Major barriers to effective adenovirus-based gene therapy include induction of an immune response and tumor-specific targeting of vectors. The use of mesenchymal stem cells (MSC) as systemic delivery ...vehicles for therapeutic genes has been proposed as a result of their combined ability to home in on the tumor site and evade the host immune response. This study is aimed at investigating factors mediating homing of human MSCs to breast cancer primary cultures and cell lines in vitro and in vivo.
Fluorescently labeled MSCs were given to mice bearing breast cancer xenografts, and tumor tissue was harvested to detect MSC engraftment. MSC migration in response to primary breast tumors in vitro was quantified, and chemokines secreted by tumor cells were identified. The role of monocyte chemotactic protein-1 (MCP-1) in cell migration was investigated using antibodies and standards of the chemokine. Serum MCP-1 was measured in 125 breast cancer patients and 86 healthy controls.
Engrafted MSCs were detected in metastatic breast tumors in mice after systemic administration. There was a significant increase in MSC migration in response to primary breast tumor cells in vitro (6-fold to 11-fold increase). Tumor explants secreted a variety of chemokines including GROalpha, MCP-1, and stromal cell-derived factor-1alpha. An MCP-1 antibody caused a significant decrease (37-42%) in MSC migration to tumors. Serum MCP-1 levels were significantly higher in postmenopausal breast cancer patients than age-matched controls (P < 0.05).
These results highlight a role for tumor-secreted MCP-1 in stimulating MSC migration and support the potential of these cells as tumor-targeted delivery vehicles for therapeutic agents.
As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of ...these mitochondria‐targeted antioxidants is MitoQ, which contains the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Here, we review what has been learned from these animal and human studies with MitoQ.
The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are ...critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.
Key Uncertainties in the Recent Air‐Sea Flux of CO2 Woolf, D.K.; Shutler, J.D.; Goddijn‐Murphy, L. ...
Global biogeochemical cycles,
December 2019, 20191201, 2019-12, Letnik:
33, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The contemporary air‐sea flux of CO2 is investigated by the use of an air‐sea flux equation, with particular attention to the uncertainties in global values and their origin with respect to that ...equation. In particular, uncertainties deriving from the transfer velocity and from sparse upper ocean sampling are investigated. Eight formulations of air‐sea gas transfer velocity are used to evaluate the combined standard uncertainty resulting from several sources of error. Depending on expert opinion, a standard uncertainty in transfer velocity of either ~5% or ~10% can be argued and that will contribute a proportional error in air‐sea flux. The limited sampling of upper ocean fCO2 is readily apparent in the Surface Ocean CO2 Atlas databases. The effect of sparse sampling on the calculated fluxes was investigated by a bootstrap method, that is, treating each ship cruise to an oceanic region as a random episode and creating 10 synthetic data sets by randomly selecting episodes with replacement. Convincing values of global net air‐sea flux can only be achieved using upper ocean data collected over several decades but referenced to a standard year. The global annual referenced values are robust to sparse sampling, but seasonal and regional values exhibit more sampling uncertainty. Additional uncertainties are related to thermal and haline effects and to aspects of air‐sea gas exchange not captured by standard models. An estimate of global net CO2 exchange referenced to 2010 of −3.0 ± 0.6 Pg C/year is proposed, where the uncertainty derives primarily from uncertainty in the transfer velocity.
Plain Language Summary
The oceanic carbon sink reduces the rate of accumulation of CO2 in the atmosphere but is also responsible for the acidification of the ocean. One method of estimating the size of the oceanic carbon sink depends on a calculation of upward and downward flows of CO2 at the sea surface. This study revisits this calculation using updated knowledge of the transfer processes at the sea surface and the results of a large international collaborative effort (Surface Ocean CO2 Atlas) to collect and compile measurements of CO2 in the upper ocean. Greater sampling of the oceans improves estimates, but direct calculation in each year is not practical. Instead, we calculate fluxes in a recent year (2010) using upper ocean measurements of CO2 over many years. The remaining uncertainty is dominated by limited knowledge of the efficiency of stirring of gas across the sea surface, the air‐sea transfer velocity. The study suggests a relatively large downward flow of CO2 into the ocean compared to previous applications of this method and other methods to estimate the oceanic carbon sink. Increased knowledge is rewarded by reduced uncertainty in the net global flux; that flux is estimated at −3.0 ± 0.6 Pg C/year. Further understanding of transfer velocities and better sampling may reduce the uncertainty in the future.
Key Points
Increased understanding of air‐sea gas transfer processes and better sampling of the upper ocean enables higher confidence in calculations of air‐sea CO2 fluxes
The calculations imply a relatively large global net air‐to‐sea flux of −3.0 Pg C/year (referenced to 2010)
This flux is known within 0.6 Pg C/year, where uncertainty in air‐sea transfer velocity is the largest contribution to the combined uncertainty
Data are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin.
To assess inhibition of platelet ...function/reactivity and platelet activation with dipyridamole in CVD.
This prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. ‘Dipyridamole-high on-treatment platelet reactivity (HTPR)’ was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin.
Dipyridamole-HTPR was identified in 71.4–75% of patients on PFA-100 C-ADP, 83.9–86.8% of patients on VerifyNow P2Y12, and 81.5–83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR.
Additional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.
