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1.
Org Biomol Chem ; 18(2): 292-304, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31844866

RESUMO

The enhanced reactivity of a series of four aza aromatic compounds (AACs) participating in the Diels-Alder (DA) reactions with ethylene has been studied using Molecular Electron Density Theory (MEDT). The analysis of the electronic structure of these AACs allows establishing that the substitution of the C-H unity by the isoelectronic N: unity linearly decreases the ring electron density (RED) of these compounds and concomitantly decreases their aromatic character and increases their electrophilic character. These behaviours not only decrease drastically the activation energies of these DA reactions, but also increase the reaction energies when they are compared with the very unfavourable DA reaction between benzene and ethylene. Very good correlations between the NICS(0) values and the electrophilicity ω indices of these AACs with the RED values are found. The present MEDT study makes it possible to establish two empirical electron density unity (EDU) indices accounting for the contribution of the C and N unities, 2.77 and 2.19 e, respectively, for the RED, which is mainly responsible for the reactivity of these AACs. Comprehensive chemical concepts such as electron density, aromaticity and electrophilicity make it possible to explain the chemical reactivity of these AACs participating in DA reactions towards ethylene.

2.
Vaccines (Basel) ; 7(4)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817622

RESUMO

Highly attenuated poxviral vectors, such as modified vaccinia virus ankara (MVA), are promising vaccine candidates against several infectious diseases. One of the approaches developed to enhance the immunogenicity of poxvirus vectors is increasing the promoter strength and accelerating during infection production levels of heterologous antigens. Here, we have generated and characterized the biology and immunogenicity of an optimized MVA-based vaccine candidate against HIV/AIDS expressing HIV-1 clade B gp120 protein under the control of a novel synthetic late/early optimized (LEO) promoter (LEO160 promoter; with a spacer length of 160 nucleotides), termed MVA-LEO160-gp120. In infected cells, MVA-LEO160-gp120 significantly increased the expression levels of HIV-1 gp120 mRNA and protein, compared to the clinical vaccine MVA-B vector expressing HIV-1 gp120 under the control of the commonly used synthetic early/late promoter. When mice were immunized with a heterologous DNA-prime/MVA-boost protocol, the immunization group DNA-gp120/MVA-LEO160-gp120 induced an enhancement in the magnitude of gp120-specific CD4+ and CD8+ T-cell responses, compared to DNA-gp120/MVA-B; with most of the responses being mediated by the CD8+ T-cell compartment, with a T effector memory phenotype. DNA-gp120/MVA-LEO160-gp120 also elicited a trend to a higher magnitude of gp120-specific CD4+ T follicular helper cells, and modest enhanced levels of antibodies against HIV-1 gp120. These findings revealed that this new optimized vaccinia virus promoter could be considered a promising strategy in HIV/AIDS vaccine design, confirming the importance of early expression of heterologous antigen and its impact on the antigen-specific immunogenicity elicited by poxvirus-based vectors.

3.
Org Biomol Chem ; 17(35): 8185-8193, 2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31451810

RESUMO

Aromatic nucleophilic substitution (SNAr) reactions of non-electrophilically activated benzenes have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311+G(d) computational level. These reactions, taking place through a one-step mechanism, present a high activation Gibbs free energy, ΔG≠ = 31.0 kcal mol-1, which decreases to 22.1 kcal mol-1 in the intramolecular process. A topological analysis of the electron localisation function along the reaction paths permits establishing the non-concerted nature of these SNAr reactions. A series of unstable structures, with similar electronic structures to those of Meisenheimer intermediates, are characterised. The present MEDT study makes it possible to establish that even these one-step SNAr reactions involving only two single bonds are non-concerted processes.

