Extracellular vesicles (EVs) mediate cellular communication through the transfer of active biomolecules, raising interest in using them as biological delivery vehicles for therapeutic drugs. For drug ...delivery applications, it is important to understand the intrinsic safety and toxicity liabilities of EVs. Nanoparticles, including EVs, typically demonstrate significant accumulation in the liver after systemic administration in vivo. We confirmed uptake of EVs derived from Expi293F cells into HepG2 cells and did not detect any signs of hepatotoxicity measured by cell viability, functional secretion of albumin, plasma membrane integrity, and mitochondrial and lysosomal activity even at high exposures of up to 5 × 1010 EVs per mL. Whole genome transcriptome analysis was used to measure potential effects on the gene expression in the recipient HepG2 cells at 24 h following exposure to EVs. Only 0.6% of all genes were found to be differentially expressed displaying less than 2-fold expression change, with genes related to inflammation or toxicity being unaffected. EVs did not trigger any proinflammatory cytokine response in HepG2 cells. However, minor changes were noted in human blood for interleukin (IL)-8, IL-6, and monocyte chemotactic protein 1 (MCP-1). Administration of 5 × 1010 Expi293F-derived EVs to BALB/c mice did not result in any histopathological changes or increases of liver transaminases or cytokine levels, apart from a modest increase in keratinocyte chemoattractant (KC). The absence of any significant toxicity associated with EVs in vitro and in vivo supports the prospective use of EVs for therapeutic applications and for drug delivery.
Purpose
The hypothesis in this study was that anaemia prior to surgery and perioperative red blood cell transfusion increases the risk for recurrence and overall mortality in patients with stages ...I–III colorectal cancer after abdominal resection with curative intent.
Methods
This is a Swedish single centre retrospective cohort study. Data on 496 consecutive radical abdominal resections stages I–III colorectal cancer performed at the Karolinska University Hospital 2007–2010 were extracted from the Swedish Colorectal Cancer Registry. Data were linked to local laboratory and transfusion databases to identify preoperative anaemia and perioperative transfusion. Disease recurrence was validated by scrutiny of patient records. A total of 496 stages I–III colorectal cancer patients were included in the analysis. Multivariate Cox regression analysis adjusted for tumour and patient characteristics were performed to assess risk for recurrence and overall mortality.
Results
Anaemia prior to surgery was associated with increased risk for overall mortality (HR 2.1, 95% CI 1.4–3.2). There was no association between anaemia and risk for recurrence (HR 1.6, 95% CI 0.97–2.6). Transfusion was not associated with increased risk of recurrence (HR 0.7, 95% CI 0.4–1.3) or overall mortality (HR 1.04, 95% CI 0.7–1.6).
Conclusions
Anaemia prior to colorectal cancer surgery was associated with increased risk for overall mortality while a no increased risk was seen for recurrence. Previous findings indicating an association between blood transfusion and increased risk for recurrence could not be confirmed.
Two >130-meter-diameter impact craters formed on Mars during the later half of 2021. These are the two largest fresh impact craters discovered by the Mars Reconnaissance Orbiter since operations ...started 16 years ago. The impacts created two of the largest seismic events (magnitudes greater than 4) recorded by InSight during its 3-year mission. The combination of orbital imagery and seismic ground motion enables the investigation of subsurface and atmospheric energy partitioning of the impact process on a planet with a thin atmosphere and the first direct test of martian deep-interior seismic models with known event distances. The impact at 35°N excavated blocks of water ice, which is the lowest latitude at which ice has been directly observed on Mars.
An insightful impact
On 24 December 2021, the seismometer for the InSight mission on Mars detected a large seismic event with a distinct signature. Posiolova
et al
. discovered that the event was caused by a meteor impact on the surface of Mars, which was confirmed by satellite observations of a newly formed 150-meter crater. The surface nature and size of the impact allowed Kim
et al
. to detect surface waves from the event, which have yet to be observed on Mars. These surface waves help to untangle the structure of the Martian crust, which has various amounts of volcanic and sedimentary rock, along with subsurface ice, in different regions of the planet (see the Perspective by Yang and Chen). The characteristics of the impact itself are important because they provide a seismic fingerprint of an impact event that is different from the marsquakes observed so far. —BG
A new crater formed on the surface of Mars was detected with the seismometer on the InSight mission.
The landforms of northern Gale crater on Mars expose thick sequences of sedimentary rocks. Based on images obtained by the Curiosity rover, we interpret these outcrops as evidence for past fluvial, ...deltaic, and lacustrine environments. Degradation of the crater wall and rim probably supplied these sediments, which advanced inward from the wall, infilling both the crater and an internal lake basin to a thickness of at least 75 meters. This intracrater lake system probably existed intermittently for thousands to millions of years, implying a relatively wet climate that supplied moisture to the crater rim and transported sediment via streams into the lake basin. The deposits in Gale crater were then exhumed, probably by wind-driven erosion, creating Aeolis Mons (Mount Sharp).
