Antineoplastic drugs in urban wastewater: Occurrence, nanofiltration treatment and toxicity screening*

Antineoplastic drugs are pharmaceuticals that have been raising concerns among the scientific community due to: (i) their increasing prescription in the fight against the disease of the twentieth century (cancer); (ii) their recalcitrance to conventional wastewater treatments; (iii) their poor environmental biodegradability; and (iv) their potential risk to any eukaryotic organism. This emerges the urgency in finding solutions to mitigate the entrance and accumulation of these hazardous chemicals in the environment. Advanced oxidation processes (AOPs) have been taken into consideration to improve the degradation of antineoplastic drugs in wastewater treatment plants (WWTPs), but the formation of by-products that are more toxic or exhibit a different toxicity profile than the parent drug is frequently reported. This work evaluates the performance of a nanofiltration pilot unit, equipped with a Desal 5DK membrane, in the treatment of real WWTP effluents contaminated (without spiking) with eleven pharmaceuticals, five of which were never studied before. Average removals of 68 & PLUSMN; 23% were achieved for the eleven compounds, with decreasing risks from feed to permeate for aquatic organisms from receiving waterbodies (with the exception of cyclophosphamide, for which a high risk was estimated in the permeate). Aditionally, no significative impact on the growth and germination of three different seeds (Lepidium sativum, Sinapis alba, and Sorghum saccharatum) were determined for permeate matrix in comparison to the control.& nbsp;This research was financially supported by: (i) Project POCI-01-0145-FEDER-031297 (CytoStraTech) -funded by FEDER funds through COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI) and by national funds (PIDDAC) through FCT/MCTES; (ii) NORTE-01-0145-FEDER-000069 (Healthy Waters) co-funded by European Regional Development Fund (ERDF) , through North Portugal Regional Operational Programme (NORTE 2020) , under the PORTUGAL 2020 Partnership Agreement; (iii) UIDB/04750/2020 (EPIUnit) and LA/P/0064/2020 (ITR) , funded by national funds through the FCT-Foundation for Science and Technology, I.P.; (iv) LA/P/0045/2020 (ALiCE) , Base Fundings UIDB/00511/2020 and UIDP/00511/2020 (LEPABE) and UIDB/50020/2020 and UIDP/50020/2020 (LSRE-LCM) , funded by national funds through FCT/MCTES (PIDDAC) . This work was also funded by Fundacao para a Ciencia e Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and the Associate Laboratory LS4FUTURE (LA/P/0087/2020) . Teresa I.A. Gouveia and Vanessa Jorge Pereira would like to thank the Portuguese Foundation for Science and Technology (FCT) for Ph.D. (SFRH/BD/147301/2019) and CEECIND/02919/2018 grants, respectively

Nanofiltration combined with ozone-based processes for the removal of antineoplastic drugs from wastewater effluents

Over the past years, there has been an increasing concern about the occurrence of antineoplastic drugs in water bodies. The incomplete removal of these pharmaceuticals from wastewaters has been confirmed by several scientists, making it urgent to find a reliable technique or a combination of techniques capable to produce clean and safe water. In this work, the combination of nanofiltration and ozone (O3)-based processes (NF + O3, NF + O3/H2O2 and NF + O3/H2O2/UVA) was studied aiming to produce clean water from wastewater treatment plant (WWTP) secondary effluents to be safely discharged into water bodies, reused in daily practices such as aquaculture activities or for recharging aquifers used as abstraction sources for drinking water production. Nanofiltration was performed in a pilot-scale unit and O3-based processes in a continuous-flow column. The peroxone process (O3/H2O2) was considered the most promising technology to be coupled to nanofiltration, all the target pharmaceuticals being removed at an extent higher than 98% from WWTP secondary effluents, with a DOC reduction up to 92%. The applicability of the clean water stream for recharging aquifers used as abstraction sources for drinking water production was supported by a risk assessment approach, regarding the final concentrations of the target pharmaceuticals. Moreover, the toxicity of the nanofiltration retentate, a polluted stream generated from the nanofiltration system, was greatly decreased after the application of the peroxone process, which evidences the positive impact on the environment of implementing a NF + O3/H2O2 process

Changes of Soluble CD40 Ligand in the Progression of Acute Myocardial Infarction Associate to Endothelial Nitric Oxide Synthase Polymorphisms and Vascular Endothelial Growth Factor But Not to Platelet CD62P Expression

Reported in vitro data implicated soluble CD40 ligand (sCD40L) in endothelial dysfunction and angiogenesis. However, whether sCD40L could exert that influence in endothelial dysfunction and angiogenesis after injury in acute myocardial infarction (AMI) patients remains unclear. In the present study, we evaluated the association of sCD40L with markers of platelet activation, endothelial, and vascular function during a recovery period early after AMI. To achieve this goal, the time changes of soluble, platelet-bound, and microparticle-bound CD40L levels over 1 month were assessed in AMI patients and correlated with endothelial nitric oxide synthase (eNOS) polymorphisms, vascular endothelial growth factor (VEGF) concentrations, and platelet expression of P-selectin (CD62P). The association of soluble form, platelet-bound, and microparticle-bound CD40L with CD62P expression on platelets, a marker of platelet activation, was also assessed to evaluate the role of CD40L in the thrombosis, whereas the association with eNOS and VEGF was to evaluate the role of CD40L in vascular dysfunction. This work shows for the first time that time changes of sCD40L over 1 month after myocardial infarct onset were associated with G894T eNOS polymorphism and with the VEGF concentrations, but not to the platelet CD62P expression. These results indicate that, in terms of AMI pathophysiology, the sCD40L cannot be consider just as being involved in thrombosis and inflammation but also as having a relevant role in vascular and endothelial dysfunction

Stratification of ST-Elevation Myocardial Infarction Patients Based on Soluble CD40L Longitudinal Changes

Involvement of soluble CD40 ligand (sCD40L) in thrombosis and inflammation on the context of coronary artery disease is currently being revised. In that perspective, we had studied the association of sCD40L with markers of platelet activation and markers of endothelial and vascular function. On that cohort, a stratification of patients with acute myocardial infarction (AMI) 1 month after percutaneous coronary intervention (PCI) was observed based on concentrations of sCD40L. The study intended to identify the groups of AMI patients with different profiles of sCD40L concentrations and verify how medication, clinical evolution, biochemical data, and markers of regulation of endothelial function at genetic (endothelial nitric oxide synthase polymorphisms) and post-transcriptional levels (circulating microRNAs) affect sCD40L serum levels. Lower quartiles of sCD40L (<2.3 ng/mL) were associated with higher concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high frequency of G894T polymorphism, and altered expression of a set of microRNAs assumed to be involved in the regulation of endothelial and cardiac function and myocardium hypertrophy, relative to patients in sCD40L upper quartiles. A characteristic sCD40L variation pattern in STEMI patients was identified. Low levels of sCD40L 1 month after PCI distinguish STEMI patients with worse prognosis, a compromised cardiac healing, and a persistent endothelial dysfunction, as given by the association between sCD40L, NT-proBNP, G894T polymorphism, and specific profile of miRNA expression. These results suggest sCD40L could have a prognostic value in STEMI patients.info:eu-repo/semantics/publishedVersio

EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM

Background and Aims: To maximize cost/efficay of boceprevirbased triple therapy (BOC) in patients with HCV-related advanced fibrosis/cirrhosis. Methods: ITT SVR12, safety and futility rules value were evaluated in the multicenter national Italian and Spanish early access Name- Patient-Program which includes treatment-experienced patients with HCVG1-related advanced fibrosis/cirrhosis (Metavir F3/4) treated with BOC in both countries. Results: 402 patients (mean age 55 years; range 22–75), 316 (78.6%) G1b, 255 (63.4%) F4, 60 (30.9%) with oesophageal varices, 137 (34.1%) relapsers, 95 (23.6%) partial and 168 (41.8%) null responders were enrolled. Platelets count <100,000 and albumin levels <3.5 g/dl were present in 49 (12.2%) and 22 (6.3%) patients, respectively. 369 (91.8%) received at least 1 dose of BOC. Overall ITT SVR12 rates and according to prior response to P/R, fibrosis stage and TW8 HCV-RNA value to P/R/BOC are reported in the table. At multivariate analysis, the strongest predictors of SVR12 were TW8 HCV-RNA undetectability (RR, 30.8; 95% CI, 8.7–108.7) and HCV-RNA detectable but <1000 IU/mL (RR, 9.1; 95% CI, 2.6–31.8) compared to those with HCV-RNA ≥1000 IU/mL. Two patients (0.5%) died from multi-organ failure, 13 (3.2%) developed hepatic decompensation, 41 (10.2%) had severe anemia (<8.5 g/dl) and 31 (7.7%) required at least one blood transfusion. Conclusions: In treatment-experienced patients with advanced fibrosis/cirrhosis, SVR12 attained by BOC was satisfactory. Mortality, life-threatening adverse events and severe anemia rates were similar to those reported in other real-practice studies. A TW8 futility rule enables a safely discontinuation of BOC in patients who are extremely unlikely to achieve SVR, thus optimizing the effectiveness of treatment in this difficult-to-cure population

Spiral attractor created by vector solitons

Mode-locked lasers emitting a train of femtosecond pulses called dissipative solitons are an enabling technology for metrology, high-resolution spectroscopy, fibre optic communications, nano-optics and many other fields of science and applications. Recently, the vector nature of dissipative solitons has been exploited to demonstrate mode locked lasing with both locked and rapidly evolving states of polarisation. Here, for an erbium-doped fibre laser mode locked with carbon nanotubes, we demonstrate the first experimental and theoretical evidence of a new class of slowly evolving vector solitons characterized by a double-scroll chaotic polarisation attractor substantially different from Lorenz, Rössler and Ikeda strange attractors. The underlying physics comprises a long time scale coherent coupling of two polarisation modes. The observed phenomena, apart from the fundamental interest, provide a base for advances in secure communications, trapping and manipulation of atoms and nanoparticles, control of magnetisation in data storage devices and many other areas

