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1.
Materials (Basel) ; 14(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810459

RESUMO

Over the years, the need for the synthesis of biodegradable materials has facilitated the drift of the asphalt industry towards eco-sustainable and cost-effective production of road pavements. The principal additives in the asphalt industry to improve the performance of road pavements and increase its lifespan are majorly rheological modifiers, adhesion promoters and anti-oxidant agents. Rheological modifiers increase physico-chemical properties such as transition temperature of asphalt binder (bitumen), adhesion promoters increase the affinity between binder and stone aggregates while anti-oxidant agents reduce the effects of oxidation caused by exposure to air, water and other natural elements during the production of asphalt pavements. In this study, we tested the effectiveness of a food grade bio-additive on these three aforementioned properties. We also sought to hypothesize the mechanisms by which the additive confers these desired features on bitumen. We present this study to evaluate the effects of turmeric, a food-based additive, on bitumen. The study was conducted through dynamic shear rheology (DSR), atomic force microscopy, scanning electron microscopy (SEM) and boiling test analysis.

2.
Sci Rep ; 11(1): 35, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420106

RESUMO

Long cellulose fiber (10-30 cm), extracted from Spartium junceum, was chemically treated with different softening agents with the aim to improve its textile applicability. A preliminary sensory evaluation of the treated fibers revealed an evident, though qualitative, improvement of the fiber softness. The effects of the softening agents on the fiber was evaluated quantitatively, by means of macroscopic measurements of the wettability, viscoelasticity, and thermal (thermal gravimetry) properties. Moreover, the effects of the softening treatments on the microscopic structure of the fiber and on its properties at a molecular level, were studied by optical and scanning electron microscope and X-ray diffraction (XRD), respectively. The macroscopic analysis showed that the softeners used increases the hydrophilicity and water wettability of the cellulose fiber with respect to the raw one. Moreover, the dynamical mechanical analysis on sample yarns showed that the softeners increase the interfiber frictional forces. A linear correlation between the interfiber friction and the increase of hydrophilicity and fiber wettability was shown. The treated fiber exhibits a more homogeneous thermal behaviour, due to more homogeneous structural features, since the thermal-induced cellulose fibrils depolimerization undergoes a marked temperature range contraction. These data can be well related with those obtained by microscopy analysis, showing that the fiber surface, after the treatment, appears thinner and less rough, as well as with the XRD analysis, which shows that softeners induce a significant decrease of the fiber crystallinity.

3.
Cancers (Basel) ; 12(11)2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33167350

RESUMO

Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.

4.
Foods ; 9(11)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33137916

RESUMO

The aim of this investigation was to prepare two solid mixtures containing a soluble polymorph of (+)-catechin and mucic (MUC) or tartaric (TAR) acids as new leavening agents. The solid mixtures were based on a polymorph of (+)-catechin, characterized through Powder X-ray Diffraction (PXRD) analysis and assayed in in vitro antioxidant and solubility assays. The dough samples were studied by dynamic rheological tests, while muffins were studied through Headspace Solid-Phase Microextraction (HS-SPME)/ Gas Chromatography-Mass Spectrometry (GC-MS) analysis to identify volatile compounds, in vitro tests to evaluate antioxidant properties, and sensory analyses. TAR powder showed a solubility in water almost one order of magnitude increased with respect to commercial (+)-catechin (40.0 against 4.6 mg mL-1) and increased antioxidant performances. In particular, TAR showed total phenolic content (TPC) and total antioxidant capacity (TAC) values of 0.0298 ± 0.021 and 0.0081 ± 0.0009 meq CT/g, while MUC showed better results in terms of 2,2-diphenyl-1-picrylhydrazyl) acid (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS), 0.518 ± 0.015 and 0.112 ± 0.010mg/mL, respectively. MS analysis identified different compounds derived from the lipid oxidation process. Muffins obtained using both powders showed interesting outcomes regarding dough process and appreciable appearance/olfactory/taste/texture profiles. Muffins obtained from TAR-based mixture showed also a total phenolic content of 0.00175 meq CT/g muffin, and almost two times improved TAC and scavenger activity against DPPH radical. The formulated powders could be used as suitable health-promoting ingredients in the food industry.

