Highly tailorable gellan gum nanoparticles as a platform for the development of T cell activator systems

Daniel B. Rodrigues,Helena R. Moreira,Mariana T. Cerqueira,Alexandra P. Marques,António G. Castro,Rui L. Reis,Rogério P. Pirraco 한국생체재료학회 2022 생체재료학회지 Vol.26 No.4

Background: T cell priming has been shown to be a powerful immunotherapeutic approach for cancer treatment in terms of efficacy and relatively weak side effects. Systems that optimize the stimulation of T cells to improve therapeutic efficacy are therefore in constant demand. A way to achieve this is through artificial antigen presenting cells that are complexes between vehicles and key molecules that target relevant T cell subpopulations, eliciting antigenspecific T cell priming. In such T cell activator systems, the vehicles chosen to deliver and present the key molecules to the targeted cell populations are of extreme importance. In this work, a new platform for the creation of T cell activator systems based on highly tailorable nanoparticles made from the natural polymer gellan gum (GG) was developed and validated. Methods: GG nanoparticles were produced by a water in oil emulsion procedure, and characterized by dynamic light scattering, high resolution scanning electronic microscopy and water uptake. Their biocompatibility with cultured cells was assessed by a metabolic activity assay. Surface functionalization was performed with anti-CD3/CD28 antibodies via EDC/NHS or NeutrAvidin/Biotin linkage. Functionalized particles were tested for their capacity to stimulate CD4+ T cells and trigger T cell cytotoxic responses. Results: Nanoparticles were approximately 150 nm in size, with a stable structure and no detectable cytotoxicity. Water uptake originated a weight gain of up to 3200%. The functional antibodies did efficiently bind to the nanoparticles, as confirmed by SDS-PAGE, which then targeted the desired CD4+ populations, as confirmed by confocal microscopy. The developed system presented a more sustained T cell activation over time when compared to commercial alternatives. Concurrently, the expression of higher levels of key cytotoxic pathway molecules granzyme B/perforin was induced, suggesting a greater cytotoxic potential for future application in adoptive cancer therapy. Conclusions: Our results show that GG nanoparticles were successfully used as a highly tailorable T cell activator system platform capable of T cell expansion and re-education.

Knowledge and Risk Behaviors Regarding Human Immunodeficiency Virus Transmission among Portuguese Healthcare Students

Bárbara Joana Alvarenga Carvalho,António Miguel da Cruz-Ferreira 대한가정의학회 2023 Korean Journal of Family Medicine Vol.44 No.1

Background: Human immunodeficiency virus (HIV), the agent responsible for acquired immunodeficiency syn-drome, remains a worldwide public health problem. Therefore, this study aimed to assess Portuguese healthcare students’ knowledge of HIV, identify risk behaviors for HIV transmission, and assess the frequency of HIV testing and its dissemination by general practitioners.Methods: A cross-sectional observational study was conducted using an anonymous questionnaire published on-line. The questionnaire was administered to Portuguese healthcare students who voluntarily agreed to participate in the study after clarifying its objectives and procedures.Results: Most students were aware of the three main HIV transmission routes; however, 66.3% were unaware of the level A recommendation for HIV screening in adolescents and adults. In addition, 59.6% of the students were never informed by their general practitioner about HIV screening tests or risk behaviors for HIV transmission. Of the sample, 78.9% had never been tested for HIV infection. Of the 74.6% of sexually active students, 82.0% had or had already had unprotected sex (without a condom). Men showed riskier sexual behaviors than women. None of the inquiries reported intravenous drug use, and most students (69.9%) never shared personal objects.Conclusion: General practitioners and awareness campaigns need to alert and disseminate HIV screening tests. Sexual health and risk behaviors should be addressed more frequently in schools to educate this population be-cause prevention is the best strategy against HIV transmission/contraction.

Frailty-Independent Undertreatment Negative Impact on Survival in Older Patients With Breast Cancer

Fernando Osório,António S. Barros,Bárbara Peleteiro,Ana Rita Barradas,Joana Urbano,José Luís Fougo,Adelino Leite-Moreira 한국유방암학회 2021 Journal of breast cancer Vol.24 No.6

Purpose: The management of older adults with breast cancer (BC) remains controversial. The challenging assessment of aging idiosyncrasies and the scarce evidence of therapeutic guidelines can lead to undertreatment. Our goal was to measure undertreatment and assess its impact on survival. Methods: Consecutive patients with BC aged 70 years or older were prospectively enrolled in 2014. Three frailty screening tools (G8, fTRST, and GFI) and two functional status scales (Karnofsky performance score and Eastern Cooperative Oncology Group Performance Status) were applied. Disease characteristics, treatment options, and causes of mortality were recorded during a 5-year follow-up. In addition, we defined undertreatment and correlated its survival impact with frailty. Results: A total of 92 patients were included in the study. The median age was 77 (range 70–94) years. The prevalence of frailty was discordant (G8, 41.9%; fTRST, 74.2%; GFI, 32.3%). Only 47.8% of the patients had a local disease, probably due to a late diagnosis (73.9% based on self-examination). Thirty-three patients (35.6%) died, of which 15 were from BC. We found a considerably high proportion (53.3%) of undertreatment, which had a frailty-independent negative impact on the 5-year survival (hazard ratio [HR], 5.1; 95% confidence interval [CI], 2.1–12.5). Additionally, omission of surgery had a frailty-independent negative impact on overall survival (HR, 3.9; 95% CI, 1.9–7.9). Conclusion: BC treatment in older adults should be individualized. More importantly, assessing frailty (not to treat) is essential to be aware of the risk-benefit profile and the patient's well-informed willingness to be treated. Undertreatment in daily practice is frequent and might have a negative impact on survival, as we report.