4.
Eur Phys J E Soft Matter ; 42(8): 110, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31444581

RESUMO

The critical region in the phase diagram of condensed matter systems such as fluids or fluid mixtures is characterized by the anomalous behaviour of specific thermodynamic properties. Here, we discuss the progress of understanding the behaviour of two intimately related properties, the dielectric constant [Formula: see text] and the refractive index n, when approaching the liquid-liquid critical point in binary liquid mixtures. Phenomenological scaling approaches, in particular, complete scaling formulation, are highlighted. In addition, experimental evidence provided by dielectric spectroscopy and optical measurements supporting the asymmetry-related critical features in [Formula: see text] and n in the one- and two-phase regions is assessed. We revisit recent experimental data and point out peculiar patterns of behaviour of polar-polar liquid mixtures as compared to (much more frequently studied) polar-non-polar mixtures. We point the necessity of additional research efforts towards the study of polar-polar mixtures, which would shed light into the influence of (microscopic) system-dependent parameters on asymmetry-related features of liquid-liquid criticality.

5.
Cien Saude Colet ; 24(6): 2351-2360, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31269191

RESUMO

Dietary practices of college students were compared before and after implementation of the University Restaurant (UR) and examined according to frequency of UR use. A natural experiment was conducted with students (n = 1131) of a Brazilian public university using a validated self-completed and identified questionnaire that inquired information on practices of substituting lunch and/or dinner with a snack (≥ 5 days/week) and on regular consumption of foods that were markers of a healthy or unhealthy diet. At the second time point, UR use by students was also assessed based on their attendance to it. Changes in food practices were examined by determining differences in proportions between the two assessments. The analysis of the association between UR use and each dietary practice was carried out using multiple logistic regression models. An association was observed between greater UR use and higher frequency of regular consumption of beans, vegetables, raw vegetables, cooked vegetables and fruit and lower frequency of regular consumption of French fries and/or fried snacks. The UR proved to be an environment that facilitated the adoption of healthy dietary practices and promoted improvement in the diets of the students who were more assiduous to the restaurant.


Assuntos
Dieta/estatística & dados numéricos , Comportamento Alimentar , Restaurantes , Estudantes/estatística & dados numéricos , Brasil , Feminino , Humanos , Masculino , Inquéritos e Questionários , Universidades , Adulto Jovem
6.
Dalton Trans ; 48(25): 9214-9224, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31157816

RESUMO

The insertion of CO into hydrogenated boron-amidine 1 yielding five-membered diazaborolone (5DAB) 3 has been studied within the molecular electron density theory (MEDT) at the DFT ωB97X-D/6-311G(d,p) level. This is a domino process comprised of two consecutive reactions: (i) the dehydrogenation of 1 yielding the frustrated Lewis pair (FLP) boron-amidine 4, which quickly equilibrates with four-membered diazaborolone (4DAB) 2; and (ii) the addition of CO into FLP 4, yielding the final 5DAB 3. Analysis of the Gibbs free energies indicates that the extrusion of H2 demands a high ΔG≠ of 28.6 kcal·mol-1, being endergonic by 6.7 kcal·mol-1. The subsequent addition of CO into FLP 4 presents a low ΔG≠ of 15.0 kcal·mol-1; formation of 5DAB 3 being exergonic by -5.7 kcal·mol-1 from hydrogenated boron-amidine 1. An analysis of the bonding changes along the insertion of CO in a smaller FLP model indicates that this reaction can be considered a [4 + 1] cycloaddition reaction taking place via a five-membered pseudocyclic transition state associated with a two-stage one-step mechanism. Analysis of the conceptual DFT reactivity indices suggests that the initial attack of CO on FLP 4 is an acid/base process in which the carbenoid carbonyl character allows CO to participate as a Lewis base, rather than a nucleophilic/electrophilic interaction. The results arising from the analysis of the Parr functions, however, coincide with this behaviour.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31242616

