Background and Purpose
In 2016, one person died and four others had mild‐to‐severe neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10‐2474.
...Experimental Approach
Pharmacodynamic and pharmacokinetic studies were performed with BIA 10‐2474, PF‐04457845 and JNJ‐42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity‐based protein profiling (APBB) in rats. BIA 10‐2474 effect in stroke‐prone spontaneously hypertensive rats (SHRSP) was investigated.
Key Results
BIA 10‐2474 was 10‐fold less potent than PF‐04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED50 values of 13.5 and 6.2 μg·kg−1, respectively. Plasma and brain BIA 10‐2474 levels were consistent with in situ potency and neither BIA 10‐2474 nor its metabolites accumulated following repeat administration. FAAH and α/β‐hydrolase domain containing 6 were the primary targets of BIA 10‐2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen‐induced protein 1. At 100 mg·kg−1 for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10‐2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.
Conclusions and Implications
BIA 10‐2474 potently inhibits FAAH in vivo, similarly to PF‐04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off‐targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off‐targets in the clinical trial accident remains unclear.
Complex wastewater matrices present a major environmental concern. Besides the biodegradable organics, they may contain a great variety of toxic chemicals, heavy metals, and other xenobiotics. The ...electrochemically activated persulfate process, an efficient way to generate sulfate radicals, has been widely applied to the degradation of such complex effluents with very good results. This review presents the fundamentals of the electro-persulfate processes, highlighting the advantages and limitations, followed by an exhaustive evaluation on the application of this process for the treatment of complex industrial effluents. An overview of the main relevant experimental parameters/details and their influence on the organic load removal is presented and discussed, having in mind the application of these technologies at an industrial scale. Finally, the future perspectives for the application of the electro-persulfate processes in the treatment of complex wastewater matrices is outlined.
Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) ...recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations.
In silico
analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multicore magnetic nanoparticles of manganese ferrite were prepared using carboxymethyl dextran as an agglutinating compound or by an innovative method using melamine as a cross-coupling agent. The ...nanoparticles prepared using melamine exhibited a flower-shape structure, a saturation magnetization of 6.16 emu/g and good capabilities for magnetic hyperthermia, with a specific absorption rate (SAR) of 0.14 W/g. Magnetoliposome-like structures containing the multicore nanoparticles were prepared, and their bilayer structure was confirmed by FRET (Förster Resonance Energy Transfer) assays. The nanosystems exhibited sizes in the range of 250–400 nm and a low polydispersity index. A new antitumor thienopyridine derivative, 7-4-(pyridin-2-yl)-1H-1,2,3-triazol-1-ylthieno3,2-bpyridine, active against HeLa (cervical carcinoma), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small-cell lung carcinoma) and HepG2 (hepatocellular carcinoma) cell lines, was loaded in these nanocarriers, obtaining a high encapsulation efficiency of 98 ± 2.6%. The results indicate that the new magnetoliposomes can be suitable for dual cancer therapy (combined magnetic hyperthermia and chemotherapy).
Background:
Most people would prefer to die at home as opposed to hospital; therefore, understanding mortality patterns by place of death is essential for health resources allocation.
Aim:
We ...examined trends and risk factors for hospital death in conditions needing palliative care in a country without integrated palliative care.
Design:
This is a death certificate study. We examined factors associated with hospital death using logistic regression.
Setting/participants:
All adults (1,045,381) who died between 2003 and 2012 in Portugal were included. We identified conditions needing palliative care from main causes of death: cancer, heart/cerebrovascular, renal, liver, respiratory and neurodegenerative diseases, dementia/Alzheimer’s/senility and HIV/AIDS.
Results:
Conditions needing palliative care were responsible for 70.7% deaths (N = 738,566, median age 80); heart and cerebrovascular diseases (43.9%) and cancer (32.2%) accounted for most. There was a trend towards hospital death (standardised percentage: 56.3% in 2003, 66.7% in 2012; adjusted odds ratio: 1.04, 95% confidence interval: 1.04–1.04). Hospital death risk was higher for those aged 18–39 years (3.46, 3.25–3.69 vs aged 90+), decreasing linearly with age; lower in dementia/Alzheimer’s/senility versus cancer (0.13, 0.13–0.13); and higher for the married and in HIV/AIDS (3.31, 3.00–3.66). Effects of gender, working status, weekday and month of death, hospital beds availability, urbanisation level and deprivation were small.
Conclusion:
The upward hospital death trend and fact that being married are risk factors for hospital death suggest that a reliance on hospitals may coexist with a tradition of extended family support. The sustainability of this model needs to be assessed within the global transition pattern in where people die.
ABSTRACT
Background
Seroepidemiological studies provide estimates of population‐level immunity, prevalence/incidence of infections, and evaluation of vaccination programs. We assessed the ...seroprevalence of protective antibodies against influenza and evaluated the correlation of seroprevalence with the cumulative annual influenza incidence rate.
Methods
We conducted an annual repeated cross‐sectional seroepidemiological survey, during June–August, from 2014 to 2019, in Portugal. A total of 4326 sera from all age groups, sex, and regions was tested by hemagglutination inhibition assay. Seroprevalence and geometric mean titers (GMT) of protective antibodies against influenza were assessed by age group, sex, and vaccine status (65+ years old). The association between summer annual seroprevalence and the difference of influenza incidence rates between one season and the previous one was measured by Pearson correlation coefficient (r).
