Summary
Introduction
Activated platelets shed microparticles from plasma membranes, but also release smaller exosomes from internal compartments. While microparticles participate in ...athero‐thrombosis, little is known of exosomes in this process.
Materials & Methods
Ex vivo biochemical experiments with human platelets and exosomes, and FeCl3‐induced murine carotid artery thrombosis.
Results
Both microparticles and exosomes were abundant in human plasma. Platelet‐derived exosomes suppressed ex vivo platelet aggregation and reduced adhesion to collagen‐coated microfluidic channels at high shear. Injected exosomes inhibited occlusive thrombosis in FeCl3‐damaged murine carotid arteries. Control platelets infused into irradiated, thrombocytopenic mice reconstituted thrombosis in damaged carotid arteries, but failed to do so after prior ex vivo incubation with exosomes.CD36 promotes platelet activation, and exosomes dramatically reduced platelet CD36.CD36 is also expressed by macrophages, where it binds and internalizes oxidized LDL and microparticles, supplying lipid to promote foam cell formation. Platelet exosomes inhibited oxidized‐LDL binding and cholesterol loading into macrophages. Exosomes were not competitive CD36 ligands, but instead sharply reduced total macrophage CD36 content. Exosomal proteins, in contrast to microparticle or cellular proteins, were highly adducted by ubiquitin. Exosomes enhanced ubiquitination of cellular proteins, including CD36, and blockade of proteosome proteolysis with MG‐132 rescued CD36 expression. Recombinant unanchored K48 poly‐ubiquitin behaved similarly to exosomes, inhibiting platelet function, macrophage CD36 expression and macrophage particle uptake.
Conclusions
Platelet‐derived exosomes inhibit athero‐thrombotic processes by reducing CD36‐dependent lipid loading of macrophages and by suppressing platelet thrombosis. Exosomes increase protein ubiquitination and enhance proteasome degradation of CD36.
Platelet-activating factor (PAF) is a phospholipid with potent, diverse
physiological actions, particularly as a mediator of inflammation. The
synthesis, transport, and degradation of PAF are tightly ...regulated, and the
biochemical basis for many of these processes has been elucidated in recent
years. Many of the actions of PAF can be mimicked by structurally related
phospholipids that are derived from nonenzymatic oxidation, because such
compounds can bind to the PAF receptor. This process circumvents much of the
biochemical control and presumably is regulated primarily by the rate of
degradation, which is catalyzed by PAF acetylhydrolase. The isolation of cDNA
clones encoding most of the key proteins involved in regulating PAF has allowed
substantial recent progress and will facilitate studies to determine the
structural basis for substrate specificity and the precise role of PAF in
physiological events.
Celotno besedilo
Dostopno za:
CMK, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Individuals with non-small cell lung cancer (NSCLC) are burdened by long-lasting symptoms (e.g., dyspnea and fatigue) post-treatment. These symptoms often reduce physical activity levels ...and increase the risk of functional decline. Though we have previously proposed cluster-set resistance training to mitigate symptom burden in lung cancer, there is currently no data on the feasibility or acceptability of this mode of exercise in cancer. Therefore, the purpose of this study was to investigate the feasibility and acceptability of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC stages I-III (i.e., early stage). Methods This study aimed to recruit individuals with NSCLC stages I-III post-treatment to participate in 8 weeks of home-based resistance training, 3 days per week. The program included supervised sessions in the participants' homes and virtual supervision via videoconferencing. The primary outcome measure of feasibility was evaluated through recruitment, retention, and intervention fidelity (i.e., proportion of exercise completed, relative to what was prescribed). Intervention acceptability (i.e., ease and quality of virtual delivery, level of difficulty, and home-based approach) was assessed using a 4-point Likert-type scale from "strongly disagree" to "strongly agree". Results Fourteen participants were recruited over a 6-month period, with 11 completing the intervention (2 withdrew due to unrelated illness, 1 withdrew due to requiring active treatment), yielding a retention rate of 79%. Characteristics of the participants who completed the intervention (n = 11) were as follows: mean age: 71 + or - 10 years, mean BMI: 29.1 + or - 6.5, and average time since diagnosis was 62 + or - 51 months. Of completers, 27% were male, and 36% were Black; 10 were stage I (91%), and one was stage II (9%). Mean session attendance was 86.4 + or - 9.5%. Mean intervention fidelity was 83.1 + or - 13.1%. With regard to acceptability, > 90% of participants positively rated all aspects of the intervention delivery. No adverse events related to exercise were recorded. Conclusions The hybrid delivery of a home-based resistance exercise program for individuals previously treated for early-stage NSCLC was found to be safe and feasible. Adaptations to the program for future interventions are required, particularly surrounding resistance exercise programming, and intervention delivery with home visits. Trial registration ClinicalTrials.gov: NCT05014035. Registered January 20, 2021. Keywords: Resistance training, Lung cancer, Cluster sets, Dyspnea, Fatigue, Physical fitness, Quality of life
