17-β-estradiol, involved in mesothelioma pathogenesis, and its precursors were explored as potential biomarkers for the early diagnosis of mesothelioma. Using enzyme-linked immunosorbent assay(ELISA) ...for 17-β-estradiol and ultra-high performance liquid chromatography/tandem mass spectrometry(UHPLC-MS/MS) for 19 17-β-estradiol precursors, a comprehensive analysis of 20steroid hormones was conducted in the serum of mesothelioma patients(n=67), asbestos-exposed healthy subjects(n=39), and non-asbestos-exposed healthy subjects(n=35). Bioinformatics analysis explored three potential serum biomarkers: 17-β-estradiol, DHEA-S, and androstenedione. The results revealed significant differences in 17-β-estradiol levels between mesothelioma patients and both non-asbestos-exposed and asbestos-exposed healthy subjects. No significant variations in serum 17-β-estradiol levels were observed among mesothelioma patients at different stages, suggesting its potential as an early diagnostic marker. 17-β-estradiol levels were similar in mesothelioma patients with environmental and occupational asbestos exposure, while males with occupational asbestos exposure exhibited significantly higher levels of 17-β-estradiol compared to females. Significant reduction in androstenedione and an increase in DHEA-S were observed in asbestos-exposed individuals compared to non-asbestos-exposed individuals. The analysis of DHEA-S-androstenedione-17-β-estradiol signature score showed an increase in asbestos-exposed individuals and mesothelioma patients compared to non-asbestos-exposed individuals, and this score effectively distinguished between the groups. The Cancer Genome Atlas data was utilized to analyze the expression of 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 genes. The findings indicated that mesothelioma patients with elevated gene values for 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 have a worse or better prognosis on overall survival, respectively. In conclusion, this study suggests 17-β-estradiol, DHEA-S, and androstenedione as biomarkers for mesothelioma risk and early diagnosis of mesothelioma in asbestos-exposed individuals, aiding timely intervention and improved care.
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•E2 increased in healthy asbestos-exposed subjects and MPM patients.•DHEA-S-androstenedione-E2 signature score increased in asbestos-exposed subjects.•The signature differentiates subjects exposed to asbestos from those not exposed.•DHEA-S-androstenedione-E2 as biomarkers of MPM risk and early diagnosis of MPM.
In recent years, the application of pulsed electric fields with very short durations (nanoseconds) and extremely high amplitudes (MV/m) has been investigated for novel medical purposes. Various ...electric protocols have been explored for different objectives, including the utilization of fractionated pulse doses to enhance cell electrosensitization to the uptake of different markers or an increase in apoptosis. This study focused on the use of fluorescence imaging to examine molecular calcium fluxes induced by different fractionated protocols of short electric pulses in neuroblastoma (SH-SY5Y) and mesenchymal stem cells (HaMSCs) that were electroporated using nanosecond pulsed electric fields. In our experimental setup, we did not observe cell electrosensitization in terms of an increase in calcium flux following the administration of fractionated doses of nanosecond pulsed electric fields with respect to the non-fractionated dose. However, we observed the targeted activation of calcium-dependent genes (c-FOS, c-JUN, EGR1, NURR-1, β3-TUBULIN) based on the duration of calcium flux, independent of the instantaneous levels achieved but solely dependent on the final plateau reached. This level of control may have potential applications in various medical and biological treatments that rely on calcium and the delivery of nanosecond pulsed electric fields.
Several contributions of circulating microvesicles (MVs) to the endothelial dysfunction have been reported in the past; a head-to-head comparison of platelet- and monocyte-derived MVs has however ...never been performed. To this aim, we assessed the involvement of these MVs in vessel damage related processes, i.e., oxidative stress, inflammation, and leukocyte-endothelial adhesion. Platelets and monocytes isolated from healthy subjects (HS,
= 15) were stimulated with TRAP-6 and LPS to release MVs that were added to human vascular endothelial cell (hECV) culture to evaluate superoxide anion production, inflammatory markers (IL-6, TNF
, NF-κB mRNA expression), and hECV adhesiveness. The effects of the MVs-induced from HS were compared to those induced by MVs spontaneously released from cells of patients with ST-segment elevation myocardial infarction (STEMI,
= 7). MVs released by HS-activated cells triggered a threefold increase in oxidative burst in a concentration-dependent manner. Only MVs released from monocytes doubled IL-6, TNF
, and NF-κB mRNA expression and monocyte-endothelial adhesion. Interestingly, the effects of the MVs isolated from STEMI-monocytes were not superimposable to previous ones except for adhesion to hECV. Conversely, MVs released from STEMI-platelets sustained both redox state and inflammatory phenotype. These data provide evidence that MVs released from activated and/or pathologic platelets and monocytes differently affect endothelial behavior, highlighting platelet-MVs as causative factors of impaired endothelial function in the acute phase of STEMI.
