Calibration and prediction assessment of different ductile damage models on Ti6Al4V and 17-4PH additive manufactured alloys

Nowadays, metal additive manufacturing is becoming always more popular, being able to deliver complex shaped high quality products. Though many studies have been conducted on the high cycle fatigue behavior of these materials, yet ductile failure has still not been completely investigated, to identify the failure limits under static complex stress states. In the present study, the calibration of three ductile damage models on two popular additive manufactured alloys was carried out. The selected alloys were Ti6Al4V, processed via Electron Beam Melting, and 17-4PH fabricated with Selective Laser Melting technology; both broadly used in actual industrial applications. For each material a set of samples, was fabricated to perform a thorough static mechanical characterization, involving tensile tests on round smooth bars, notched bars, tests under plane strain conditions and torsion tests. The stress state in the critical points was retrieved relying on FEM simulations, and the data collected via the hybrid experimental-numerical procedure subsequently used to tune the damage models. Specifically, the selected models are the Rice and Tracey, the Modified Mohr-Coulomb by Wierzbicki and the one proposed by Coppola and Cortese. While the former does not take into account the effect of Lode parameter, the latter two consider its influence on fracture onset. A minimization algorithm was used for their calibration, and different optimization strategies were adopted to check the robustness of identified parameters. The resulting strains to fracture as a function of damage parameters were plotted for each formulation. The failure prediction accuracy of all models was assessed and compared to the others

Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding

Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

SAT0368 PREGNANCY IN WOMEN WITH SPONDYLOARTHRITIS: WHO ARE THE PATIENTS AT RISK OF DISEASE FLARE?

Background:Patients with Spondyloarthritis (SpA) can experience flares during pregnancy and postpartum even though the available data are limited and not conclusive.Objectives:To assess disease activity and treatment modification during pregnancy and postpartum in patients with SpA and to identify risk factors for disease flare.Methods:Data on SpA pregnancies prospectively-followed in a pregnancy clinic from 2010 to 2019 were retrospectively analysed. Disease activity was assessed during each trimester and postpartum using ASDAS-CRP or DAS28-CRP. Flare was defined as an increase of disease activity leading to treatment modification (introduction or increase ≥5mg/day of prednisone, introduction of cDMARD or bDMARD)1.Results:Data on 50 pregnancies in 46 patients were collected (mean age at conception 33±4.7 years; median disease duration: 60 months (IQR 24-132); 33 psoriatic arthritis, 6 axialSpA, 2 reactive arthritis, 2 IBD-related SpA; 6 undifferentiated SpA, 1 juvenile idiopathic arthritis). Six pregnancies ended in miscarriage, so they weren't considered for the analysis of flares during pregnancy (table 1). Fifteen out of 44 (34%) pregnancies had at least one flare during pregnancy (6, 7 and 4 during 1st, 2ndand 3rdtrimester respectively; 2 pregnancies had multiple flares). A higher rate of flare was observed in pregnancies of patients with axial involvement (p=0.01), on treatment with bDMARDs at preconceptional visit (p=0.03) and who stopped TNFi at positive pregnancy test (p=0.03). Peripheral involvement was associated with a lower rate of flares (p=0.02). Medications resumed during pregnancy were steroids (in 6 pregnancies), cDMARDs (2 sulfasalazine, 1 cyclosporine) and bDMARDs (4 certolizumab, 4 etanercept). During postpartum period flares were recorded in 46% of patients.Table 1.clinical features, medication and disease activity in pregnancies with flare vs without flareCLINICAL FEATURESFLARE (15)NO FLARE (29)pAxial involvement, n (%)11/15 (73)9/29 (31)0.01Peripheral arthritis, n (%)8/15 (53)26/29 (90)0.02Enthesitis, n (%)5/15 (33)14/29 (48)nsDactilitis, n (%)3/15 (20)8/29 (28)nsPsoriasis, n (%)6/15 (40)17/29 (59)nsIBD, n (%)2/15 (13)0nsUveitis, n(%)1/15 (7)3/29 (10)nsHLAB27 +7/11 (64)5/12 (42)nsMEDICATION HISTORYbDMARDs, n (%)11/15 (73)7/29 (24)0.003bDMARDs at preconception visit, n (%)8/15 (53)6/29 (21)0.04bDMARDs stopped at positive pregnancy test, n (%)7/15 (47)4/29 (14)0.03cDMARDs, n (%)12/15 (80)25/29 (86)nsDISEASE ACTIVITYACTIVE DISEASE* preconception visit, n(%)3/14 (21)4/23 (17)nsACTIVE DISEASE 1sttrimester, n(%)6/15 (40)1/29 (3)0.004ACTIVE DISEASE 2ndtrimester, n(%)8/15 (47)2/29 (7)0.001ACTIVE DISEASE 3rdtrimester, n(%)2/15 (13)1/29 (3)ns*DAS28-CRP>3.2 or ASDAS-CRP≥2.1Conclusion:In our cohort of prospectively-followed SpA pregnancies, 34% experienced a flare during pregnancy and 46% during postpartum. Flares occurred especially in those patients who discontinued TNFi early in pregnancy and with axial involvement. When resumed during pregnancy, TNFi was able to control the disease. At preconception counselling, the continuation of TNFi during pregnancy should be considered to ensure a better control of disease.References:[1]Fischer-Betz R et al.Arthritis Rheumatol. 2015; 67.Disclosure of Interests: :None declare

Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

Antibodies Against Domain 1 and Domain 4/5 of β2 Glycoprotein I : Clinical Relevance in Obstetric Anti-Phospholipid Syndrome

Background/Purpose: The domain reactivity of antibodies against b2 glycoprotein I (anti-b2GPI) has been investigated in patients with thrombotic anti-phospholipid syndrome (APS), leading to the identification of antibodies targeting domain 1 of the molecule (anti-D1) as the most relevant autoantibody subpopulation. Scarce attention has been paid to the domain profiling of patients with pregnancy morbidity (PM). The aim of this study was to characterize the relevance of the fine epitope reactivity of anti-b2GPI antibodies in anti-phospholipid antibody (aPL)-associated PM. Methods: Women with persistent positivity for anti-b2GPI IgG antibodies at medium-high titers, with at least one pregnancy and without systemic autoimmune disease were included. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash b2GPI IgG and QUANTA Lite, Inova Diagnostics). Statistical analysis was performed using R package. Results: 138 women fulfilling the inclusion criteria were retrospectively recruited at 3 referral centres. 49 patients (35%) had obstetric APS, 18 (13%) thrombotic APS, 37 (27%) thrombotic and obstetric APS while 34 women (25%) were asymptomatic aPL carriers. 81 women (60%) displayed triple aPL positivity, 32 (23%) had two positive aPL test and 23 (17%) carried a single aPL positivity. 110 patients had at least one untreated pregnancy, culminating in a live birth in 31 cases (28%). 89 women underwent a pregnancy course while receiving treatment, with 71 women (80%) having a live birth. A significant difference in the distribution of positive anti-D1 antibodies emerged between women with or without PM and with or without thrombosis (p=0.05, c2=2.710 and p<0.001, c2=12.174, respectively); no significant difference was observed for anti-D4/5 antibodies (Table 1). In a multivariate logistic regression model also encompassing treatment, positive anti-D1 antibodies, but not anti-D4/5, were significantly associated with obstetric complications, conferring an odds ratio (OR) of 2.32 (p=0.040 and p=0.724, respectively). Triple aPL positivity corrected by treatment significantly predicted PM (p=0.015, OR=2.78). Conclusion: Our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis but also with obstetric morbidity while positive anti-D4/5 antibodies are not predictive of PM

Design of price incentives for adjunct policy goals in formula funding for hospitals and health services

Background. Hospital policy involves multiple objectives: efficiency of service delivery, pursuit of high quality care, promoting access. Funding policy based on hospital casemix has traditionally been considered to be only about promoting efficiency. Discussion. Formula-based funding policy can be (and has been) used to pursue a range of policy objectives, not only efficiency. These are termed 'adjunct' goals. Strategies to incorporate adjunct goals into funding design must, implicitly or explicitly, address key decision choices outlined in this paper. Summary. Policy must be clear and explicit about the behaviour to be rewarded; incentives must be designed so that all facilities with an opportunity to improve have an opportunity to benefit; the reward structure is stable and meaningful; and the funder monitors performance and gaming

Anti–Neutrophil Extracellular Trap Antibodies in Antiphospholipid Antibody–Positive Patients: Results From the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Clinical Database and Repository

OBJECTIVE: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti–neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody–positive patients who did not have lupus. METHODS: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. RESULTS: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)–DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO–DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. CONCLUSION: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens