4,013 research outputs found

    Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

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    Manganese oxide (MnO) nanoparticles (NPs) can serve as robust pH-sensitive contrast agents for magnetic resonance imaging (MRI) due to Mn2+ release at low pH, which generates a ~30 fold change in T1 relaxivity. Strategies to control NP size, composition, and Mn2+ dissolution rates are essential to improve diagnostic performance of pH-responsive MnO NPs. We are the first to demonstrate that MnO NP size and composition can be tuned by the temperature ramping rate and aging time used during thermal decomposition of manganese(II) acetylacetonate. Two different temperature ramping rates (10°C/min and 20°C/min) were applied to reach 300°C and NPs were aged at that temperature for 5, 15, or 30 min. A faster ramping rate and shorter aging time produced the smallest NPs of ~23 nm. Shorter aging times created a mixture of MnO and Mn3O4 NPs, whereas longer aging times formed MnO. Our results indicate that a 20°C/min ramp rate with an aging time of 30 min was the ideal temperature condition to form the smallest pure MnO NPs of ~32 nm. However, Mn2+ dissolution rates at low pH were unaffected by synthesis conditions. Although Mn2+ production was high at pH 5 mimicking endosomes inside cells, minimal Mn2+ was released at pH 6.5 and 7.4, which mimic the tumor extracellular space and blood, respectively. To further elucidate the effects of NP composition and size on Mn2+ release and MRI contrast, the ideal MnO NP formulation (~32 nm) was compared with smaller MnO and Mn3O4 NPs. Small MnO NPs produced the highest amount of Mn2+ at acidic pH with maximum T1 MRI signal; Mn3O4 NPs generated the lowest MRI signal. MnO NPs encapsulated within poly(lactide-co-glycolide) (PLGA) retained significantly higher Mn2+ release and MRI signal compared to PLGA Mn3O4 NPs. Therefore, MnO instead of Mn3O4 should be targeted intracellularly to maximize MRI contrast

    Neuroprotective fragment C of tetanus toxin modulates IL-6 in an ALS mouse model

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    Neuroinflammation plays a significant role in amyotrophic lateral sclerosis (ALS) pathology, leading to the development of therapies targeting inflammation in recent years. Our group has studied the tetanus toxin C-terminal fragment (TTC) as a therapeutic molecule, showing neuroprotective properties in the SOD1G93A mouse model. However, it is unknown whether TTC could have some effect on inflammation. The objective of this study was to assess the effect of TTC on the regulation of inflammatory mediators to elucidate its potential role in modulating inflammation occurring in ALS. After TTC treatment in SOD1G93A mice, levels of eotaxin-1, interleukin (IL)-2, IL-6 and macrophage inflammatory protein (MIP)-1 alpha (ff) and galectin-1 were analyzed by immunoassays in plasma samples, whilst protein expression of caspase-1, IL-1ÎČ, IL-6 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was measured in the spinal cord, extensor digitorum longus (EDL) muscle and soleus (SOL) muscle. The results showed reduced levels of IL-6 in spinal cord, EDL and SOL in treated SOD1G93A mice. In addition, TTC showed a different role in the modulation of NLRP3 and caspase-1 depending on the tissue analyzed. In conclusion, our results suggest that TTC could have a potential anti-inflammatory effect by reducing IL-6 levels in tissues drastically affected by the disease. However, further research is needed to study more in depth the anti-inflammatory effect of TTC in ALS

    Chemotherapeutic agent 5-fluorouracil increases survival of SOD1 mouse model of ALS

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    Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease with no cure. Currently there are only two ALS drugs approved by the FDA, both with a limited therapeutic effect. In the search for drug candidates for ALS, we studied the effect of known stem cell mobilizing agents (treatment) and antimetabolite 5-fluorouracil (5-FU) (anti-treatment) in SOD1G93A model of ALS. Surprisingly, we found that anti-cancer drug 5-FU increases lifespan, delays the disease onset and improves motor performance in ALS mice. Although we were not able to demonstrate the mechanistic basis of the beneficial 5-FU action in ALS mice, our findings suggest that 5-FU or similar drugs are possible drug candidates for the treatment of motor neuron diseases through drug repurposing

