Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly ...understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia- or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia- and monocyte-derived TAMs were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors, but were outnumbered by monocyte-derived TAMs following recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.
Abstract
Background
Epidemiological and animal studies provide compelling indications that environmental and engineered nanomaterials (NMs) pose a risk for pregnancy, fetal development and offspring ...health later in life. Understanding the origin and mechanisms underlying NM-induced developmental toxicity will be a cornerstone in the protection of sensitive populations and the design of safe and sustainable nanotechnology applications.
Main body
Direct toxicity originating from NMs crossing the placental barrier is frequently assumed to be the key pathway in developmental toxicity. However, placental transfer of particles is often highly limited, and evidence is growing that NMs can also indirectly interfere with fetal development. Here, we outline current knowledge on potential indirect mechanisms in developmental toxicity of NMs.
Short conclusion
Until now, research on developmental toxicity has mainly focused on the biodistribution and placental translocation of NMs to the fetus to delineate underlying processes. Systematic research addressing NM impact on maternal and placental tissues as potential contributors to mechanistic pathways in developmental toxicity is only slowly gathering momentum. So far, maternal and placental oxidative stress and inflammation, activation of placental toll-like receptors (TLRs), impairment of placental growth and secretion of placental hormones, and vascular factors have been suggested to mediate indirect developmental toxicity of NMs. Therefore, NM effects on maternal and placental tissue function ought to be comprehensively evaluated in addition to placental transfer in the design of future studies of developmental toxicity and risk assessment of NM exposure during pregnancy.
Bolus Calculators Schmidt, Signe; Nørgaard, Kirsten
Journal of Diabetes Science and Technology,
09/2014, Letnik:
8, Številka:
5
Book Review, Journal Article
Recenzirano
Odprti dostop
Matching meal insulin to carbohydrate intake, blood glucose, and activity level is recommended in type 1 diabetes management. Calculating an appropriate insulin bolus size several times per day is, ...however, challenging and resource demanding. Accordingly, there is a need for bolus calculators to support patients in insulin treatment decisions. Currently, bolus calculators are available integrated in insulin pumps, as stand-alone devices and in the form of software applications that can be downloaded to, for example, smartphones. Functionality and complexity of bolus calculators vary greatly, and the few handfuls of published bolus calculator studies are heterogeneous with regard to study design, intervention, duration, and outcome measures. Furthermore, many factors unrelated to the specific device affect outcomes from bolus calculator use and therefore bolus calculator study comparisons should be conducted cautiously. Despite these reservations, there seems to be increasing evidence that bolus calculators may improve glycemic control and treatment satisfaction in patients who use the devices actively and as intended.
The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated ...pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce protective immunity, and they are often combined with adjuvants to ensure robust immune responses. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells (APCs) concomitantly with conferring immune activation signals. Few adjuvant systems have been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell-mediated immunity (CMI). Adjuvants constitute a heterogeneous group of compounds, which can broadly be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode. Immunostimulators represent highly diverse classes of molecules, e.g., lipids, nucleic acids, proteins and peptides, and they are ligands for pattern-recognition receptors (PRRs), which are differentially expressed on APC subsets. Different formulation strategies might thus be required for incorporation of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the specific PRR expression profile of the target APCs. Here, we review state-of-the-art formulation approaches employed for the inclusion of immunostimulators and subunit antigens into liposome dispersion and their optimization towards robust vaccine formulations.
Protophloem and metaphloem sieve tubes are essential for transporting carbohydrates and signalling molecules towards sink tissues. OCTOPUS (OPS) was previously identified as an important regulator of ...protophloem differentiation in Arabidopsis roots. Here, we investigated the role of OCTOPUS-LIKE 2 (OPL2), a gene homologous to OPS.
OPL2 expression patterns were analysed, and functional equivalence of OPS and OPL2 was tested. Mutant and double mutant phenotypes were investigated.
OPS and OPL2 displayed overlapping expression patterns and a high degree of functional overlap. A mutation in OPL2 revealed redundant functions of OPS and OPL2 in developmental processes in which OPS was known to play a role, notably cotyledon vascular patterning and protophloem development. Moreover, we also uncovered redundant roles for OPS and OPL2 in leaf vascular patterning and, most interestingly, metaphloem sieve tube differentiation.