Constitutive modeling for path-dependent behavior and its influence on twist springback

Liao, Juan,Xue, Xin,Lee, Myoung-Gyu,Barlat, Fré,dé,ric,Vincze, Gabriela,Pereira, Antó,nio B. Elsevier 2017 International journal of plasticity Vol.93 No.-

<P><B>Abstract</B></P> <P>The aim of this study is to investigate the path-dependent elastic-plastic behavior of dual-phase steel and its influence on the prediction of twist springback in the channel forming process. The anisotropic hardening responses of the sheet material for non-proportional loading, as well as the degradation of the elastic modulus in uniaxial and biaxial tension are investigated. A recently proposed distortional plasticity model combined with a dislocation density-based hardening approach was adopted to describe the flow behavior of the material. The results indicate that the present model simultaneously reproduces all of the experimentally observed features for both load reversal and changes of the principal strain axis. This constitutive description is employed in the finite element analysis of the forming of two channels with obvious twist springback characteristics. The complex strain path changes during the forming process are then analyzed using a proposed indicator. Finally, the relevance of the load changes and the stress distribution in the channel regarding twist springback predictions are discussed. The influence of loading path-dependent elastic modulus degradation for the prediction of twist springback is also assessed based on two different application geometries.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The enhanced HAH model captures DP500's plastic flow behavior at various strain path changes. </LI> <LI> Hardening model affects twist springback prediction in sheet forming. </LI> <LI> A proposed indicator represents well the complex loading path history. </LI> <LI> The influence of strain path changes other than pure load reversal is assessed. </LI> <LI> Path-dependent elastic behavior and its influence on twist springback are studied. </LI> </UL> </P>

Recursive Approach of Sub-Optimal Excitation Signal Generation and Optimal Parameter Estimation

Marina B. A. Souza,Leonardo de Melo Honório,Edimar José de Oliveira,António Paulo G. M. Moreira 제어·로봇·시스템학회 2020 International Journal of Control, Automation, and Vol.18 No.8

Optimal Input Design (OID) methodologies are developed to find a signal that could best estimate a set of parameters of a given model. Their application in constrained nonlinear systems, especially when the search space limits or the initial conditions are unknown, may present several difficulties due to the numerical instability related to the optimization processes. A good choice over the parameters possible ranges is a trade-off among numerical stability, search space size, and effectiveness, and it is hardly found. To deal with this problem, this paper proposes a series of changes in the Sub-Optimal Excitation Signal Generation and Optimal Parameter Estimation (SOESGOPE) methodology. First, the limits over the parameters are tightly adjusted according to their confidence. A recursive approach runs the optimization methodology, analyzes the solution’s feasibility and marginal costs given by the Lagrange Multipliers, and selects a direction that could improve the system’s response. This approach improves the convergence and the assertiveness of the estimation process. To validate this approach, some cases, including a parameters estimation of a mobile robot nonlinear system, are tested.

Applied element method simulation of experimental failure modes in RC shear walls

Corneliu Cismasiu,António Pinho Ramos,Ionut D. Moldovan,Diogo F. Ferreira,Jorge B. Filho 사단법인 한국계산역학회 2017 Computers and Concrete, An International Journal Vol.19 No.4

With the continuous evolution of the numerical methods and the availability of advanced constitutive models, it became a common practice to use complex physical and geometrical nonlinear numerical analyses to estimate the structural behavior of reinforced concrete elements. Such simulations may yield the complete time history of the structural behavior, from the first moment the load is applied until the total collapse of the structure. However, the evolution of the cracking pattern in geometrical discontinuous zones of reinforced concrete elements and the associated failure modes are relatively complex phenomena and their numerical simulation is considerably challenging. The objective of the present paper is to assess the applicability of the Applied Element Method in simulating the development of distinct failure modes in reinforced concrete walls subjected to monotonic loading obtained in experimental tests. A pushover test was simulated numerically on three distinct RC shear walls, all presenting an opening that guarantee a geometrical discontinuity zone and, consequently, a relatively complex cracking pattern. The presence of different reinforcement solutions in each wall enables the assessment of the reliability of the computational model for distinct failure modes. Comparison with available experimental tests allows concluding on the advantages and the limitations of the Applied Element Method when used to estimate the behavior of reinforced concrete elements subjected to monotonic loading.

