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Although prebiotic condensations of glycerol, phosphate and fatty acids produce phospholipid esters with a racemic backbone, most experimental studies on vesicles intended as protocell models have been carried out by employing commercial enantiopure phospholipids. Current experimental research on realistic protocell models urgently requires racemic phospholipids and efficient synthetic routes for their production. Here we propose three synthetic pathways starting from glycerol or from racemicdoi:10.3390/sym12071108 fatcat:rjoj6mkypbe5zliwyvb5lmnbg4
more »... lketal (α,β-isopropylidene-dl-glycerol) for the gram-scale production (up to 4 g) of racemic phospholipid ester precursors. We describe and compare these synthetic pathways with literature data. Racemic phosphatidylcholines and phosphatidylethanolamines were obtained in good yields and high purity from 1,2-diacylglycerols. Racemic POPC (rac-POPC, (R,S)-1-palmitoyl-2-oleoyl-3-phosphocholine), was used as a model compound for the preparation of giant vesicles (GVs). Confocal laser scanning fluorescence microscopy was used to compare GVs prepared from enantiopure (R)-POPC), racemic POPC (rac-POPC) and a scalemic mixture (scal-POPC) of (R)-POPC enriched with rac-POPC. Vesicle morphology and size distribution were similar among the different (R)-POPC, rac-POPC and scal-POPC, while calcein entrapments in (R)-POPC and in scal-POPC were significantly distinct by about 10%.
Pre-targeting approaches based on the inverse-electron-demand Diels-Alder (iEDDA) reaction between strained trans-cyclooctenes (TCO) and electron-deficient tetrazines (Tz) have emerged in recent years as valid alternatives to classic targeted strategies to improve the diagnostic and therapeutic properties of radioactive probes. To explore these pre-targeting strategies based on in vivo click chemistry, a small family of clickable chelators was synthesized and radiolabelled with medicallydoi:10.3389/fmed.2021.647379 pmid:34179038 pmcid:PMC8225959 fatcat:kwmgqe2vtfh4nafzpc4m3gseaq
more »... t trivalent radiometals. The structure of the clickable chelators was diversified to modulate the pharmacokinetics of the resulting [111In]In-radiocomplexes, as assessed upon injection in healthy mice. The derivative DOTA-Tz was chosen to pursue the studies upon radiolabelling with 90Y, yielding a radiocomplex with high specific activity, high radiochemical yields and suitable in vitro stability. The [90Y]Y-DOTA-Tz complex was evaluated in a prostate cancer PC3 xenograft by ex-vivo biodistribution studies and Cerenkov luminescence imaging (CLI). The results highlighted a quick elimination through the renal system and no relevant accumulation in non-target organs or non-specific tumor uptake. Furthermore, a clickable bombesin antagonist was injected in PC3 tumor-bearing mice followed by the radiocomplex [90Y]Y-DOTA-Tz, and the mice imaged by CLI at different post-injection times (p.i.). Analysis of the images 15 min and 1 h p.i. pointed out an encouraging quick tumor uptake with a fast washout, providing a preliminary proof of concept of the usefulness of the designed clickable complexes for pre-targeting strategies. To the best of our knowledge, the use of peptide antagonists for this purpose was not explored before. Further investigations are needed to optimize the pre-targeting approach based on this type of biomolecules and evaluate its eventual advantages.
et al.. Crude phosphorylation mixtures containing racemic lipid amphiphiles self-assemble to give stable primitive compartments. It is an open question how the chemical structure of prebiotic vesicle-forming amphiphiles complexified to produce robust primitive compartments that could safely host foreign molecules. Previous work suggests that comparingly labile vesicles composed of plausibly prebiotic fatty acids were eventually chemically transformed with glycerol and a suitable phosphatedoi:10.1038/s41598-017-18053-y pmid:29273739 pmcid:PMC5741756 fatcat:comozlcmwzamtpsgeth63nmrpy
more »... into phospholipids that would form robust vesicles. Here we show that phosphatidic acid (PA) and phosphatidylethanolamine (PE) lipids can be obtained from racemic dioleoyl glycerol under plausibly prebiotic phosphorylation conditions. Upon in situ hydration of the crude phosphorylation mixtures only those that contained rac-DOPA (not rac-DOPE) generated stable giant vesicles that were capable of encapsulating watersoluble probes, as evidenced by confocal microscopy and flow cytometry. Chemical reaction sideproducts (identified by IR and MS and quantified by 1 H NMR) acted as co-surfactants and facilitated vesicle formation. To mimic the compositional variation of such primitive lipid mixtures, self-assembly of a combinatorial set of the above amphiphiles was tested, revealing that too high dioleoyl glycerol contents inhibited vesicle formation. We conclude that a decisive driving force for the gradual transition from unstable fatty acid vesicles to robust diacylglyceryl phosphate vesicles was to avoid the accumulation of unphosphorylated diacylglycerols in primitive vesicle membranes. The spontaneous supramolecular self-assembly of amphiphiles to give vesicles is a powerful thermodynamic drive for the emergence of primitive cell-like compartments on the early Earth 1-7 . Fatty acid vesicles are plausible models of primitive cells 8,9 but contemporary cell membranes are based on mixtures of phospholipids, glycolipids and proteins. This elicits the questions about the stepwise transition from very early achiral or racemic amphiphiles to enantiopure glycerophospholipids. It has been argued that the complexification and the compositional evolution of primitive membranes was subjected not only to chemical rules (which chemical transformation is possible?) but also to a sort of supramolecular selection based on the 'performance' of the resulting membranes and whole vesicles -e.g., low critical aggregation (micelle, vesicle) concentration, membrane permeability, capture and retention of non-lipidic organic molecules, membrane growth and vesicle division upon the addition of membrane components, vesicle stability at high magnesium and calcium ions concentrations 8, 9 . Although chemistry suggests several plausible pathways for the stepwise transformation of simple amphiphiles into complex lipids 10-15 , the experimental verifications of the existence, stability, and properties of vesicles composed of plausibly primitive amphiphile mixtures are still limited 9,16-21 . Here we report on primitive membrane systems that originate from crude lipid phosphorylation mixtures. Our starting point is a non-phosphorylated diacylglycerol racemate. Glycerol is a reduced formose C 3 reaction Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SciEnTific REPORTS | (2017) 7:18106 |
, Turkheimer, Emery, Harden, et al., 2007; D'Onofrio, Turkheimer, Emery, Maes, et al., 2007) . ... et al., 2005 D'Onofrio et al., , 2006 O'Connor et al., 2000) may increase child psychopathology. ...doi:10.1037/a0021362 pmid:21142367 pmcid:PMC3086974 fatcat:r2cfa4motjgx7kek74yltkoyt4
Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. Indoi:10.1186/s13058-015-0634-8 pmid:26328589 pmcid:PMC4557314 fatcat:lgxua3zbsbewpko5aldfha5ska
more »... s article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.
Understanding individual capability to adjust to protracted confinement and isolation may inform adaptive plasticity and disease vulnerability/resilience, and may have long-term implications for operations requiring prolonged presence in distant and restricted environments. Individual coping depends on many different factors encompassing psychological dispositional traits, endocrine reactivity and their underlying molecular mechanisms (e.g. gene expression). A positive view of self and othersdoi:10.1038/s41398-020-00869-4 pmid:32518224 pmcid:PMC7283351 fatcat:xbvmtrz53bbqvl44dnvxvzw7tm
more »... ecure attachment style) has been proposed to promote individual resilience under extreme environmental conditions. Here, we tested this hypothesis and investigated the underlying molecular mechanisms in 13 healthy volunteers confined and isolated for 12 months in a research station located 1670 km away from the south geographic pole on the Antarctic Plateau at 3233 m above sea level. Study participants, stratified for attachment style, were characterised longitudinally (before, during and after confinement) for their psychological appraisal of the stressful nature of the expedition, diurnal fluctuations in endocrine stress reactivity, and gene expression profiling (transcriptomics). Predictably, a secure attachment style was associated with reduced psychological distress and endocrine vulnerability to stress. In addition, while prolonged confinement and isolation remarkably altered overall patterns of gene expression, such alteration was largely reduced in individuals characterised by a secure attachment style. Furthermore, increased resilience was associated with a reduced expression of genes involved in energy metabolism (mitochondrial function and oxidative phosphorylation). Ultimately, our data indicate that a secure attachment style may favour individual resilience in extreme environments and that such resilience can be mapped onto identifiable molecular substrates.