Results
Significant differences in seroprevalence of protective antibodies against influenza were observed in the population. Higher seroprevalence and GMT for A(H1N1)pdm09 and A(H3N2) were observed in children (5–14); influenza B seroprevalence in adults 65+ was 1.6–4.4 times than in children (0–4). Vaccinated participants (65+) showed significant higher seroprevalence/GMT for influenza. A strong negative and significant correlation was found between seroprevalence and ILI incidence rate for A(H1N1)pdm09 in children between 5 and 14 (r = −0.84; 95% CI, −0.98 to −0.07); a weak negative correlation was observed for A(H3N2) and B/Yamagata (r ≤ −0.1).
Conclusions
The study provides new insight into the anti‐influenza antibodies seroprevalence measured in summer on the ILI incidence rate in the next season and the need for adjusted preventive health care measures to prevent influenza infection and transmission.
In this study, Bi-doped SrTiO3 perovskites (Sr1−xBixTiO3, x = 0, 0.03, 0.05, 0.07 and 0.1) were synthesized using the solid-state method, characterized, and tested as photocatalysts in the ...degradation of the azo dye acid orange 7 (AO7) under visible light. The perovskites were successfully synthesized, and XRD data showed a predominant, well-crystallized phase, belonging to the cubic perovskite symmetry. For the doped samples, a minority phase, identified as bismuth titanate, was detected. All doped samples exhibited improved photocatalytic activity under visible light, on the degradation of AO7 (10 mg L−1), when compared with the undoped SrTiO3, with an increase in relative Abs484 nm decay from 3.7% to ≥67.8% after 1 h, for a powder suspension of 0.2 g L−1. The best photocatalytic activity was exhibited by the Sr0.95Bi0.05TiO3 perovskite. Reusability studies showed no significant loss in photocatalytic activity under visible light. The final solutions showed no toxicity towards D. magna, proving the efficiency of Sr0.95Bi0.05TiO3 as a visible-light-driven photocatalyst to degrade both the AO7 dye as well as its toxic by-products. A degradation mechanism is proposed.
Introduction: Innovations in 3D spatial technology and augmented reality imaging driven by digital high-tech industrial science have accelerated experimental advances in breast cancer imaging and the ...development of medical procedures aimed to reduce invasiveness. Presentation of case: A 57-year-old post-menopausal woman presented with screen-detected left-sided breast cancer. After undergoing all staging and pre-operative studies the patient was proposed for conservative breast surgery with tumor localization. During surgery, an experimental digital and non-invasive intra-operative localization method with augmented reality was compared with the standard pre-operative localization with carbon tattooing (institutional protocol). The breast surgeon wearing an augmented reality headset (Hololens) was able to visualize the tumor location projection inside the patient’s left breast in the usual supine position. Discussion: This work describes, to our knowledge, the first experimental test with a digital non-invasive method for intra-operative breast cancer localization using augmented reality to guide breast conservative surgery. In this case, a successful overlap of the previous standard pre-operative marks with carbon tattooing and tumor visualization inside the patient’s breast with augmented reality was obtained. Conclusion: Breast cancer conservative guided surgery with augmented reality can pave the way for a digital non-invasive method for intra-operative tumor localization.
Neurocutaneous syndromes (NCS) are a heterogeneous group of conditions with multiorgan involvement and diverse manifestations, evolving throughout life with significant morbidity. A multidisciplinary ...approach to NCS patients has been advocated, although a specific model is not yet established. The aim of this study was 1) to describe the organization of the recently created Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases (MOCND) at a Portuguese pediatric tertiary hospital; 2) to share our institutional experience focusing on the most common conditions, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC); 3) to analyze the advantages of a multidisciplinary center and approach in NCS.
Retrospective analysis of 281 patients enrolled in the MOCND over the first five years of activity (October 2016 to December 2021), reviewing genetics, family history, clinical features, complications, and therapeutic strategies for NF1 and TSC.
The clinic works weekly with a core team of pediatricians and pediatric neurologists supported by other specialties as needed. Of the 281 patients enrolled, 224 (79.7%) had identifiable syndromes such as NF1 (n = 105), TSC (n = 35), hypomelanosis of Ito (n = 11), Sturge-Weber syndrome (n = 5), and others. In NF1 patients, 41.0% had a positive family history, all manifested café-au-lait macules, 38.1% neurofibromas with 45.0% being large plexiform neurofibromas. Sixteen were under treatment with selumetinib. Genetic testing was performed in 82.9% of TSC patients with pathogenic variants found in TSC2 gene in 72.4% patients (82.7% if considered contiguous gene syndrome). Family history was positive in 31.4%. All TSC patients presented hypomelanotic macules and fulfilled diagnostic criteria. Fourteen patients were being treated with mTOR inhibitors.
Offering a systematic and multidisciplinary approach to NCS patients enables timely diagnosis, promotes a structured follow-up, and encourages discussion to outline management plans for optimal care to every patient, with significant impact on the quality of life of patients and families.
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