    Impact of the COVID-19 pandemic on the care of cancer patients in Spain

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    Background: Studies evaluating the effects of the COVID-19 pandemic on public healthcare systems are limited, particularly in cancer management. As no such studies have been carried out in Spain, our objective is to describe and quantify the impact of the COVID-19 pandemic on cancer patients in Spanish hospitals during the first wave of the pandemic. Materials and methods: This retrospective, multicenter, nationwide study collected information from hospital departments treating oncology patients. An electronic questionnaire comparing outcomes and management of oncohematological patients for the March-June 2019 and March-June 2020 periods was used. Results: Information from 78 departments (36 tertiary hospitals) was analyzed. Forty-four departments implemented adapted protocols during March 2020. Most of these (n = 38/44; 86.4%) carried out COVID-19 triage, while 26 of 44 (59.1%) carried out onsite polymerase chain reaction tests for clinically suspected cases. A shift from in-person to telephone visits was observed in 43 of 44 (97.7%) departments. Comparing the March-June 2019 and March-June 2020 periods, the number of new patients decreased by 20.8% (from 160.2 to 126.4). Decreases were also seen in the mean number of total (2858.2 versus 1686.1) and cancer (465.5 versus 367.2) biopsies, as well as the mean number of bone marrow biopsies (30.5 versus 18.6). Concerning the number of patients visiting specific cancer care departments, a decrease from 2019 to 2020 was seen for mean number of chemotherapy treatments (712.7 versus 643.8) and radiation therapy (2169.9 versus 2139.9). Finally, a reduction from 2019 to 2020 of 12.9% (from 8.6 to 7.4) in the mean number of patients included in clinical trials was noted. Conclusions: This study provides the first comprehensive data concerning the impact of COVID-19 on cancer care in Spain. The pandemic caused a 20.8% decrease in newly diagnosed patients, which may impact future outcomes. Measures must be taken to ensure cancer management receives priority in times of healthcare emergencies

    Modular framework to assess the risk of African swine fever virus entry into the European Union

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    BACKGROUND The recent occurrence and spread of African swine fever (ASF) in Eastern Europe is perceived as a serious risk for the pig industry in the European Union (EU). In order to estimate the potential risk of ASF virus (ASFV) entering the EU, several pathways of introduction were previously assessed separately. The present work aimed to integrate five of these assessments (legal imports of pigs, legal imports of products, illegal imports of products, fomites associated with transport and wild boar movements) into a modular tool that facilitates the visualization and comprehension of the relative risk of ASFV introduction into the EU by each analyzed pathway. RESULTS The framework's results indicate that 48% of EU countries are at relatively high risk (risk score 4 or 5 out of 5) for ASFV entry for at least one analyzed pathway. Four of these countries obtained the maximum risk score for one pathway: Bulgaria for legally imported products during the high risk period (HRP); Finland for wild boar; Slovenia and Sweden for legally imported pigs during the HRP. Distribution of risk considerably differed from one pathway to another; for some pathways, the risk was concentrated in a few countries (e.g., transport fomites), whereas other pathways incurred a high risk for 4 or 5 countries (legal pigs, illegal imports and wild boar). CONCLUSIONS The modular framework, developed to estimate the risk of ASFV entry into the EU, is available in a public domain, and is a transparent, easy-to-interpret tool that can be updated and adapted if required. The model's results determine the EU countries at higher risk for each ASFV introduction route, and provide a useful basis to develop a global coordinated program to improve ASFV prevention in the EU

    Heterogeneity of melanoma cell responses to sleep apnea-derived plasma exosomes and to intermittent hypoxia

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    Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-to-severe OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL-1424 cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

    Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia

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    Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-tosevere OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL1424 cells

    Calibration and first results of relative humidity sensor MEDA HS onboard M2020 rover

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    MEDA HS is the relative humidity sensor on the Mars 2020 Perseverance rover provided by theFinnish Meteorological Institute (FMI). The sensor is a part of Mars Environmental DynamicAnalyzer (MEDA), a suite of environmental sensors provided by Centro de AstrobiologĂ­a in Madrid,Spain. MEDA HS, along with METEO-H in ExoMars 2022 surface platform, is a successor of REMS-Hon board Curiosity.Calibration of relative humidity (RH) instruments for Mars missions is challenging due to the rangeof RH (from 0 to close to 100%) and temperature conditions (from about -90 ÂșC to + 22 ÂșC) thatneed to be simulated in the lab. Thermal gradients in different parts of the system need to be wellknown and controlled to ensure reliable reference RH readings. For MEDA HS the calibration testshave been performed for different models of MEDA HS in three Martian humidity simulatorlaboratories: FMI laboratory, Michigan Mars Environmental Chamber (MMEC) and DLR PASLAB(Planetary Analog Simulation Laboratory). MEDA HS flight model was tested at FMI together with flight spare and ground reference models inlow pressure dry CO2 gas from +22ÂșC to -70ÂșC and in saturation conditions from -40ÂșC down to-70ÂșC. Further, the MEDA HS flight model final calibration is complemented by calibration datatransferred from an identical ground reference model which has gone through rigorous testingalso after the flight model delivery. During the test campaign at DLR PASLAB that started inAutumn 2020, MEDA HS has been calibrated over the full relative humidity scale between -70 to-40ÂșC in CO2 in the pressure ranges from 5.5 to 9.5 hPa, representative of Martian surfaceatmospheric pressure. The results can be extrapolated to higher and lower temperatures.In this presentation the final flight calibration and performance of the MEDA HS will be presentedtogether with first results expected from the surface of Mars by the Perseverance rover
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