2016) Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostatespecific antigen (PSA) level: a meta-analysis. BJU International. ISSN 1464-4096 , http://dx. The Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access todoi:10.1111/bju.13417 pmid:26779889 fatcat:w4fwgvvqhnac5j23kfxpm5qgme
more »... 's intellectual output. Abstract: 236 words Manuscript text: 2810 words Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate specific antigen (PSA): a meta-analysis Abstract Objective: To review and quantify the association between endogenous and exogenous testosterone and prostate specific antigen (PSA) and prostate cancer. Methods: Literature searches were performed following the PRISMA guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo controlled randomised trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Metaanalyses were performed using random-effects models with tests for publication bias and heterogeneity. Results: Twenty estimates were included in a meta-analysis which produced a summary relative risk of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% CI (0.96, 1.02)) without heterogeneity (I² = 0%). Based on 26 trials, the overall difference in PSA levels following onset of use of TRT was 0.10 ng/mL (-0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of testosterone replacement therapy. The summary relative risk of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (0.30; 2.50). Results were consistent across studies. Conclusions : Prostate cancer appears to be unrelated to endogenous testosterone levels. Testosterone replacement therapy for symptomatic hypogonadism does not appear to increase PSA levels nor the risk of prostate cancer development. The current data are reassuring although some care is essential until multiple studies with longer follow-up are available.
Our findings are consistent with those of D'Onofrio et al., in indicating a direct connection between problems in the parent and offspring generations. ... Further, some plausible environmental confounds might influence only one co-twin's family (D'Onofrio et al., 2005) , which would influence the within-family estimates. ...doi:10.1017/thg.2012.55 pmid:22958575 pmcid:PMC3678725 fatcat:ulitzj3y4bauhe2blwd6tifaqi
BackgroundNutritional derangements are common hallmarks of non-small-cell lung cancer (NSCLC). Nevertheless, their early detection is overlooked in clinical routine. This study aimed to evaluate nutritional status and its correlation with outcome in NSCLC patients.MethodsData regarding NSCLC patients undergoing nutritional evaluation were prospectively collected (May 2016–October 2018). Nutritional risk was assessed by Nutritional Risk Screening 2002 (NRS-2002). Bilateral psoas major musclesdoi:10.1136/esmoopen-2020-000689 pmid:32424067 fatcat:6ksxrsvrfzdcxpyed5h2dude2u
more »... e measured at L3 vertebrae level with routine staging-computed tomography and changes were evaluated using Wilcoxon signed-rank test. Clinico-pathological and nutritional data were correlated to progression-free/overall survival (PFS/OS) and response rate (ORR) using a Cox and logistic regression model. Kaplan–Meier curves were compared with log-rank test.ResultsThirty-eight patients were included. The majority (65.8%) of them were at nutritional risk (NRS-2002 ≥3). At multivariate analysis for patients with advanced disease, age (HR 2.44, p=0.05), performance status (HR 2.48, p=0.043) and NRS-2002 (HR 1.74, p=0.001) were significant independent predictors for PFS and weight loss (HR 1.07, p=0.008) for OS. Patients with baseline NRS-2002 <3 had significantly longer 1-year PFS (85.7% vs 19.4%, p=0.02) and higher ORR (66.7% vs 21.4%) than those with NRS-2002 ≥3. An explorative evaluation demonstrated that NRS-2002 score significantly decreased after nutritional intervention (p=0.001) for 3 months.ConclusionBaseline nutritional risk represents a prognostic factor in NSCLC. Nutritional counselling should be applied as a fundamental tool to improve nutritional risk in a short period, ameliorating patients' outcome.
Endothelial Progenitor Cells (EPCs), a minor subpopulation of the mononuclear cell fraction in peripheral blood, play a critical role in cancer development as they contribute to angiogenesis-mediated pathological neovascularization. In response to tumor cytokines, including VEGF, EPCs mobilize from the bone marrow into the peripheral circulation and move to the tumor bed where they incorporate into sprouting neovessels. In the present study, we evaluated the effects of everolimus (Afinitor,doi:10.1371/journal.pone.0079658 pmid:24244540 pmcid:PMC3823580 fatcat:ijfah3g3o5c4jgoetmxdyyuvvm
more »... rtis), a rapamycin analogue, alone or in combination with chloroquine, a 4-alkylamino substituted quinoline family member, one of the autophagy inhibitors, on EPCs biological functions. We found that either everolimus or chloroquine induce growth inhibition on EPCs in a dose-dependent manner after 72 h from the beginning of incubation. The combined administration of the two drugs to EPC was synergistic in inducing growth inhibition; in details, the maximal pharmacological synergism between everolimus and chloroquine in inducing growth inhibition on EPCs cells was recorded when chloroquine was administered 24 h before everolimus. Moreover, we have studied the mechanisms of cell death induced by the two agents alone or in combination on EPCs and we have found that the synergistic effect of combination on EPC growth inhibition was paralleled by increased apoptosis induction and reduced autophagy. These effects occurred together with biochemical features that are typical of reduced autophagic death such as increased co-immunoprecipitation between Beclin 1 and Bcl-2. Chloroquine antagonized the inhibition of the activity of AktR4EBP1 axis mediated by everolimus and at the same time it blocked the feed-back activation of Erk-1/2 induced by RAD in EPCs. These data suggest a new strategy in order to block angiogenesis in tumours in which this process plays a key role in both the sustainment and spreading of cancer cells.
Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques,doi:10.3390/ijms23020617 pmid:35054798 pmcid:PMC8775581 fatcat:zn6wpmmbnfdgrp53xv35kmfkpu
more »... ncluding TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.
D'Onofrio, G. Piaggio, R. Pellicciari Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): ...doi:10.1158/0008-5472.can-15-0439 pmid:26359458 fatcat:vfg3vfxm7nayxm6rdn4p4zua74
Coastal areas are under continuous and increasing pressure from different human activities. A mixture of contaminants (e.g. hydrocarbons, pesticides, persistent organic pollutants (POPs), emerging contaminants, and others), originating mainly from populated, industrialised and agricultural areas, can reach the marine environment through different means such as wastewater discharge, soil runoffs, leaching from agriculture, and volatilisation/deposition. In this context, marine sediments havedoi:10.1016/j.ecoenv.2021.112010 pmid:33550081 fatcat:gm2reylnlbe33enkqfs6fkzpsu
more »... easingly been considered repositories for a variety of pollutants that can accumulate and be stored for long periods, acting as a secondary source of contaminants during subsequent dredging operation or vessel manoeuvring. Chemical and ecotoxicological analyses of sediments are routinely conducted to evaluate the potential hazard/risk to the environment, either on bulk sediment or elutriate. In general, sediment elutriates are commonly prepared according to ASTM Guide even if alternative protocols are proposed by USACE for the various condition that they have to represent. The goal of the present study was to determine if the toxicological properties of ASTMprepared elutriates are comparable to those obtained from the USACE protocol. Sediment coming from 3 harbours (Olbia, Cagliari, and Toulon), as part of the "Se.D.Ri.Port" Interreg Project, were processed to obtain elutriates according to ASTM Guide and USACE Dredging Elutriate protocol and tested with the sea urchin Paracentrotus lividus embryo development test. Moreover, the significance of different stirring times of water/sediment mixture (1 h, 3 h, and 24 h) was tested with both the ASTM and USACE protocol. In addition to the biological analysis, for each sediment sample, heavy metals concentration, granulometry, and organic matter were determined. Even if for the ports of Toulon and Cagliari, the ASTM and USACE elutriates showed comparable results with P. lividus bioassay, for the port of Olbia the two protocols showed different criticalities. Preliminary results show that for the site Olbia elutriates prepared with the USACE protocol resulted in higher toxicity than elutriates obtained with ASTM (p < 0.001). In conclusion, differences in preparation protocols appear to be significant and can lead to different results in biological testing. To overcome this problem and to obtain more reliable evaluations of risk to the environment, standardisation and regulation must be the next goals in sediment management procedure.
JAMA Network Open
D'Onofrio Leo Da Costa Zeynep Dadaci Sam Dagogo-Jack Anders Dahl Morten Dahl Philipp Dahm Robin Daly Kirstie Kay Danielson Dawood Darbar Ara W. ... Doyle Alice Dragomir Joseph P. Drozda Annette DuBard Erik R. Dubberke Donald J. Dudley Daniela Dunkler Dorothy D. Dunlop Erin Dunn Daniel J. ...doi:10.1001/jamanetworkopen.2019.0298 fatcat:aeushyl4g5g3blik3dvbdzkzyq
Educational and Psychological Measurement
1054 EDUCATIONAL AND PSYCHOLOGICAL MEASUREMENT D’Onofrio, Amelio 1016 Drake, Carolyn C. 675 Dreger, Ralph Mason 785 Dubuisson, Anne Dumenci, Levent Edens, Kellah M. ... Meshbane, Alice Michael, William B. Michael, William B. Michael, William B. Michael, William B. Michael, William B. Michael, William B. Mielke, Paul W., Jr. Miller, Marc D. Milligan, Glenn W. ...
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