RESUMO

This study aimed to evaluate the functional impact of a shared intervention model by the mobile physiotherapy and rehabilitation team (MPRT) and primary care case management nurses (PCCMNs) on chronic patients. This was a prospective, observational study involving 1086 patients (mean age, 80 years; 63.7% females) in the province of Almeria, which was conducted between 2004 and 2018. Most of the registered diseases included cerebrovascular and neurological diseases (56.7%), osteoarticular diseases (45.3%), diabetes mellitus (25.7%), cardiovascular diseases (25.5%), and chronic respiratory diseases. The study included a home care intervention by the MPRT and PCCMNs and included the following main outcome measures: age, sex, main caregiver, disabling process (ICD-9), type and number of inclusion categories for chronic disease, initial and final Barthel index (BI), treatment or intervention on the patient (techniques), objectives, and number of sessions. The main techniques used were kinesiotherapy (44.6%) and caregiver training (23%), along with technical aid. An equation predicting the patients' final BI, according to the initial BI, was constructed using multiple linear regression modelling. A marked improvement in functional capacity was found after an average of 10 physiotherapy sessions. A lower patient age was correlated with a higher functional capacity, both initial and final BI, as well as a greater number of sessions.


Assuntos
Doença Crônica/terapia , Cuidados de Enfermagem , Modalidades de Fisioterapia , Idoso , Idoso de 80 Anos ou mais , Cuidadores , Feminino , Serviços de Assistência Domiciliar , Humanos , Masculino , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos
8.
Ciênc. Saúde Colet ; 24(6): 2351-2360, jun. 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1011797

RESUMO

Abstract Dietary practices of college students were compared before and after implementation of the University Restaurant (UR) and examined according to frequency of UR use. A natural experiment was conducted with students (n = 1131) of a Brazilian public university using a validated self-completed and identified questionnaire that inquired information on practices of substituting lunch and/or dinner with a snack (≥ 5 days/week) and on regular consumption of foods that were markers of a healthy or unhealthy diet. At the second time point, UR use by students was also assessed based on their attendance to it. Changes in food practices were examined by determining differences in proportions between the two assessments. The analysis of the association between UR use and each dietary practice was carried out using multiple logistic regression models. An association was observed between greater UR use and higher frequency of regular consumption of beans, vegetables, raw vegetables, cooked vegetables and fruit and lower frequency of regular consumption of French fries and/or fried snacks. The UR proved to be an environment that facilitated the adoption of healthy dietary practices and promoted improvement in the diets of the students who were more assiduous to the restaurant.


Resumo Práticas alimentares de universitários foram comparadas antes e após implementação do Restaurante Universitário (RU) e examinadas segundo a assiduidade ao RU. Experimento natural foi conduzido com estudantes (n = 1.131) de uma universidade pública utilizando questionário validado autopreenchido e identificado que abarcou as práticas de substituir o almoço e/ou jantar por lanche (≥ 5 dias/semana) e o consumo regular de alimentos marcadores de alimentação saudável e não saudável. No segundo momento, foi examinada a adesão dos estudantes ao RU por meio de sua assiduidade a ele. A variação das práticas alimentares foi examinada pela diferença entre proporções obtidas nos dois momentos de avaliação. A análise da associação entre a assiduidade ao RU e cada uma das práticas alimentares regulares foi feita por meio de modelos de regressão logística múltipla. Observou-se associação entre maior assiduidade ao RU e maior frequência de consumo regular de feijão, hortaliças, hortaliças cruas, hortaliças cozidas e frutas e menor frequência de consumo regular de batata frita e/ou salgados fritos. A implementação do RU se constituiu como um espaço facilitador da adoção de práticas alimentares saudáveis e promoveu a melhoria da alimentação dos estudantes com maior assiduidade a ele.

9.
Biomimetics (Basel) ; 4(1)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31105194

RESUMO

Lipid bilayers represent the interface between the cell and its environment, serving as model systems for the study of various biological processes. For instance, the addition of small molecules such as alcohols is a well-known process that modulates lipid bilayer properties, being considered as a reference for general anesthetic molecules. A plethora of experimental and simulation studies have focused on alcohol's effect on lipid bilayers. Nevertheless, most studies have focused on lipid membranes formed in the presence of alcohols, while the effect of n-alcohols on preformed lipid membranes has received much less research interest. Here, we monitor the real-time interaction of short-chain alcohols with solid-supported vesicles of dipalmitoylphosphatidylcholine (DPPC) using quartz crystal microbalance with dissipation monitoring (QCM-D) as a label-free method. Results indicate that the addition of ethanol at different concentrations induces changes in the bilayer organization but preserves the stability of the supported vesicle layer. In turn, the addition of 1-pentanol induces not only changes in the bilayer organization, but also promotes vesicle rupture and inhomogeneous lipid layers at very high concentrations.