Our results reveal a novel OPS-like protein that, together with OPS, is an important regulator of vascular patterning, root growth and phloem development. OPS and OPL2 are the first genes identified that play a role in metaphloem sieve tube differentiation.
The aim of this work was to assess the impact of solvent selection on the microfluidic production of liposomes. To achieve this, liposomes were manufactured using small-scale and bench-scale ...microfluidics systems using three aqueous miscible solvents (methanol, ethanol or isopropanol, alone or in combination). Liposomes composed of different lipid compositions were manufactured using these different solvents and characterised to investigate the influence of solvents on liposome attributes. Our studies demonstrate that solvent selection is a key consideration during the microfluidics manufacturing process, not only when considering lipid solubility but also with regard to the resultant liposome critical quality attributes. In general, reducing the polarity of the solvent (from methanol to isopropanol) increased the liposome particle size without impacting liposome short-term stability or release characteristics. Furthermore, solvent combinations such as methanol/isopropanol mixtures can be used to modify solvent polarity and the resultant liposome particle size. However, the impact of solvent choice on the liposome product is also influenced by the liposome formulation; liposomes containing charged lipids tended to show more sensitivity to solvent selection and formulations containing increased concentrations of cholesterol or pegylated-lipids were less influenced by the choice of solvent. Indeed, incorporation of 14 wt% or more of pegylated-lipid was shown to negate the impact of solvent selection.
The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how ...the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.Maternal immune activation during pregnancy can negatively impact the developing fetus. Here, applying multi-omics (RNA-seq, phosphoproteomics and lipidomics) and imaging, the authors show that while maternal immune activation induces strong innate response in maternal organs it does not extend through the placenta but leads to fetal metabolic changes.
Display omitted
Successful oral delivery of liposomes requires formulations designed to withstand harsh gastrointestinal conditions, e.g., by converting to solid-state followed by loading into ...gastro-resistant delivery devices. The hypothesis was that the use of dextran-trehalose mixtures for spray drying would improve the rehydration kinetics of dried liposomes. The objectives were to determine the protective capacity of trehalose-dextran dehydration precursors and to increase the concentration of liposomes in the dry formulation volume. The study successfully demonstrated that 8.5% dextran combined with 76.5% trehalose protected CAF®04 liposomes during drying, with the liposome content maintained at 15% of the dry powder. Accordingly, the rehydration kinetics were slightly improved in formulations containing up to 8.5% dextran in the dry powder volume. Additionally, a 2.4-fold increase in lipid concentration (3 mM vs 7.245 mM) was achieved for spray dried CAF®04 liposomes. Ultimately, this study demonstrates the significance of trehalose as a primary carrier during spray drying of CAF®04 liposomes and highlights the advantage of incorporating small amounts of dextran to tune rehydration kinetics of spray-dried liposomes.
The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, ...a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF
09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.
The aim was to compare the accuracy of the Dexcom
G4 Platinum continuous glucose monitor (CGM) sensor inserted on the upper arm and the abdomen in adults.
Fourteen adults with type 1 diabetes wore ...two CGMs, one placed on the upper arm and one placed on the abdomen. Three in-clinic visits of 5 h with YSI (2300 STAT, Yellow Springs Instrument) measurements as comparator were performed. Each visit was followed by 4 days with seven-point self-monitoring of blood glucose (SMBG) in free-living conditions. Accuracy analyses on the paired CGM-YSI and CGM-SMBG measurements of the two CGM sensors were performed.
Using YSI as comparator, the overall Mean Absolute Relative Difference (MARD) for the CGM
was 12.3% and CGM
was 12.0%. The percentage of the CGM measurements in zone A of Clarke error grid analysis for the CGM
was 85.6% and CGM
was 86.0%. The hypoglycemia sensitivity for the CGM
and CGM
was 69.3%. Using SMBG as comparator, the overall MARD for the CGM
was 12.5% and CGM
was 12.0%. The percentage of the CGM measurements in zone A for the CGM
was 84.1% and the CGM
was 85.0%. The hypoglycemia sensitivity for the CGM
was 60.0% and the CGM
was 71.1%. All the
-values from the comparisons between the accuracy of CGM
and CGM
were >0.05.
The accuracy of a Dexcom G4 Platinum CGM sensor placed on the upper arm was not different from the accuracy of the sensor placed on the abdomen in adults with type 1 diabetes.
PDF