5.
Adv Colloid Interface Sci ; 285: 102283, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33099178

RESUMO

Asphalt concretes are biphasic systems, with a predominant phase (c.a. 93-96% w/w) made by the macro-meter sized inorganic aggregates hold together by small amounts of a viscoelastic binding bitumen (c.a. 5%). Even if the bitumen is in minor amount, it plays an important role dictating all the desired properties: rheological performances, resistance to aging etc. What happens if nanoparticles are used as additive in such materials? They usually confer enhanced resistance under mechanical stress and give sometimes interesting added-values properties so, despite the high costs of their production, nanoparticles are interesting materials which are being monitored for large scales applications. This work introduces the reader to the properties of nanoparticles in an easy to review their use in bitumen and asphalt preparation. Silica, ceramic, clay, other oxides and inorganic nanoparticles are presented and critically discussed in the framework of their use in bitumen and asphalt preparation for various scopes. Organic and functionalized nanoparticles are likewise discussed. Perspectives and cost analysis are also given for a more complete view of the problematic, hoping this could help researchers in their piloted design of material for road pavements with ever-increasing performances.

6.
Am J Hum Genet ; 107(3): 499-513, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32721402

RESUMO

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.


Assuntos
Carcinogênese/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Transtornos do Neurodesenvolvimento/genética , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Noonan/fisiopatologia , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais , Sequenciamento Completo do Exoma , Proteínas ras/genética
7.
Nanomaterials (Basel) ; 10(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575602

RESUMO

The asphalt industry's incentive to reduce greenhouse gas emissions has increased since the 1990s due to growing concerns on environmental issues such as global warming and carbon footprint. This has stimulated the introduction of Warm Mix Asphalt (WMA) and its technologies which serve the purpose of reducing greenhouse gas emissions by reducing the mixing and compaction temperatures of asphalt mix. WMA gained popularity due to the environmental benefit it offers without compromising the properties, performance and quality of the asphalt mix. WMA is produced at significantly lower temperatures (slightly above 100 °C) and thus results in less energy consumption, fewer emissions, reduced ageing, lower mixing and compaction temperatures, cool weather paving and better workability of the mix. The latter of these benefits is attributed to the incorporation of additives into WMA. These additives can also confer even better performance of WMA in comparison to conventional Hot Mix Asphalt (HMA) methods. Even though there are recommended dosages of several WMA additives, there is no general standardized mixture design procedure and this makes it challenging to characterize the mechanism(s) of action of these additives in the warm mix. The effects of the addition of additives into WMA are known to a reasonable extent but not so much is known about the underlying interactions and phenomena which bring about the mechanism(s) by which these additives confer beneficial features into the warm mix. Additives in a certain way are being used to bridge the gap and minimize or even nullify the effect of the mixing temperature deficit involved in WMA processes while improving the general properties of the mix. This review presents WMA technologies such as wax, chemical additives and foaming processes and the mechanisms by which they function to confer desired characteristics and improve the durability of the mix. Hybrid techniques are also briefly mentioned in this paper in addition to a detailed description of the specific modes of action of popular WMA technologies such as Sasobit, Evotherm and Advera. This paper highlights the environmental and technical advantages of WMA over the conventional HMA methods and also comprehensively analyzes the mechanism(s) of action of additives in conferring desirable characteristics on WMA, which ultimately improves its durability.

8.
Ital J Pediatr ; 46(1): 53, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32326958

RESUMO

BACKGROUND: An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis. METHODS: Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed. RESULTS: Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue. CONCLUSIONS: This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled.

9.
Chempluschem ; 85(3): 426-440, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32154993

RESUMO

Ag(I)-containing ethylcellulose (EC) films suitable as antbacterial packaging materials have been prepared and fully characterized. Different preparation methods, including the use of green casting solvents, are proposed. The Ag(I) acylpyrazolonato complexes, [Ag(Qpy,CF3 )(L)], L=benzylimidazole (Bzim) and L=ethylimidazole (EtimH), used as active additives, display different modes of interactions with EC, depending on their structural features. A thorough investigation of the EC liquid-crystalline lyotropic phase and its changes with the introduction of silver additives, has been conducted, revealing either the inclusion of complex molecules into the inner structure of the EC matrix or their dispersion on its surface. Moreover, the bactericidal activity of the prepared Ag(I) films seems to be related to the interaction between silver additives and the polymeric EC matrix. Indeed, the EC-2b films show a particularly good performance even with a low silver content, with a relative bacterial killing of about 100 %. Tests for Ag(I) migration have been performed by using three food stimulants under two assay conditions. Low values of silver release are recorded, particularly at low concentration of silver content, in the case of all new prepared Ag(I) films.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32221274

