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1.
Chempluschem ; 85(3): 426-440, 2020 Mar.
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.

2.
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.

3.
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.

4.
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
5.
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.

6.
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
7.
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
8.
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
10.
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
11.
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 Ambiente
12.
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 Ambiente
13.
Am J Med Genet A ; 167A(11): 2786-94, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26227443

RESUMO

RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed.


Assuntos
Estatura/efeitos dos fármacos , Crescimento e Desenvolvimento/efeitos dos fármacos , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Puberdade/efeitos dos fármacos , Proteínas ras/deficiência , Criança , Estudos de Coortes , Feminino , Hormônio do Crescimento Humano/farmacologia , Humanos , Recém-Nascido , Masculino , Fatores de Tempo , Resultado do Tratamento , Proteínas ras/metabolismo
14.
Hum Mutat ; 36(11): 1080-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26173643

RESUMO

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.


Assuntos
Estudos de Associação Genética , Mutação , Síndrome de Noonan/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteínas Son Of Sevenless/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Exoma , Facies , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Síndrome de Noonan/diagnóstico , Fenótipo , Conformação Proteica , Proteínas Son Of Sevenless/química , Adulto Jovem
15.
Colloids Surf B Biointerfaces ; 134: 273-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26209777

RESUMO

Ferrogels (or magnetic hydrogels) are cross-linked polymer networks containing magnetic nanoparticles: they are mechanically soft and highly elastic and at the same time they exhibit a strong magnetic response. Our work focuses on an combinatorial strategy to improve the efficacy of 5-Fluorouracil (5-FU) assisted chemotherapy, by developing novel multifunctional pH-sensitive ferrogels. We designed gels based on N,N'-dimethylacrylamide monomers polymerized in presence of methacrylic acid or 2-aminoethyl methacrylate hydrochloride, containing ferro-nanoparticles. The influence of polymeric matrix composition and exposition to magnetic field (MF) on swelling behavior and drugs release were investigated at pH 7.4 and 5. In particular, the magnetic field was obtained by using permanent magnetic bar (0.25 T) or electromagnet (0.5 and 1.2 T), with the aim to analyze quantitatively the magnetic effects. A strong influence of the magnetic field on ferrogels properties have been observed. Swelling analysis indicated a dependence on both pH and network composition, reaching a maximum at pH 7.4, for formulations containing methacrylic acid, while the application of MF appeared to decrease the swelling percentages. Release profiles of 5-FU showed effective modulation in release by application of MF: drug release is always higher in the presence of a magnetic field and generally increases with its intensity. The combining effect of pH sensitive properties and application of MF improved the performance of the systems. Results showed that our ferrogels may be technologically applicable as devices for delivery of 5-FU in a controllable manner.


Assuntos
Portadores de Fármacos , Fluoruracila/administração & dosagem , Géis , Concentração de Íons de Hidrogênio , Magnetismo , Neoplasias/tratamento farmacológico , Fluoruracila/uso terapêutico , Técnicas In Vitro
16.
Am J Med Genet A ; 167A(8): 1902-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846317

RESUMO

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.


Assuntos
Neuroblastoma/complicações , Síndrome de Noonan/fisiopatologia , Humanos , Recém-Nascido , Masculino , Síndrome de Noonan/complicações
17.
Am J Med Genet A ; 164A(12): 3120-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25331583

RESUMO

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is a developmental disorder clinically related to Noonan syndrome (NS) and characterized by facial dysmorphisms, postnatal growth retardation, cardiac anomalies (in particular dysplasia of the mitral valve and septal defects), variable neurocognitive impairment, and florid ectodermal features. A distinctive trait of NS/LAH is its association with easily pluckable, slow growing, sparse, and thin hair. This rare condition is due to the invariant c.4A > G missense (p.Ser2Gly) change in SHOC2, which encodes a regulatory protein that participate in RAS signaling. Here we report two patients with molecularly confirmed NS/LAH, with extremely different phenotypic expression, in particular concerning the severity of the cardiac phenotype and neurocognitive profile. While the first available clinical records outlined a relatively homogeneous phenotype in NS/LAH, the present data emphasize that the phenotype spectrum associated with this invariant mutation is wider than previously recognized.


Assuntos
Cardiopatias Congênitas/patologia , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome dos Cabelos Anágenos Frouxos/patologia , Mutação de Sentido Incorreto/genética , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Fenótipo , Eletroencefalografia , Cardiopatias Congênitas/genética , Humanos , Deficiência Intelectual/genética , Itália , Imagem por Ressonância Magnética , Masculino
18.
Soft Matter ; 10(35): 6783-90, 2014 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-25074753

RESUMO

In order to obtain new functional soft systems for use as templating agents for the construction of functional mesostructured materials, the dynamic ordered soft systems formed by a hydrophilic ionic iridium(III) complex (IrPa) embedded into two different concentration F127-water mixtures have been investigated. To this aim, combined spectral and time-resolved photophysical techniques and rheological methods have been employed. The position of the chromophore inside the micellar, cubic and hexagonal phases of the F127 polymeric neutral surfactant in water was effectively determined. The hydrophilic character of the iridium(III) complex chosen allowed preferential functionalization of the F127 corona in the micellar and cubic phases.

19.
Langmuir ; 30(28): 8336-41, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-24979330

RESUMO

Pure surfactant liquids and their binary mixtures, because of the amphiphilic nature of the molecules involved, can exhibit nanosegregation and peculiar transport properties. The idea that inspired this work is that the possibility of including in such media salts currently used for technological applications should lead to a synergy between the properties of the salt and those of the medium. Therefore, the dynamic features of bis(2-ethylhexyl)amine (BEEA) and bis(2-ethylhexyl)phosphoric acid (HDEHP) liquid mixtures were investigated as a function of composition and temperature by (1)H nuclear magnetic resonance (NMR) spectroscopy and rheometry. Inclusion of litium trifluoromethanesulfonate (LiT) has been investigated by infrared spectroscopy, pulsed field gradient NMR, and conductimetry methods to highlight the solubilizing and confining properties of these mixtures as well as the lithium conductivity. It was found that BEEA/HDEHP binary liquid mixtures show zero-threshold percolating self-assembly with a maximum in viscosity and a minimum in molecular diffusion at a 1:1 composition. Dissolution of LiT in such system can occur via confinement in the locally self-assembled polar domains. Despite this confinement, Li(+) conduction is scarcely dependent on the medium composition because of the possibility of a field-induced hopping decoupled by the structural and dynamical features of the medium.

20.
Hum Mol Genet ; 23(16): 4315-27, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24705357

RESUMO

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.


Assuntos
Carcinogênese/genética , Mutação/fisiologia , Fenótipo , Proteínas ras/genética , Animais , Caenorhabditis elegans , Estudos de Coortes , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Juvenil/genética , MAP Quinase Quinase Quinases/metabolismo , Síndrome de Noonan/genética , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/genética , Proteínas ras/química , Proteínas ras/metabolismo
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