Delay Dependent Local Stabilization Conditions for Time-delay Nonlinear Discrete-time Systems Using Takagi-Sugeno Models

Luís F. P. Silva,Valter J. S. Leite,Eugênio B. Castelan,Gang Feng 제어·로봇·시스템학회 2018 International Journal of Control, Automation, and Vol.16 No.3

We propose convex conditions for stabilization of nonlinear discrete-time systems with time-varying delay in states through a fuzzy Takagi-Sugeno (T-S) modeling. These conditions are developed from a fuzzy Lyapunov-Krasovskii function and they are formulated in terms of linear matrix inequalities (LMIs). The results can be applied to a class of nonlinear systems that can be exactly represented by T-S fuzzy models inside a specific region called the region of validity. As a consequence, we need to provide an estimate of the set of safe initial conditions called the region of attraction such that the closed-loop trajectories starting in this set are assured to remain in the region of validity and to converge asymptotically to the origin. The estimate of the region of attraction is done with the aid of two sets: one dealing with the current state, and the other concerning the delayed states. Then, we can obtain the feedback fuzzy control law depending on the current state, xk, and the maximum delayed state vector, xk-d. It is shown that such a control law can locally stabilize the nonlinear discrete-time system at the origin. We also develop convex optimization procedures for the computation of the fuzzy control gains that maximize the estimates of the region of attraction. We present two examples to demonstrate the efficiency of the developed approach and to compare it with other approaches in the literature.

Plasma Levels of Tumor Necrosis Factor Superfamily Molecules Are Increased in Bipolar Disorder

Izabela G. Barbosa,Gabriela Neves Vaz,Natalia Pessoa Rocha,Rodrigo Machado-Vieira,Marcio Rogerio Diniz Ventura,Rodrigo B. Huguet,Moises E. Bauer,MIchael Berk,Antônio L. Teixeira 대한정신약물학회 2017 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.15 No.3

Objective: Patients with bipolar disorder (BD) exhibit peripheral low-grade inflammation. The aim of the current study was to investigate the involvement of hitherto unexplored components of the tumor necrosis factor (TNF) superfamily in BD. Methods: Eighty patients with type I BD and 50 healthy controls matched for age and gender were enrolled in this study. All subjects were assessed with the Mini-Plus to evaluate psychiatric comorbidities; the Young Mania Rating Scale and the Hamilton Depression Rating Scale to evaluate manic and depressive symptoms severity, respectively. TNF superfamily molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], TNF-related apoptosis-inducing ligand [TRAIL], soluble TNF receptor type 1 [sTNFR1], and soluble TNF receptor type 2 [sTNFR2]) levels were measured by ELISA. Results: Patients with BD, regardless of mood state, presented increased plasma levels of sTNFR1 and TWEAK in comparison with controls. Conclusion: These findings corroborate the view that TNF superfamily may play a role in BD pathophysiology.

Saline extract of Portulaca elatior leaves with photoprotective and antioxidant activities does not show acute oral and dermal toxicity in mice

da Silva Suéllen Pedrosa,da Costa Clarice Barbosa Lucena,de Freitas Anderson Felipe Soares,da Silva José Dayvid Ferreira,Costa Wêndeo Kennedy,da Silva Wênio Sandoval Filho Lima,Machado Janaina Carla B 한국독성학회 2023 Toxicological Research Vol.39 No.2

The present study aimed to evaluate saline extracts from the leaves (LE) and stem (SE) of Portulaca elatior in relation to their phytochemical composition and photoprotective and antioxidant effects, as well as to evaluate the toxicity of the leaf extract. The extracts were characterized for protein concentration and phenol and flavonoid contents, as well as for thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) profiles. Total antioxidant capacity and DPPH and ABTS+ scavenging activities were determined. In the photoprotective activity assay, the sun protection factor (SPF) was calculated. The toxicity evaluation of LE included in vitro hemolytic assay and in vivo oral and dermal acute toxicity assays in Swiss mice. LE showed the highest protein, phenol, and flavonoid (8.79 mg/mL, 323.46 mg GAE/g, and 101.96 QE/g, respectively). TLC revealed the presence of flavonoids, reducing sugars, terpenes, and steroids in both extracts. In HPLC profiles, LE contained flavonoids, while SE contained flavonoids and ellagic tannins. The antioxidant activity assays showed the lowest IC50 values (34.15–413.3 μg/mL) for LE, which presented relevant SPF (> 6) at 50 and 100 μg/mL. LE demonstrated low hemolytic capacity, and no signs of intoxication were observed in mice treated orally or topically at 1000 mg/kg. However, at 2000 mg/kg, an increase in the mean corpuscular volume of erythrocytes and a reduction in lymphocytes were observed; animals treated topically with 2000 mg/kg displayed scratching behavior during the first hour of observation and showed edema and erythema that regressed after six days. In conclusion, LE did not present acute oral or dermal toxicity in Swiss mice at a dose of 1000 mg/kg and showed slight toxicity in animals treated with 2000 mg/kg.