We report the results of an 87 deg{sup 2} point-source survey centered at R.A. 5{sup h}30{sup m}, decl. -55{sup 0} taken with the South Pole Telescope at 1.4 and 2.0 mm wavelengths with arcminute ...resolution and milli-Jansky depth. Based on the ratio of flux in the two bands, we separate the detected sources into two populations, one consistent with synchrotron emission from active galactic nuclei and the other consistent with thermal emission from dust. We present source counts for each population from 11 to 640 mJy at 1.4 mm and from 4.4 to 800 mJy at 2.0 mm. The 2.0 mm counts are dominated by synchrotron-dominated sources across our reported flux range; the 1.4 mm counts are dominated by synchrotron-dominated sources above {approx}15 mJy and by dust-dominated sources below that flux level. We detect 141 synchrotron-dominated sources and 47 dust-dominated sources at signal-to-noise ratio S/N >4.5 in at least one band. All of the most significantly detected members of the synchrotron-dominated population are associated with sources in previously published radio catalogs. Some of the dust-dominated sources are associated with nearby (z << 1) galaxies whose dust emission is also detected by the Infrared Astronomy Satellite. However, most of the bright, dust-dominated sources have no counterparts in any existing catalogs. We argue that these sources represent the rarest and brightest members of the population commonly referred to as submillimeter galaxies (SMGs). Because these sources are selected at longer wavelengths than in typical SMG surveys, they are expected to have a higher mean redshift distribution and may provide a new window on galaxy formation in the early universe.
Frailty is increasingly seen among patients with acute cardiovascular disease. A combination of an ageing population, improved disease survival, treatable long-term conditions as well as a greater ...recognition of the syndrome has accelerated the prevalence of frailty in the modern world. Yet, this has not been matched by an expansion of research. National and international bodies have identified acute cardiovascular disease in the frail as a priority area for care and an entity that requires careful clinical decisions, but there remains a paucity of guidance on treatment efficacy and safety, and how to manage this complex group. This position paper from the Acute Cardiovascular Care Association presents the latest evidence about frailty and the management of frail patients with acute cardiovascular disease, and suggests avenues for future research.
Symptom burden remains a critical concern for individuals with non-small cell lung cancer (NSCLC) following the completion of treatment. The most common symptom clusters, dyspnea (shortness of ...breath) and fatigue, can contribute to physical decline, reductions in quality of life, and a higher risk of comorbidities and mortality. Dyspnea is a primary limiter of exercise capacity in individuals with lung cancer, resulting in exercise avoidance and an accelerated physical decline. As such, designing resistance training with cluster sets to mitigate symptoms of dyspnea and fatigue may result in improved exercise tolerance. Thus, maintaining the exercise stimulus via cluster sets, combined with improved tolerance of the exercise, could result in the maintenance of physical function and quality of life. The purpose of this study is to investigate the feasibility and preliminary efficacy of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC.
Individuals with NSCLC (n = 15), within 12 months of completion of treatment, will be recruited to participate in this single-arm feasibility trial. Participants will complete 8 weeks of home-based resistance training designed to minimize dyspnea and fatigue. The hybrid delivery of the program will include supervised sessions in the participants' home and virtual supervision via video conferencing. The primary outcome of feasibility will be quantified by recruitment rates, retention, acceptability, and intervention fidelity. Exploratory outcomes (dyspnea, fatigue, quality of life, physical function, and body composition) will be assessed pre- and post-intervention.
This study will provide important data on the feasibility of delivering this intervention and inform procedures for a future randomized controlled trial.
Record not yet public.
