reduced precision, and this method may not be appropriate when capture and recapture rates are low. None of the methods for detecting heterogeneity were robust, and we do not recommend that researchers rely on them. Rather, we suggest separating populations by sex, age, or other subgroups whenever sample sizes permit.
PDF