A proper restoration of hip biomechanics is fundamental to achieve satisfactory outcomes after total hip arthroplasty (THA). A global hip offset (GO) postoperatively reduction of more than 5 mm was ...known to impair hip functionality after THA. This study aimed to verify the restoration of the GO radiographic parameter after primary THA by the use of a cementless femoral stem available in three different offset options without length changing.
From a consecutive series of 201 patients (201 hips) underwent primary cementless THA in our center with a minimum 3-year follow up, 80 patients (80 hips) were available for complete radiographic evaluation for GO and limb length (LL) and clinical evaluation with Harris hip score (HHS). All patients received the same femoral stem with three different offset options (option A with - 5 mm offset, option B and option C with + 5 mm offset, constant for each sizes) without changing stem length.
Mean GO significantly increased by + 3 mm (P < 0.05) and mean LL significantly decreased by + 5 mm (P < 0.05) after surgery, meaning that postoperatively the limb length of the operated side increased by + 5 mm. HHS significantly improved from 56.3 points preoperatively to 95.8 postoperatively (P < 0.001). Offset option A was used in 1 hip (1%), B in 59 hips (74%) and C in 20 hips (25%).
The femur is lateralized with a mean of + 5 mm after surgery than, the native anatomy, whatever type of stem was used. Thus, the use of this 3-offset options femoral stem is effective in restoring the native biomechanical hip parameters as GO, even if 2 offset options were considered sufficient to restore GO.
Nossana represents an important pre-Alpine karst spring for drinking supply, sustaining a water distribution system serving 300,000 people. The goal of this study was to project Nossana discharges ...and evaluate potential supply limits for four future periods (2021–2040, 2041–2060, 2061–2080, 2081–2100). Bias-corrected Regional Climate Models (RCMs), part of the EURO-CORDEX experiment and forced by three emission scenarios (RCP2.6, RCP4.5, RCP8.5), were evaluated, statistically downscaled, and used as input in a calibrated rainfall-runoff model ensemble. For each emission scenario, the calibrated model ensemble considered three RCMs and ten rainfall-runoff parameterizations. Projected ensemble mean discharges are lower than observations (3%–23%) for all RCPs, though they do not show a clear trend between the four time periods. Days characterized by discharges lower than actual water demand are projected to decrease, except for the RCP8.5 emission scenarios and the period 2081–2100. Conversely, the same consecutive days are expected to increase after 2060 for all emission scenarios. These results reflect the projected precipitation trend, characterized by longer, drier summer periods and wetter autumns in comparison to today’s climate. Also, they indicate a possible need for alternative drinking water resources. The proposed methodology was demonstrated to deliver useful quantitative information for water management in the mid- long-term period.
ABSTRACT
The evolution of the gravitational potentials on large scales due to the accelerated expansion of the Universe is an important and independent probe of dark energy, known as the integrated ...Sachs–Wolfe (ISW) effect. We measure this ISW effect through cross-correlating the cosmic microwave background maps from the Planck satellite with a radio continuum galaxy distribution map from the recent Rapid ASKAP Continuum Survey (RACS). We detect a positive cross-correlation at $\sim 2.8\, \sigma$ relative to the null hypothesis of no correlation. We parametrize the strength of the ISW effect through an amplitude parameter and find the constraints to be $A_{\mathrm{ISW}} = 0.94^{+0.42}_{-0.41}$, which is consistent with the prediction of an accelerating universe within the current concordance cosmological model, ΛCDM. The credible interval on this parameter is independent of the different bias models and redshift distributions that were considered when marginalizing over the nuisance parameters. We also detect a power excess in the galaxy autocorrelation angular power spectrum on large scales (ℓ ≤ 40), and investigate possible systematic causes.