RESUMO

BACKGROUND: The incidence of cutaneous melanoma (cM) has increased in the last decades. Germline mutations in the high-penetrance melanoma susceptibility gene CDKN2A (Cyclin- dependent kinase inhibitor 2A) are associated with a younger age at diagnosis and an increased risk to develop pancreatic cancer. METHODS: We retrospectively analysed the data of patients with prior diagnosis of cM referring to our service from January 2005 to May 2017. The aim was to investigate the rate of multiple cMs (MPM), assessing their clinical/pathological features. Moreover, the genetic tests of patients who had undergone CDKN2A/CDKN2B, CDK4 and MITF screening were evaluated. RESULTS: 115 patients (9.26%) were diagnosed with MPMs: 70 males (60.87%) and 45 women (39.13%). 75 patients (43 males and 32 females) underwent genetic screening for germline mutations. The screening revealed that 4/75 patients (5.33%) were carriers of the non-synonymous missense variation c.442G>A (p.Ala148Thr) in CDKN2A exon 2 in heterozygosis, 3 of whom had at least one in-situ melanoma. In 1 patient (1.33%) we detected the variation c.249C>A, p.His83Gln in CDKN2A exon 2 in heterozygosis and in 1 patient (1.33%) the mutation c.952G>A (p.Glu318Lys) in MITF gene was found. CONCLUSIONS: This study confirms the need for a full body skin examination and a prolonged surveillance in patients affected by cM, as MPMs were detected in up to 10% of total cases in our series and synchronous lesions in 1/5. Moreover, it reflects the great variability of cM high- susceptibility genes mutational status within the Italian territory. Patients carrying c.952G>A (p.Glu318Lys) MITF mutation have a higher risk to develop a nodular cM.

11.
J Nanosci Nanotechnol ; 20(7): 4574-4579, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31968520

RESUMO

Bitumens are composite systems extensively used in road pavements. Due to their complex nature, a rational understanding of the relationships between composition, structure and performances of these materials is still far from being achieved, so research attempting to shed more light in this field is required. Here, we exploit Wide Angle X-ray Scattering (WAXS) as a technique of choice to shed light on the bitumen structure at different length scales. Diagnostic fingerprints, characterizing the WAXS profile, are correlated to specific Bragg distances which can be reasonably attributed to the molecular and supramolecular aggregation taking place at various levels of complexity leading to the formation of hierarchical structures. Due to the inherent instability of these materials some indications are given to obtain reliable structural data.

12.
Cardiovasc Pathol ; 44: 107157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31760239

RESUMO

An apparently healthy man died suddenly at the age of 49 during physical activity. The heart was referred to our Cardiovascular Pathology Unit for valve tissue banking. Pathology findings led to the diagnosis of arrhythmogenic left ventricular cardiomyopathy. Molecular autopsy was performed and two variants of interest were identified in genes associated with arrhythmogenic cardiomyopathy. The 19-year-old son underwent a cardiac screening comprehensive of electrocardiogram (ECG), echocardiogram, cardiac magnetic resonance and genetic testing, and the diagnosis of arrhythmogenic left ventricular cardiomyopathy was achieved. This case report highlights the need of a systematic evaluation of all sudden death victims with autopsy performed by expert cardiovascular pathologists and implemented by molecular analysis, aiming to identify also rare hereditary diseases and activate proper family screening.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Morte Súbita Cardíaca/etiologia , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/patologia , Autopsia , Causas de Morte , Morte Súbita Cardíaca/patologia , Evolução Fatal , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Molecular
13.
Respiration ; 98(2): 125-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266032