10.
Fungal Biol ; 123(6): 481-488, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31126425

RESUMO

Maize plants infected by Ustilago maydis develop galls known as "cuitlacoche", a food product appreciated in the Mexican gastronomy. The virulence of different U. maydis isolates was assessed, as well as the development of the infection on one commercial maize variety. Sporidia were isolated of wild galls collected in Mexico. Sexual compatibility patterns were determined using the Fuzz reaction, showing a 1:1:1:1 segregation of mating type specificities. Ten U. maydis compatible strains were selected on the basis of their virulence, namely: four wild-type compatible sporidia, one multi-teliosporic strain, two hybrids between wild-type and tester strains, and three tester strains. Maize plants of a commercial hybrid (Tornado XR™) were inoculated with these strains of U. maydis, using a randomized complete block experimental design. Phenological and phenotypic characteristics of plants, as well as production, quality and sensory attributes of the resulting galls, were evaluated. Greater yields of galls were recorded in tester strains (incidence >90 %, severity >80 %, productivity >12 t/ha), a hybrid strain (EM1-6 × FB1) [incidence 82.6 %, severity 51.8 %, productivity 5.6 t/ha] and a wild-type strain (EM4-10 × EM2-4) [incidence 68.2 %, severity 44.0 %, productivity 4.8 t/ha]. Wild-type strains showed better flavor, characterized by less bitterness and acidity, but prevailing sweet, umami and maize flavor.


Assuntos
Ustilago/fisiologia , Zea mays/microbiologia , Alimentos , Genótipo , Humanos , Tumores de Planta/microbiologia , Paladar , Ustilago/genética
12.
J Clin Exp Hematop ; 59(1): 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918139

RESUMO

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/química , Linfócitos B/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Fatores Imunológicos , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Linfócitos T/química
13.
Phys Chem Chem Phys ; 21(14): 7412-7428, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30864565

RESUMO

In this paper, we assess the performance of 24 density functional theory (DFT) based methods classified into 5 categories (GGA, MGGA, HGGA, HMGGA and DHGGA) in predicting reaction energetics, transition state geometries, and the degree of synchronicity/nonsynchronicity in the formation of two new C-C single-bonds in three Diels-Alder reactions between symmetrically and unsymmetrically substituted cyanoethylenes and cyclopentadiene, which gradually proceed from fully synchronous to highly asynchronous concerted mechanisms. This important concept in reaction mechanisms is revealed by the fine structure of the reaction force constant κ(ξ) along the transition region. Some wave function theory (WFT) based methods are also assessed against the CCSD(T) and CCSD benchmarks for the energy and geometry, respectively. The results and the statistical analysis of the errors confirm the robustness of SCS-MP2 (a WFT-based method) as one of the most reliable computational approaches. Regarding DFT-based methods, hybrid exchange-correlation functionals combined with medium-range electron correlation effects or long-range corrected exchange appear as the best performing methods, highlighting both M11 and M06-2X, since a certain percentage of exact Hartree-Fock exchange could counterbalance the delocalization errors that affect pure functionals. Thus, they reliably describe energetics, geometries and the degree of synchronicity in the formation of new C-C single bonds in Diels-Alder reactions. Noticeably, moderate performance for double hybrid functionals and poor performance for the most popular B3LYP method were found as well.

