In the last decade, Acute Kidney Injury (AKI) diagnosis and therapy have not notably improved probably due to delay in the diagnosis, among other issues. Precocity and accuracy should be critical ...parameters in novel AKI biomarker discovery. microRNAs are key regulators of cell responses to many stimuli and they can be secreted to the extracellular environment. Therefore, they can be detected in body fluids and are emerging as novel disease biomarkers. We aimed to identify and validate serum miRNAs useful for AKI diagnosis and management. Using qRT-PCR arrays in serum samples, we determined miRNAs differentially expressed between AKI patients and healthy controls. Statistical and target prediction analysis allowed us to identify a panel of 10 serum miRNAs. This set was further validated, by qRT-PCR, in two independent cohorts of patients with relevant morbi-mortality related to AKI: Intensive Care Units (ICU) and Cardiac Surgery (CS). Statistical correlations with patient clinical parameter were performed. Our results demonstrated that the 10 selected miRNAs (miR-101-3p, miR-127-3p, miR-210-3p, miR-126-3p, miR-26b-5p, miR-29a-3p, miR-146a-5p, miR-27a-3p, miR-93-3p and miR-10a-5p) were diagnostic biomarkers of AKI in ICU patients, exhibiting areas under the curve close to 1 in ROC analysis. Outstandingly, serum miRNAs estimated before CS predicted AKI development later on, thus becoming biomarkers to predict AKI predisposition. Moreover, after surgery, the expression of the miRNAs was modulated days before serum creatinine increased, demonstrating early diagnostic value. In summary, we have identified a set of serum miRNAs as AKI biomarkers useful in clinical practice, since they demonstrate early detection and high diagnostic value and they recognize patients at risk.
In this work, we show that TGF‐β produced by colorectal cancer cells activates pericytes that in turn promote their tumorigenic properties through the release of soluble factors, including IGFBP‐3, ...with a prominent role in cancer cell migration and invasion. Moreover, co‐implantation of colorectal cancer cells and pericytes in immunodeficient mice increased tumor growth.
The crosstalk between cancer cells and the tumor microenvironment has been implicated in cancer progression and metastasis. Fibroblasts and immune cells are widely known to be attracted to and modified by cancer cells. However, the role of pericytes in the tumor microenvironment beyond endothelium stabilization is poorly understood. Here, we report that pericytes promoted colorectal cancer (CRC) cell proliferation, migration, invasion, stemness, and chemoresistance in vitro, as well as tumor growth in a xenograft CRC model. We demonstrate that coculture with human CRC cells induced broad transcriptomic changes in pericytes, mostly associated with TGF‐β receptor activation. The prognostic value of a TGF‐β response signature in pericytes was analyzed in CRC patient data sets. This signature was found to be a good predictor of CRC relapse. Moreover, in response to stimulation by CRC cells, pericytes expressed high levels of TGF‐β1, initiating an autocrine activation loop. Investigation of secreted mediators and underlying molecular mechanisms revealed that IGFBP‐3 is a key paracrine factor from activated pericytes affecting CRC cell migration and invasion. In summary, we demonstrate that the interplay between pericytes and CRC cells triggers a vicious cycle that stimulates pericyte cytokine secretion, in turn increasing CRC cell tumorigenic properties. Overall, we provide another example of how cancer cells can manipulate the tumor microenvironment.
Formaldehyde (CH2O) is a tracer of the photochemical activity of the atmosphere. Linked to air quality, CH2O is an ozone (O3) precursor and serves as a proxy for natural and anthropogenic reactive ...organic emissions. As a product of the photooxidation of methane (CH4) and other hydrocarbons (e.g., isoprene), CH2O represents an important source of radicals in the remote free troposphere. This work aims at improving the characterization of this part of the troposphere where data are scarce. In particular, this study assesses the presence of CH2O at two high-altitude remote sites: El Teide (TEI, 3570 m a.s.l., Tenerife, Canary Islands, Spain) and Pic du Midi (PDM, 2877 m a.s.l., French Pyrenees). Through ground-based remote sensing measurements performed during two field campaigns in July (TEI) and September (PDM) 2013, this study presents the vertical distribution of CH2O at both locations. Results at PDM show that CH2O mixing ratios follow a decreasing vertical profile with a mean maximum of 0.5 ± 0.2 nmol mol−1 (i.e., ppbv) at the instruments' altitude. At TEI, observations indicate an uplifted layer of CH2O with a mean maximum of 1.3 ± 0.3 nmol mol−1 at 3.8 km a.s.l. (i.e., 300 m above the instrument's altitude). At both remote sites, the observed CH2O levels are higher than expected for background methane oxidation (a threefold increase in the case of TEI). Air mass back trajectory analysis links CH2O observations with abundant natural (e.g. forests) and/or anthropogenic isoprene emissions from the region nearby PDM, while the high CH2O levels detected at TEI indicate in-plume formation of CH2O resulting from its precursors emitted from west-African and Canadian fires. Finally, as a key trace gas for O3 and HOx chemistries, we estimate the upper limit of bromine monoxide (BrO) in the free troposphere at TEI and PDM to be 0.8 and 1.5 pmol mol−1 (i.e., pptv) respectively.
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•Vertical profiles of formaldehyde mixing ratios at two high-altitude remote sites.•Uplifted layer of formaldehyde above El Teide.•Long-range transport of wildfire emissions into the North Atlantic free troposphere.•Isoprene emissions from the Pyrenees and/or Spain reach Pic du Midi.•First reported observations of atmospheric formaldehyde in the Pyrenees.
Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited ...to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.
A reduction in
levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated ...with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case.
Adverse ventricular remodeling is the heart's response to damaging stimuli and is linked to heart failure and poor prognosis. Formyl-indolo 3,2-b carbazole (FICZ) is an endogenous ligand for the aryl ...hydrocarbon receptor (AhR), through which it exerts pleiotropic effects including protection against inflammation, fibrosis, and oxidative stress. We evaluated the effect of AhR activation by FICZ on the adverse ventricular remodeling that occurs in the early phase of pressure overload in the murine heart induced by transverse aortic constriction (TAC). Cardiac structure and function were evaluated by cardiac magnetic resonance imaging (CMRI) before and 3 days after Sham or TAC surgery in mice treated with FICZ or with vehicle, and cardiac tissue was used for biochemical studies. CMRI analysis revealed that FICZ improved cardiac function and attenuated cardiac hypertrophy. These beneficial effects involved the inhibition of the hypertrophic calcineurin/NFAT pathway, transcriptional reduction in pro-fibrotic genes, and antioxidant effects mediated by the NRF2/NQO1 pathway. Overall, our findings provide new insight into the role of cardiac AhR signaling in the injured heart.
The Radiation and Dust Sensor is one of six sensors of the Mars Environmental Dynamics Analyzer onboard the Perseverance rover from the Mars 2020 NASA mission. Its primary goal is to characterize the ...airbone dust in the Mars atmosphere, inferring its concentration, shape and optical properties. Thanks to its geometry, the sensor will be capable of studying dust-lifting processes with a high temporal resolution and high spatial coverage. Thanks to its multiwavelength design, it will characterize the solar spectrum from Mars' surface. The present work describes the sensor design from the scientific and technical requirements, the qualification processes to demonstrate its endurance on Mars' surface, the calibration activities to demonstrate its performance, and its validation campaign in a representative Mars analog. As a result of this process, we obtained a very compact sensor, fully digital, with a mass below 1 kg and exceptional power consumption and data budget features.
For decades, reactive halogen species (RHSs) have been the subject of detailed
scientific research due to their influence on the oxidizing capacity of the
atmosphere and on the climate. From the ...RHSs, those containing bromine are of
particular interest in the polar troposphere as a result of their link to
ozone-depletion events (ODEs) and to the perturbation of the cycle of toxic mercury, for example. Given its remoteness and related limited accessibility
compared to the Arctic region, the RHSs in the Antarctic troposphere are still
poorly characterized. This work presents ground-based observations of
tropospheric BrO from two different Antarctic locations: Marambio Base
(64∘13′ S, 56∘37′ W) and Belgrano II Base
(77∘52′ S, 34∘7′ W) during the sunlit
period of 2015. By means of MAX-DOAS (Multi-axis Differential Optical
Absorption Spectroscopy) measurements of BrO performed from the two research
sites, the seasonal variation in this reactive trace gas is described along
with its vertical and geographical distribution in the Antarctic environment.
Results show an overall vertical profile of BrO mixing ratio decreasing with
altitude, with a median value of 1.6 pmol mol−1 in the lowest layers
of the troposphere. Additionally, observations show that the polar sunrise
triggers a geographical heterogeneous increase in bromine content in the
Antarctic troposphere yielding a maximum BrO at Marambio (26 pmol mol−1), amounting to 3-fold the values observed at Belgrano at dawn.
Data presented herein are combined with previous studies and ancillary data
to update and expand our knowledge of the geographical and vertical
distribution of BrO in the Antarctic troposphere, revealing Marambio as one
of the locations with the highest BrO reported so far in Antarctica. Furthermore,
the observations gathered during 2015 serve as a proxy to investigate the
budget of reactive bromine (BrOx = Br + BrO) and the
bromine-mediated ozone loss rate in the Antarctic troposphere.
The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the ...reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes.
We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y.
Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%.
Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.
► Field assays with caged lugworms are a valuable tool for sediment quality assessment. ► Lugworm biochemical biomarkers are useful detecting toxicity and chemical exposure. ► Cadiz Bay sediments ...were not toxic for Arenicola marina. ► Sediment PAHs in Santander Bay and LPGC Port induced toxic responses in A. marina. ► PPCPs were identified as possible cause of toxicity for lugworms.
Sediment toxicity assessments using caged organisms present advantages over using laboratory and native community studies. The use of caged Arenicola marina in sediment toxicity assessments was evaluated. Lugworms were exposed in situ to sediments from coastal and port areas in Spain for seven days, and the activities of the biotransformation enzymes ethoxyresorufin O-deethylase, dibenzylfluorescein dealkylase and glutathione S-transferase, the activities of the antioxidant enzymes glutathione reductase and glutathione peroxidase and lipid peroxidation were then analyzed as biomarkers. Biomarker results and sediment physicochemical data were integrated. Cádiz Bay (SW Spain) sediments presented metal contamination that was not linked to a biochemical response. In LPGC Port (SW Spain), Pb contamination exhibited a moderate toxic potential, while PAHs, and presumably pharmaceuticals, provoked biochemical responses that efficiently prevented lipid peroxidation. In Santander Bay (N Spain), exposure to PAHs and, presumably, pharmaceuticals induced biomarker responses, but lipid peroxidation occurred nevertheless. These results indicated that caged A. marina were effective for the assessment of sediment quality and that the selected biomarkers were sufficiently sensitive to identify chemical exposure and toxicity.
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