RESUMO

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal-dominant inherited disorder characterized by inactivation of the gene Folliculin (FLCN), pulmonary cysts with recurrent spontaneous pneumothorax, dermatological lesions, and an increased risk of developing renal malignancies. OBJECTIVES: We aimed to investigate the real prevalence of BHDS and its prevalence among patients with a familial history of pneumothorax. METHODS: From July 2014 to December 2016, we consecutively studied all patients with spontaneous pneumothorax and a positive family history for the same condition referring to our Institution. The suspicious cases underwent genetic analysis of the BHDS-causative gene FLCN. FLCN-positive cases were further evaluated with routine blood tests, chest radiography, chest CT, abdominal MRI, and dermatological evaluation. RESULTS: Among 114 patients admitted with spontaneous pneumothorax, 7 patients had a family history of pneumothorax, and 6/7 (85.7%) patients had positive genetic test for FLCN as well as 7/13 family members. Pulmonary cysts were found in all patients with a FLCN-positive genetic test. Most patients (10/13, 76.9%) had tiny pulmonary cysts less than 1 cm in diameter. The vast majority of cysts were intraparenchymal (12/13, 92.3%) and located in lower lobes. Dermatological lesions were found in 7/13 (54%) patients, renal cysts in 4/13 (31%) patients, and renal cancer in 1 (1/13, 7.7%) patient. CONCLUSIONS: Although BHDS is considered a rare disease, BHDS underlies spontaneous pneumothorax more often than usually believed, especially whenever a family history of pneumothorax is present. Diagnosis of BHDS is essential to start monitoring patients for the risk of developing renal malignancies.


Assuntos
Síndrome de Birt-Hogg-Dubé/diagnóstico , Anamnese , Pneumotórax/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Síndrome de Birt-Hogg-Dubé/epidemiologia , Síndrome de Birt-Hogg-Dubé/genética , Cistos/diagnóstico por imagem , Feminino , Testes Genéticos , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prevalência
14.
Colloids Surf B Biointerfaces ; 173: 623-631, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368209

RESUMO

The low efficacy of Acyclovir topical therapy is due to its physicochemical properties that limit the permeation across the stratum corneum. The goal of this research was to evaluate the ability of biodegradable surfactant, Brij97, to self-assembly in different types of colloid systems which can improve the Acyclovir permeation and accumulation at the target site (the basal epidermis). New Acyclovir formulation based on Brij97 have been analyzed in order to investigate the effect of drug encapsulation on the structure. After that, the in vitro percutaneous permeation of Acyclovir has been compared with that one of the commercial specialty Zovirax® 5%. To estimate the potential of the new formulations proposed as topical delivery, it has been essential to quantify the Acyclovir in the skin layers. The results confirmed that the self-assembly of the surfactant in different nanosized structures improved the amount of permeated Acyclovir and the formation of intracutaneous drug reservoir. Furthermore, the different lipophilicity and structural organization of carriers based on Brij97 showed different influence on the promotion of permeation. The experimental data suggest that the designed carriers could be a valid alternative to improve the efficacy of the current antiviral therapy.


Assuntos
Aciclovir/farmacocinética , Antivirais/farmacocinética , Portadores de Fármacos , Lipossomos/química , Nanoestruturas/química , Óleos Vegetais/química , Polietilenoglicóis/química , Aciclovir/química , Animais , Antivirais/química , Colesterol/química , Composição de Medicamentos/métodos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/metabolismo , Nanoestruturas/ultraestrutura , Permeabilidade , Coelhos , Pele/metabolismo , Absorção Cutânea
15.
Am J Hum Genet ; 102(2): 309-320, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29394990

RESUMO

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Heterogeneidade Genética , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Síndrome de Noonan/genética , Proteína cdc42 de Ligação ao GTP/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Masculino , Modelos Moleculares , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Noonan/metabolismo , Síndrome de Noonan/patologia , Fenótipo , Estrutura Secundária de Proteína , Índice de Gravidade de Doença , Proteína cdc42 de Ligação ao GTP/química , Proteína cdc42 de Ligação ao GTP/metabolismo
16.
Interact Cardiovasc Thorac Surg ; 25(5): 813-817, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29049801

RESUMO

OBJECTIVES: Mutations in ACTA2 have been reported as a cause of familiar thoracic aortic aneurysm (TAA) with associated bicuspid aortic valve (BAV) in some individuals. Our aim is to investigate the role of ACTA2 mutations in BAV associated with TAA in 20 patients. METHODS: We recruited 20 patients who underwent surgery for BAV and TAA; clinical genetic evaluation and ACTA2 mutation analysis were performed on each patient, along with next-generation sequencing analysis of BAV-related genes. Available first-degree relatives were enrolled and evaluated with echocardiography and clinical genetic examination. RESULTS: No mutations were found in ACTA2 or in BAV-related genes in our probands nor any common clinical signs possibly related to their heart disease. One-third of probands did not have any cardiovascular risk factor. Surgery was required at a young age (mean age 47.2 years) and at relatively small ascending aortic diameters (mean size 49.7 mm). In 77 first-degree relatives, 1 new diagnosis of TAA requiring surgery was made and 8 previous BAV/TAA diagnoses (9/77 = 11.7%) were confirmed. The phenotype BAV ± TAA segregated in 25% of our families. CONCLUSIONS: Although based on a small cohort, our results seemed to justify the conclusion that ACTA2 did not play a significant role in the pathogenesis of BAV aortopathy. The underlying genetic factors of this condition remain elusive and both large association studies and exome or genome sequencing could represent promising tools to unravel its pathogenesis. Aortic resection of TAA at elective surgery in these patients should be recommended as well as echocardiography in their first-degree relatives.