15.
Arch. méd. Camaguey ; 23(1): 112-121, ene.-feb. 2019. graf
Artigo em Espanhol | LILACS-Express | ID: biblio-989314

RESUMO

RESUMEN Fundamento: los tumores de células granulares son lesiones benignas infrecuentes de crecimiento lento que pueden aparecer en cualquier sitio del organismo. La región de cabeza y cuello incluye las localizaciones más frecuentes (entre el 30 y el 50 % de todos los tumores de este tipo, hasta los del sistema nervioso central). Objetivo: presentar un caso de tumor de células granulares intratiroideo. Caso clínico: se presenta el caso de una paciente femenina de 37 años de edad con enfermedad nodular de la glándula tiroides de crecimiento lento con escasa sintomatología, con confirmación histológica tumor de células de la granulosa. Al examen físico se identificó aumento de volumen en la región anterolateral del cuello, en relación con el lóbulo derecho de la glándula tiroidea, que correspondía con lesión tumoral de 3 cm, mal delimitada, adherida a planos profundos, no dolorosa a la palpación. En la ecografía se observó: lóbulo derecho del tiroides de 4,3 cm x 1,2 cm x 1,4 cm, no homogéneo con lesión nodular de 2,8 x 1,4 cm mal delimitada, de bordes irregulares. Se realizó biopsia transoperatoria que se reportó como positiva de células neoplásicas malignas, sin embargo, el estudio histológico extemporáneo reveló un tumor benigno de células granulares intratiroideo. El tratamiento quirúrgico es curativo en este caso. Conclusiones: el diagnóstico de tumor de células granulares intratiroideo benigno, se presenta con las características de una lesión tumoral maligna, debe tenerse en cuenta en el diagnóstico diferencial de los tumores de la glándula tiroides.


ABSTRACT Background: the granular cells tumors are uncommon benign lesions of slow growth that can appear in any place of the organism. The head and neck region includes the most frequent localizations (between the 30 and 50% of all the tumors of this type, including those of the central nervous system). Objective: to present a case of intra-thyroid granular cell tumor. Clinical case: a case of a 37 year-old female patient with nodular illness of the thyroid of slow growth with scarce symptoms, with histologic confirmation of granular cells tumor is presented. To the physical exam, an increase of volume was identified in the anterolateral region of the neck, in connection with the right lobe of the thyroid gland that corresponded with a tumoral lesion of 3cm approximately, not well defined, stuck to deep planes, not painful to the palpation. In the echography, it was observed: right lobe of the thyroid of 4.3 cm x 1.2cm x 1.4 cm, not homogeneous with a nodular lesion of 2.8 x 1.4 cm not well defined, of irregular borders. During the surgery, a frozen section was examined and reported as positive of malignancy, however, the untimely histologic study revealed a benign intra-thyroid granular cell tumor. The surgical treatment is healing in this case. Conclusions: the diagnosis of intra-thyroid benign granular cell tumor is presented with the characteristics of a malign tumor, it should be kept in mind in the differential diagnosis of the tumors of the thyroid.

16.
Am J Surg ; 218(5): 993-999, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30665612

RESUMO

BACKGROUND: Hypocalcemia is one of the most common complications after total thyroidectomy. Recently, indocyanine green (ICG) angiography of the parathyroid glands (PGs) has been suggested as a reliable tool for predicting postoperative hypocalcemia. The aim of our study was to evaluate the performance of a simple quantitative score based on ICG angiography of the PGs (4-ICG score) for predicting postoperative hypocalcemia. METHODS: Thirty nine consecutive patients who underwent total thyroidectomy for multinodular goiter were included. For each patient, the 4-ICG score was calculated, adding the individual viability value of the four PGs. Discrimination and correlation analyses were performed. RESULTS: In 32/39 patients, the four PGs were identified. Patients with postoperative hypocalcemia (n = 6, 19%) had a lower 4-ICG score (2.5 [1.8-3.3] vs. 4.0 [3.0-6.0]; p = 0.003). The 4-ICG score showed good discrimination in terms of predicting postoperative hypocalcemia (AUC = 0.875 (0.710-0.965); p = 0.001) and a good correlation with postoperative parathyroid function. CONCLUSIONS: The 4-ICG score predicts postoperative hypocalcemia and correlates well with postoperative parathyroid function in patients undergoing total thyroidectomy for multinodular goiter.