This study tested the hypothesis that the amount of blood loss during surgery for colonic cancer influences long-term survival.
The perioperative blood loss during surgery for colorectal cancer ...relates to the risk for complications and early mortality.
All patients who underwent surgery for colon cancer between 1997 and 2003 in the health-care region of Uppsala/Örebro were prospectively registered at the regional oncological center. Data on patients who underwent radical surgery for stages I to III disease were analyzed. Patients who died within 6 months after surgery were excluded. Hazard ratios were calculated with uni- and multivariate Cox proportional hazard regression. Because of covariation, blood loss, blood transfusion, and complications were tested in separate multivariate analyses.
Blood loss of 250 mL or more during surgery, male gender, occurrence of complications, age more than 75 years, and stage III disease were risk factors for overall mortality in the uni- and multivariate analyses. Perioperative blood transfusion was shown to be a risk factor in the univariate analysis only.
The results support the hypothesis that degree of blood loss during surgery for colon cancer is a factor that influences long-term survival.
Context.
Young giant planets are the best targets for characterization with direct imaging. The Medium Resolution Spectrometer (MRS) of the Mid-Infrared Instrument (MIRI) of the recently launched
...James Webb
Space Telescope (JWST) will give access to the first spectroscopic data for direct imaging above 5 µm with unprecedented sensitivity at a spectral resolution of up to 3700. This will provide a valuable complement to near-infrared data from ground-based instruments for characterizing these objects.
Aims.
We aim to evaluate the performance of MIRI/MRS in detecting molecules in the atmosphere of exoplanets and in constraining atmospheric parameters using Exo-REM atmospheric models.
Methods.
The molecular mapping technique based on cross-correlation with synthetic models was recently introduced. We test this promising detection and characterization method on simulated MIRI/MRS data.
Results.
Directly imaged planets can be detected with MIRI/MRS, and we are able to detect molecules (H
2
O, CO, NH
3
, CH
4
, HCN, PH
3
, CO
2
) at various angular separations depending on the strength of the molecular features and brightness of the target. We find that the stellar spectral type has a weak impact on the detection level. This method is globally most efficient for planets with temperatures below 1500 K, for bright targets, and for angular separations of greater than 1′′. Our parametric study allows us to anticipate the ability to characterize planets that will be detected in the future.
Conclusions.
The MIRI/MRS will give access to molecular species not yet detected in exoplanetary atmospheres. The detection of molecules acting as indicators of the temperature of the planets will make it possible to discriminate between various hypotheses of the preceding studies, and the derived molecular abundance ratios should bring new constraints on planet-formation scenarios.
Relatively young landforms on Mars, seen in high-resolution images acquired by the Mars Global Surveyor Mars Orbiter Camera since March 1999, suggest the presence of sources of liquid water at ...shallow depths beneath the martian surface. Found at middle and high martian latitudes (particularly in the southern hemisphere), gullies within the walls of a very small number of impact craters, south polar pits, and two of the larger martian valleys display geomorphic features that can be explained by processes associated with groundwater seepage and surface runoff. The relative youth of the landforms is indicated by the superposition of the gullies on otherwise geologically young surfaces and by the absence of superimposed landforms or cross-cutting features, including impact craters, small polygons, and eolian dunes. The limited size and geographic distribution of the features argue for constrained source reservoirs.
Sedimentary Rocks of Early Mars Malin, Michael C.; Edgett, Kenneth S.
Science (American Association for the Advancement of Science),
12/2000, Letnik:
290, Številka:
5498
Journal Article
Recenzirano
Layered and massive outcrops on Mars, some as thick as 4 kilometers, display the geomorphic attributes and stratigraphic relations of sedimentary rock. Repeated beds in some locations imply a dynamic ...depositional environment during early martian history. Subaerial (such as eolian, impact, and volcaniclastic) and subaqueous processes may have contributed to the formation of the layers. Affinity for impact craters suggests dominance of lacustrine deposition; alternatively, the materials were deposited in a dry, subaerial setting in which atmospheric density, and variations thereof mimic a subaqueous depositional environment. The source regions and transport paths for the materials are not preserved.
In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating ...recent-onset polyarticular JIA.
In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4-15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety.
In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare.
In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.
This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose,
51
...Cr-EDTA, mannitol or iohexol) from eight studies (
n
= 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg 95% confidence interval (CI) 117–125. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1–50.5), with a Hill coefficient of 3.40 (95%CI 3.03–3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.
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