Assuntos
Actinas/genética , Aneurisma da Aorta Torácica/genética , Valva Aórtica/anormalidades , DNA/genética , Doenças das Valvas Cardíacas/genética , Mutação , Actinas/metabolismo , Adolescente , Adulto , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/metabolismo , Análise Mutacional de DNA , Feminino , Seguimentos , Marcadores Genéticos/genética , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Adulto Jovem
18.
Hum Mutat ; 38(4): 451-459, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28074573

RESUMO

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 , and Arg265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262 and Arg265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Modelos Moleculares , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Ligação Proteica , Domínios Proteicos , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Domínios de Homologia de src
19.
Mater Sci Eng C Mater Biol Appl ; 69: 358-65, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27612723

RESUMO

Bigels are biphasic systems formed by water-based hydrogels and oil-based organogels, mainly studied, in the last few years, for pharmaceutical and cosmetic application focused on the controlled delivery of both lipophilic and hydrophilic active agents. The rheological properties of bigels depend on both the amount and the rheological characteristics of single structured phases. Moreover, it can be expected that, at large fractions of one of the starting gels, systems more complex than oil-in-water or water-in-oil can be obtained, yielding bicontinuous or matrix-in-matrix arrangement. Model bigels were investigated from a microstructural (i.e. microscopy and electrical conductivity tests) and rheological point of view. The hydrogel was prepared by using a low-methoxyl pectin whereas the organogel was prepared by using olive oil and, as gelator, a mixture of glyceryl stearate and policosanol. Model bigels were obtained by increasing the amount of organogel mixed with the hydrogel, and microstructural characterisation evidenced an organogel-in-hydrogel behaviour for all investigated samples, even though at the highest organogel content a more complex structure seems to arise. A semi-empirical model, based on theoretical equations developed for suspensions of elastic spheres in elastic media, was proposed to relate bigel rheological properties to single phase properties and fractions.


Assuntos
Cosméticos/química , Hidrogéis/química , Preparações Farmacêuticas/química , Portadores de Fármacos/química , Condutividade Elétrica , Microscopia , Azeite de Oliva/química , Tamanho da Partícula , Reologia , Temperatura
20.
Int J Pharm ; 511(2): 703-8, 2016 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-27484834

RESUMO

Inclusion of lipids or polymers with a transition temperature closer to physiological body temperature (40-42°C) is a strategy used in tumor therapy for more than 30 years, because it allows induction of drug release from delivery systems by mild hyperthermia. Unfortunately, most of these thermo-sensitive carriers are removed from circulation before completion of their function. Thus, novel multi-functional niosomes possessing spontaneous stealth and thermo-sensitive properties were developed from L64 Pluronic(®) and L64ox as its derivative, in presence or absence of cholesterol. The use of L64 both as amphiphilic constituent and thermo-sensitive molecule, gave the possibility to bypass the use of additional excipients and increased the system biocompatibility. Niosomes diameter ranged from 400 to 750nm and were long term stable. Calcein and 5-FU possess great affinity to niosomal matrices rich in PEO groups. Negative Z-potential values were attributed to the negative charges onto the niosomes surface and generally change according to the temperature. The in vitro drugs release studies were performed at 25°C, 37°C and 42°C, that are representative of certain conditions (storage, physiological condition and mild hyperthermia, respectively). Results showed that L64-based niosomes possess spontaneous thermo-sensitive properties: drugs releases were found to be more pronounced at 42°C. These early results are a promising first step for the development of multi-functional devices that combine several advantages such as stealth properties and temperature controllability at the desired location and time, for a more specific and efficient pharmacological therapy.


Assuntos
Fluoresceínas/farmacocinética , Fluoruracila/farmacocinética , Lipossomos/química , Poloxâmero/química , Colesterol/química , Portadores de Fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fluoresceínas/química , Fluoruracila/química , Tamanho da Partícula , Temperatura
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