17.
J Virol ; 93(7)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674625

RESUMO

Hepatitis C is a liver disease caused by the hepatitis C virus (HCV) affecting 71 million people worldwide with no licensed vaccines that prevent infection. Here, we have generated four novel alphavirus-based DNA-launched self-amplifying RNA replicon (DREP) vaccines expressing either structural core-E1-E2 or nonstructural p7-NS2-NS3 HCV proteins of genotype 1a placed under the control of an alphavirus promoter, with or without an alphaviral translational enhancer (grouped as DREP-HCV or DREP-e-HCV, respectively). DREP vectors are known to induce cross-priming and further stimulation of immune responses through apoptosis, and here we demonstrate that they efficiently trigger apoptosis-related proteins in transfected cells. Immunization of mice with the DREP vaccines as the priming immunization followed by a heterologous boost with a recombinant modified vaccinia virus Ankara (MVA) vector expressing the nearly full-length genome of HCV (MVA-HCV) induced potent and long-lasting HCV-specific CD4+ and CD8+ T cell immune responses that were significantly stronger than those of a homologous MVA-HCV prime/boost immunization, with the DREP-e-HCV/MVA-HCV combination the most immunogenic regimen. HCV-specific CD4+ and CD8+ T cell responses were highly polyfunctional, had an effector memory phenotype, and were mainly directed against E1-E2 and NS2-NS3, respectively. Additionally, DREP/MVA-HCV immunization regimens induced higher antibody levels against HCV E2 protein than homologous MVA-HCV immunization. Collectively, these results provided an immunization protocol against HCV by inducing high levels of HCV-specific T cell responses as well as humoral responses. These findings reinforce the combined use of DREP-based vectors and MVA-HCV as promising prophylactic and therapeutic vaccines against HCV.IMPORTANCE HCV represents a global health problem as more than 71 million people are chronically infected worldwide. Direct-acting antiviral agents can cure HCV infection in most patients, but due to the high cost of these agents and the emergence of resistant mutants, they do not represent a feasible and affordable strategy to eradicate the virus. Therefore, a vaccine is an urgent goal that requires efforts to understand the correlates of protection for HCV clearance. Here, we describe for the first time the generation of novel vaccines against HCV based on alphavirus DNA replicons expressing HCV antigens. We demonstrate that potent T cell immune responses, as well as humoral immune responses, against HCV can be achieved in mice by using a combined heterologous prime/boost immunization protocol consisting of the administration of alphavirus replicon DNA vectors as the priming immunization followed by a boost with a recombinant modified vaccinia virus Ankara vector expressing HCV antigens.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Replicon/imunologia , Vírus Vaccinia/imunologia , Vacinas Virais/imunologia , Alphavirus/imunologia , Animais , Anticorpos Antivirais/imunologia , DNA/imunologia , Vetores Genéticos/imunologia , Imunização/métodos , Camundongos , RNA/imunologia , Vacinação/métodos , Vacinas de DNA/imunologia , Proteínas não Estruturais Virais/imunologia
18.
Lancet Public Health ; 4(2): e107-e115, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30683584