Monocytes and macrophages have a central role in all phases of an inflammatory reaction. To understanding the regulation of monocyte activation during a physiological or pathological inflammation, we ...propose two
models that recapitulate the different phases of the reaction (recruitment, initiation, development, and resolution vs. persistence of inflammation), based on human primary blood monocytes exposed to sequential modifications of microenvironmental conditions. These models exclusively describe the functional development of blood-derived monocytes that first enter an inflammatory site. All reaction phases were profiled by RNA-Seq, and the two models were validated by studying the modulation of IL-1 family members. Genes were differentially modulated, and distinct clusters were identified during the various phases of inflammation. Pathway analysis revealed that both models were enriched in pathways involved in innate immune activation. We observe that monocytes acquire an M1-like profile during early inflammation, and switch to a deactivated M2-like profile during both the resolving and persistent phases. However, during persistent inflammation they partially maintain an M1 profile, although they lose the ability to produce inflammatory cytokines compared to M1 cells. The production of IL-1 family molecules by ELISA reflected the transcriptomic profiles in the distinct phases of the two inflammatory reactions. Based on the results, we hypothesize that persistence of inflammatory stimuli cannot maintain the M1 activated phenotype of incoming monocytes for long, suggesting that the persistent presence of M1 cells and effects in a chronically inflamed tissue is mainly due to activation of newly incoming cells. Moreover, being IL-1 family molecules mainly expressed and secreted by monocytes during the early stages of the inflammatory response (within 4-14 h), and the rate of their production decreasing during the late phase of both resolving and persistent inflammation, we suppose that IL-1 factors are key regulators of the acute defensive innate inflammatory reaction that precedes establishment of longer-term adaptive immunity, and are mainly related to the presence of recently recruited blood monocytes. The well-described role of IL-1 family cytokines and receptors in chronic inflammation is therefore most likely dependent on the continuous influx of blood monocytes into a chronically inflamed site.
This study aims to highlight the impact of physicochemical properties on the behaviour of nanopharmaceuticals and how much carrier structure and physiochemical characteristics weigh on the effects of ...a formulation. For this purpose, two commercially available nanosimilar formulations of Doxil and their respective carriers were compared as a case study. Although the two formulations were “similar”, we detected different toxicological effects (profiles) in terms of in vitro toxicity and immunological responses at the level of cytokines release and complement activation (iC3b fragment), that could be correlated with the differences in the physicochemical properties of the formulations. Shedding light on nanosimilar key quality attributes of liposome-based materials and the need for an accurate characterization, including investigation of the immunological effects, is of fundamental importance considering their great potential as delivery system for drugs, genes, or vaccines and the growing market demand.
Lithium codoping has emerged as an effective strategy to enhance the light yield of oxide scintillators for radiation detection applications, but the understanding of the actual role played by Li+ ...remains unclear. In this work, we comprehensively study the effects of Li codoping on optical and scintillation properties of Lu2SiO5:Ce (LSO:Ce) single crystals and reveal the critical role of site occupancy of Li. High-quality LSO:Ce single crystals codoped with 0.05, 0.1, and 0.3 at. % Li ions were grown by the Czochralski method. The optical absorption spectra confirm nonconversion of stable Ce3+ to Ce4+ in Li-codoped LSO:Ce regardless of the Li codoping concentration. The photoluminescence decay kinetics suggest an enhanced ionization of the excited 5d1 state of Ce3+ centers in highly codoped samples. A simultaneous improvement of scintillation light yield, decay time, and afterglow is achieved in LSO:Ce codoped with low concentrations of Li. The preferential occupation of Li at interstitial spaces and lutetium sites is proven to rely on its codoping concentration by using the 7Li nuclear magnetic resonance technique. The concentration-dependent site occupancy of Li alters the defect structures of LSO:Ce, in particular resulting in a distinct change in the number of cerium spatially correlated oxygen vacancies confirmed by thermoluminescence and afterglow measurements.
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