Polysialic Acid Is Required for Dopamine D2 Receptor-Mediated Plasticity Involving Inhibitory Circuits of the Rat Medial Prefrontal Cortex

Decreased expression of dopamine D2 receptors (D2R), dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT) after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN) neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA-NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R influences structural plasticity of mPFC interneurons and point to PSA-NCAM as a key player in this remodeling

A parameter-free total Lagrangian smooth particle hydrodynamics algorithm applied to problems with free surfaces

This paper presents a new Smooth Particle Hydrodynamics computational framework for the solution of inviscid free surface flow problems. The formulation is based on the Total Lagrangian description of a system of first-order conservation laws written in terms of the linear momentum and the Jacobian of the deformation. One of the aims of this paper is to explore the use of Total Lagrangian description in the case of large deformations but without topological changes. In this case, the evaluation of spatial integrals is carried out with respect to the initial undeformed configuration, yielding an extremely efficient formulation where the need for continuous particle neighbouring search is completely circumvented. To guarantee stability from the SPH discretisation point of view, consistently derived Riemann-based numerical dissipation is suitably introduced where global numerical entropy production is demonstrated via a novel technique in terms of the time rate of the Hamiltonian of the system. Since the kernel derivatives presented in this work are fixed in the reference configuration, the non-physical clumping mechanism is completely removed. To fulfil conservation of the global angular momentum, a posteriori (least-squares) projection procedure is introduced. Finally, a wide spectrum of dedicated prototype problems is thoroughly examined. Through these tests, the SPH methodology overcomes by construction a number of persistent numerical drawbacks (e.g. hour-glassing, pressure instability, global conservation and/or completeness issues) commonly found in SPH literature, without resorting to the use of any ad-hoc user-defined artificial stabilisation parameters. Crucially, the overall SPH algorithm yields equal second order of convergence for both velocities and pressure

Influence of the Temperature and the Genotype of the HSP90AA1 Gene over Sperm Chromatin Stability in Manchega Rams

The present study addresses the effect of heat stress on males' reproduction ability. For that, we have evaluated the sperm DNA fragmentation (DFI) by SCSA of ejaculates incubated at 37°C during 0, 24 and 48 hours after its collection, as a way to mimic the temperature circumstances to which spermatozoa will be subject to in the ewe uterus. The effects of temperature and temperature-humidity index (THI) from day 60 prior collection to the date of semen collection on DFI were examined. To better understand the causes determining the sensitivity of spermatozoa to heat, this study was conducted in 60 males with alternative genotypes for the SNP G/C−660 of the HSP90AA1 promoter, which encode for the Hsp90α protein. The Hsp90α protein predominates in the brain and testis, and its role in spermatogenesis has been described in several species. Ridge regression analyses showed that days 29 to 35 and 7 to 14 before sperm collection (bsc) were the most critical regarding the effect of heat stress over DFI values. Mixed model analyses revealed that DFI increases over a threshold of 30°C for maximum temperature and 22 for THI at days 29 to 35 and 7 to 14 bsc only in animals carrying the GG−660 genotype. The period 29–35 bsc coincide with the meiosis I process for which the effect of the Hsp90α has been described in mice. The period 7–14 bsc may correspond with later stages of the meiosis II and early stages of epididymal maturation in which the replacement of histones by protamines occurs. Because of GG−660 genotype has been associated to lower levels of HSP90AA1 expression, suboptimal amounts of HSP90AA1 mRNA in GG−660 animals under heat stress conditions make spermatozoa DNA more susceptible to be fragmented. Thus, selecting against the GG−660 genotype could decrease the DNA fragmentation and spermatozoa thermal susceptibility in the heat season, and its putative subsequent fertility gainsPublishe

Measurement of nuclear effects in neutrino-argon interactions using generalized kinematic imbalance variables with the MicroBooNE detector

We present a set of new generalized kinematic imbalance variables that can be measured in neutrino scattering. These variables extend previous measurements of kinematic imbalance on the transverse plane and are more sensitive to modeling of nuclear effects. We demonstrate the enhanced power of these variables using simulation and then use the MicroBooNE detector to measure them for the first time. We report flux-integrated single- and double-differential measurements of charged-current muon neutrino scattering on argon using a topology with one muon and one proton in the final state as a function of these novel kinematic imbalance variables. These measurements allow us to demonstrate that the treatment of charged current quasielastic interactions in genie version 2 is inadequate to describe data. Further, they reveal tensions with more modern generator predictions particularly in regions of phase space where final state interactions are important