RESUMO

BACKGROUND: In Cuba, hypertension control in primary care has been prioritised as a cost-effective means of addressing premature death from cardiovascular disease. However, there is little evidence from large-scale studies on the prevalence and management of hypertension in Cuba, and no direct evidence of the expected benefit of such efforts on cardiovascular mortality. METHODS: In a prospective cohort study, adults in the general population identified via local family medical practices were interviewed between Jan 1, 1996, and Nov 24, 2002, in five areas of Cuba, and a subset of participants were resurveyed between July 14, 2006, and Oct 19, 2008, in one area. During household visits, blood pressure was measured and information obtained on diagnosis and treatment of hypertension. We calculated the prevalence of hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or receiving treatment for hypertension) and the proportion of people with hypertension in whom it was diagnosed, treated, and controlled (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg). Deaths were identified through linkage by national identification numbers to the Cuban Public Health Ministry records, to Dec 31, 2016. We used Cox regression analysis to compare cardiovascular mortality between participants with versus without uncontrolled hypertension. Rate ratios (RRs) were used to estimate the fraction of cardiovascular deaths attributable to hypertension. FINDINGS: 146 556 participants were interviewed in the baseline survey in 1996-2002 and 24 345 were interviewed in the resurvey in 2006-08. After exclusion for incomplete data and age outside the range of interest, 136 111 respondents aged 35-79 years (mean age 54 [SD 12] years; 75 947 [56%] women, 60 164 [44%] men) were eligible for inclusion in the analyses. 34% of participants had hypertension. Among these, 67% had a diagnosis of hypertension. 76% of participants with diagnosed hypertension were receiving treatment and blood pressure was controlled in 36% of those people. During 1·7 million person-years of follow-up there were 5707 cardiovascular deaths. In the age groups 35-59, 60-69, and 70-79 years, uncontrolled hypertension at baseline was associated with RRs of 2·15 (95% CI 1·88-2·46), 1·86 (1·69-2·05), and 1·41 (1·32-1·52), respectively, and accounted for around 20% of premature cardiovascular deaths. INTERPRETATION: In this Cuban population, a third of people had hypertension. Although levels of hypertension diagnosis and treatment were commensurate with those in some high-income countries, the proportion of participants whose blood pressure was controlled was low. As well as reducing hypertension prevalence, improvement in blood pressure control among people with diagnosed hypertension is required to prevent premature cardiovascular deaths in Cuba. FUNDING: Medical Research Council, British Heart Foundation, Cancer Research UK.

19.
Asian Pac J Cancer Prev ; 20(1): 1-4, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30677862

RESUMO

Background: Lung cancer (LC) is the second leading cause of cancer death in Chile, causing >3,000 deaths every year. Epidemiological LC data in Chile is scarce and scattered. Here, we aimed to quantify the prevalence of Epidermal Growth Factor Receptor (EGFR) gene mutations in a Chilean cancer center. These data may identify individuals that could benefit from targeted therapies such as Tyrosine Kinase Inhibitors (TKIs). Methods: A total of 1,405 Biopsies from 1,381 LC patients were retrospectively analyzed retrieving clinical data from EGFR mutants including age, gender, histological type, smoking habits and type of EGFR mutation. We also analyzed overall survival (OS) rates. Results: From all patients 21.7% had clinically relevant EGFR mutations, and a median age at diagnosis of 65 years. Most were female (64%), classified as adenocarcinomas (94.5%), and non-smokers/light smokers (93.1%). The most prevalent mutation was exon-19 deletions (50.6%) followed by Leucine-to Arginine 858; OS was 15 months. Clinical follow-up information was available for 83 patients. The use of TKIs in these patients significantly improved OS. Conclusion: The prevalence of EGFR mutations in the studied population was 21.7%, comparable to other countries in Latin America. The most frequent EGFR mutation was exon-19 deletion, OS in this group was 15 months, and TKIs significantly improved OS.


Assuntos
Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Chile/epidemiologia , Estudos Transversais , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
20.
Org Biomol Chem ; 17(3): 498-508, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30569052

RESUMO

[3 + 2] cycloaddition (32CA) reactions of cyclohexyne, a cyclic strained acetylene, with methyl azide and methoxycarbonyl diazomethane have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d) computational level. These 32CA reactions, which take place through a one-step mechanism involving highly asynchronous transition state structures, proceed with relatively low activation enthalpies of 6.0 and 4.3 kcal mol-1, respectively, both reactions being strongly exothermic. The reactions are initiated by the creation of a pseudoradical center at one of the two acetylenic carbons of cyclohexyne with a very low energy cost, 1.0 kcal mol-1, which promotes the easy formation of the first C-N(C) single bond in the adjacent acetylenic carbon. This scenario is completely different from that of the 32CA reaction involving non-strained but-2-yne; thus, strain in cyclohexyne triggers a high reactivity as a consequence of its unusual electronic structure at the ground state. Finally, the experimental regioselectivity of the 32CA reactions involving 3-alkoxy-cyclohexyne derivatives is correctly explained within MEDT.

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