Native arteriovenous fistula (AVF) is the vascular access of choice and its use cf. catheters is associated with sustained reduction in mortality. This may be due to factors beyond dialysis ...catheter-associated sepsis. This study aimed to investigate the impact of AVF formation on the spectrum of cardiovascular factors that might be important in the pathophysiology of cardiovascular diseases in chronic kidney disease (CKD) patients.
We recruited 43 pre-dialysis patients who underwent AVF formation. Patients were studied 2 weeks prior to AVF operation and 2 weeks and 3 months post-operatively. Haemodynamic variables were measured using pulse wave analysis, carotid femoral pulse wave velocity (CF-PWV) by applanation tonometry and AVF blood flow by Doppler ultrasound. Bioimpedence analysis was performed and patients underwent serial transthoracic echocardiography.
AVF formation was successful in 30/43 patients. Two weeks post-operatively, total peripheral resistance decreased (-17 ± 18%, P = 0.001), stroke volume tended to rise (12 ± 30 mL, P = 0.053) and both heart rate (4 ± 8 bpm, P = 0.01) and cardiac output (1.1 ± 1.5 L/min, P = 0.001) increased. Systolic and diastolic blood pressures (BPs) reduced (-9 ± 18 mmHg; -9 ± 10 mmHg; ≤ P = 0.006) and CF-PWV reduced (-1.1 ± 1.5 m/s, P = 0.004). Left ventricular ejection fraction (LVEF) increased (6 ± 8%, P < 0.001). All the observed changes were largely maintained after 3 months. No change in hydration status/body composition was observed.
AVF formation resulted in a sustained reduction in arterial stiffness and BP as well as an increase in LVEF. Overall, post-AVF adaptations might be characterized as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals.
Evidence is compelling for a positive correlation between climate change, urbanisation and prevalence of allergic sensitisation and diseases. The reason for this association is not clear to date. ...Some data point to a pro-allergenic effect of anthropogenic factors on susceptible individuals.
To evaluate the impact of urbanisation and climate change on pollen allergenicity.
Catkins were sampled from birch trees from different sites across the greater area of Munich, pollen were isolated and an urbanisation index, NO2 and ozone exposure were determined. To estimate pollen allergenicity, allergen content and pollen-associated lipid mediators were measured in aqueous pollen extracts. Immune stimulatory and modulatory capacity of pollen was assessed by neutrophil migration assays and the potential of pollen to inhibit dendritic cell interleukin-12 response. In vivo allergenicity was assessed by skin prick tests.
The study revealed ozone as a prominent environmental factor influencing the allergenicity of birch pollen. Enhanced allergenicity, as assessed in skin prick tests, was mirrored by enhanced allergen content. Beyond that, ozone induced changes in lipid composition and chemotactic and immune modulatory potential of the pollen. Higher ozone-exposed pollen was characterised by less immune modulatory but higher immune stimulatory potential.
It is likely that future climate change along with increasing urbanisation will lead to rising ozone concentrations in the next decades. Our study indicates that ozone is a crucial factor leading to clinically relevant enhanced allergenicity of birch pollen. Thus, with increasing temperatures and increasing ozone levels, also symptoms of pollen allergic patients may increase further.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cyclooxygenase-2 (COX-2) is up-regulated in many cancers and is a rate-limiting step in colon carcinogenesis. Nonsteroidal antiinflammatory drugs, which inhibit COX-2, prevent colon cancer and cause ...apoptosis. The mechanism for this response is not clear, but it might result from an accumulation of the substrate, arachidonic acid, an absence of a prostaglandin product, or diversion of the substrate into another pathway. We found that colon adenocarcinomas overexpress another arachidonic acid-utilizing enzyme, fatty acid-CoA ligase (FACL) 4, in addition to COX-2. Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C. These findings suggested that unesterified arachidonic acid in cells is a signal for induction of apoptosis. To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as "sinks" for unesterified arachidonic acid. Activation of the enzymatic sinks blocked apoptosis, and the reduction of cell death was inversely correlated with the cellular level of arachidonic acid. Inhibition of the COX-2 component by nonsteroidal antiinflammatory drugs restored the apoptotic response. Cell death caused by exposure to tumor necrosis factor α or to calcium ionophore also was prevented by removal of unesterified arachidonic acid. We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level.
We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent ...anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2(V617F)-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2(V617F)-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.
PDF