Transtracheal jet ventilation (TTJV) is recommended in several airway guidelines as a potentially life-saving procedure during the ‘Can’t Intubate Can’t Oxygenate’ (CICO) emergency. Some studies have ...questioned its effectiveness.
Our goal was to determine the complication rates of TTJV in the CICO emergency compared with the emergency setting where CICO is not described (non-CICO emergency) or elective surgical setting. Several databases of published and unpublished literature were searched systematically for studies describing TTJV in human subjects. Complications were categorized as device failure, barotrauma (including subcutaneous emphysema), and miscellaneous. Device failure was defined by the inability to place and/or use the TTJV device, not patient survival.
Forty-four studies (428 procedures) met the inclusion criteria. Four studies included both emergency and elective procedures. Thirty studies described 132 emergency TTJV procedures; 90 were CICO emergencies. Eighteen studies described 296 elective TTJV procedures. Device failure occurred in 42% of CICO emergency vs 0% of non-CICO emergency (P<0.001) and 0.3% of elective procedures (P<0.001). Barotrauma occurred in 32% of CICO emergency vs 7% of non-CICO emergency (P<0.001) and 8% of elective procedures (P<0.001). The total number of procedures with any complication was 51% of CICO emergency vs 7% of non-CICO emergency (P<0.001) and 8% of elective procedures (P<0.001). Several reports described TTJV-related subcutaneous emphysema hampering subsequent attempts at surgical airway or tracheal intubation.
TTJV is associated with a high risk of device failure and barotrauma in the CICO emergency. Guidelines and recommendations supporting the use of TTJV in CICO should be reconsidered.
We present Very Large Array observations of the 33 GHz radio continuum emission from 22 local ultraluminous and luminous infrared (IR) galaxies (U/LIRGs). These observations have spatial (angular) ...resolutions of 30-720 pc (0 07-0 67) in a part of the spectrum that is likely to be optically thin. This allows us to estimate the size of the energetically dominant regions. We find half-light radii from 30 pc to 1.7 kpc. The 33 GHz flux density correlates well with the IR emission, and we take these sizes as indicative of the size of the region that produces most of the energy. Combining our 33 GHz sizes with unresolved measurements, we estimate the IR luminosity and star formation rate per area and the molecular gas surface and volume densities. These quantities span a wide range (4 dex) and include some of the highest values measured for any galaxy (e.g., ). At least 13 sources appear Compton thick ( ). Consistent with previous work, contrasting these data with observations of normal disk galaxies suggests a nonlinear and likely multivalued relation between star formation rate and molecular gas surface density, though this result depends on the adopted CO-to-H2 conversion factor and the assumption that our 33 GHz sizes apply to the gas. Eleven sources appear to exceed the luminosity surface density predicted for starbursts supported by radiation pressure and supernova feedback; however, we note the need for more detailed observations of the inner disk structure. U/LIRGs with higher surface brightness exhibit stronger C ii 158 m deficits, consistent with the suggestion that high energy densities drive this phenomenon.
Background
Assessment of ‘high on-treatment platelet reactivity (HTPR)’ could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on ...antiplatelet therapy.
Methods
This prospective, multi-centre study assessed antiplatelet–HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50–99% carotid stenosis. Platelet function/reactivity was assessed under ‘moderately high shear stress’ with the PFA-100
®
and ‘low shear stress’ with VerifyNow
®
and Multiplate
®
analysers. Bilateral 1-h transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES + ve or MES − ve.
Results
Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the ‘early phase’ (≤ 4 weeks) and 37 patients in the ‘late phase’ (≥ 3 months) after TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg;
P
< 0.001), but not late symptomatic (75 mg;
P
= 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin–HTPR in early (28.6%;
P
= 0.028), but not late symptomatic (38.9%;
P
= 0.22) compared with asymptomatic patients (56.7%) on the PFA-100
®
, but not on the VerifyNow
®
or Multiplate
®
(P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin–HTPR on the PFA-100
®
(28.6%) vs. VerifyNow
®
(9.5%;
P
= 0.049), but not Multiplate
®
assays (11.9%,
P
= 0.10). There was no difference in aspirin–HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES − ve subgroup.
Discussion
Recently symptomatic moderate–severe carotid stenosis patients had a lower prevalence of aspirin–HTPR than their asymptomatic counterparts on the PFA-100
®
, likely related to higher aspirin doses. The prevalence of antiplatelet–HTPR was positively influenced by higher shear stress levels, but not MES status.
We present new 0.6-10 GHz observations of the binary neutron star merger GW170817 covering the period up to 300 days post-merger, taken with the upgraded Karl G. Jansky Very Large Array, the ...Australia Telescope Compact Array, the Giant Metrewave Radio Telescope and the MeerKAT telescope. We use these data to precisely characterize the decay phase of the late-time radio light curve. We find that the temporal decay is consistent with a power-law slope of t−2.2, and that the transition between the power-law rise and decay is relatively sharp. Such a slope cannot be produced by a quasi-isotropic (cocoon-dominated) outflow, but is instead the classic signature of a relativistic jet. This provides strong observational evidence that GW170817 produced a successful jet, and directly demonstrates the link between binary neutron star mergers and short-hard gamma-ray bursts. Using simple analytical arguments, we derive constraints on the geometry and the jet opening angle of GW170817. These results are consistent with those from our companion very long baseline interferometry paper, reporting superluminal motion in GW170817.
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