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1.
Clin Genet ; 97(2): 264-275, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31573083

RESUMO

Children with neurofibromatosis type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist in children with other RASopathies or with other genetic conditions if only multiple café-au-lait macules (CALMs) are present. The syndromes that can converge in these inconclusive phenotypes have different clinical courses. In this context, an early genetic testing has been proposed to be clinically useful to manage these patients. We present the validation and implementation into diagnostics of a custom NGS panel (I2HCP, ICO-IMPPC Hereditary Cancer Panel) for testing patients with a clinical suspicion of a RASopathy (n = 48) and children presenting multiple CALMs (n = 102). We describe the mutational spectrum and the detection rates identified in these two groups of individuals. We identified pathogenic variants in 21 out of 48 patients with clinical suspicion of RASopathy, with mutations in NF1 accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the NF1 gene, but also in SPRED1, in more than 50% of children with multiple CALMs, exhibiting an NF1 mutational spectrum different from a group of clinically diagnosed NF1 patients (n = 80). An NGS panel strategy for the genetic testing of these two phenotype-defined groups outperforms previous strategies.

2.
Orphanet J Rare Dis ; 14(1): 286, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801570

RESUMO

BACKGROUND: Neurofibromatosis type 1 is an inherited condition with variable phenotypic expression and a high medical and social burden. The objectives of this patient survey were to better understand the real-world experiences of patients living with cutaneous neurofibromas (cNF), to perceive their satisfaction and feelings about cNF current management (only laser and surgery are currently available), and to highlight their expectations of new therapeutic modalities. RESULTS: One hundred seventy patients from 4 European countries took part in the study, 65% (n = 110) were women and mean age was 39 years old. 96% (n = 164) of respondents have cNF on visible parts of the body and the survey confirmed that total number of cNF and visibility increase with age. Patients reported that cNF mainly impacts everyday mood, general daily life and social life. The visibility of cNF had a higher impact than their number. 92% (n = 156) of patients have a regular and multidisciplinary medical follow-up. The dermatologist is one of the most consulted healthcare professionals. 76% (n = 130) of respondents have treated their cNF: 65% (n = 111) had surgery and 38% (n = 64) had multiple laser sessions. Frequency of operations and regrowth of cNF were the two most unsatisfactory aspects with both treatments for patients. Indeed, after removal, new cNF appear in more than 75% (n = 128) of cases. As a future treatment, patients expected a topical (30%, n = 51) or oral medication (29%, n = 50). Around 2 out of 3 patients would agree to take it at least once a day or more for life but they would like a well-tolerated treatment. According to patients, the most important effectiveness criteria of a new treatment are to block cNF growth and reduce their number. 70% (n = 119) of patients would consider a future treatment moderately effective to very effective if it could clear 30% of cNF. CONCLUSIONS: This first cNF European patient community survey confirmed that the visible stigma and unaesthetic aspect of cNF have an important impact on patients' quality of life. The survey highlighted that patients were not entirely satisfied with the actual surgery and laser treatments and revealed their clear and realistic expectations for future treatment of cNF.

3.
Acta Biomater ; 99: 247-257, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539656

RESUMO

The therapeutic effects of secreted factors (secretome) produced by bone marrow-derived human mesenchymal stem cells (MSCs) were evaluated as a function of their growth in 2D culture conditions and on 3D electrospun fiber scaffolds. Electrospun fiber scaffolds composed of polycaprolactone and gelatin were fabricated to provide a 3D microenvironment for MSCs, and their mechanical properties were optimized to be similar to corneal tissue. The secretome produced by the MSCs cultured on 3D fiber matrices versus 2D culture dishes were analyzed using a Luminex immunoassay, and the secretome of MSCs cultured on the 3D versus 2D substrates showed substantial compositional differences. Concentrations of factors such as HGF and ICAM-1 were increased over 5 times in 3D cultures compared to 2D cultures. In vitro proliferation and scratch-based wound healing assays were performed to compare the effects of the secretome on corneal fibroblast cells (CFCs) when delivered synchronously from co-cultured MSCs through a trans-well co-culture system versus asynchronously after harvesting the factors separately and adding them to the media. Cell viability of CFCs was sustained for 6 days when co-cultured with MSCs seeded on the fibers but decreased with time under other conditions. Scratch assays showed 95% closure at 48 h when CFCs were co-cultured with MSCs seeded on fibers, while the control group only exhibited 50% closure at 48 h. Electrospun fibers seeded with MSCs were then applied to a rabbit corneal organ culture system, and MSCs seeded on fibers promoted faster epithelialization and less scarring. Corneas were fixed and stained for alpha smooth muscle actin (α-SMA), and then analyzed by confocal microscopy. Immunostaining showed that expression of α-SMA was lower in corneas treated with MSCs seeded on fibers, suggesting suppression of myofibroblastic transformation. MSCs cultured on electrospun fibers facilitate wound healing in CFCs and on explanted corneas through differential secretome profiles compared to MSCs cultured on 2D substrates. Future work is merited to further understand the nature and basis of these differences and their effects in animal models. STATEMENT OF SIGNIFICANCE: Previous studies have shown that the secretome of bone marrow-derived mesenchymal stem cells (MSC) is promotes corneal wound healing by facilitating improved wound closure rates and reduction of scarring and neovascularization. The present research is significant because it provides evidence for the modulation of the secretome as a function of the MSC culture environment. This leads to differential expression of therapeutic factors secreted, which can impact corneal epithelial and stromal healing after severe injury. In addition, this article shows that co-continuous delivery of the MSC secretome improves cell migration and proliferation over aliquoted delivery, and that MSCs grown on three-dimensional electrospun fiber constructs may provide a favorable microenvironment for cultured MSCs and as a carrier to deliver their secreted factors to the ocular surface.

4.
Front Immunol ; 10: 1013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134083

RESUMO

Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30858900

RESUMO

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

8.
Stem Cell Reports ; 12(2): 411-426, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30713041

RESUMO

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disease caused by mutations in the NF1 tumor suppressor gene. Plexiform neurofibromas (PNFs) are benign Schwann cell (SC) tumors of the peripheral nerve sheath that develop through NF1 inactivation and can progress toward a malignant soft tissue sarcoma. There is a lack of non-perishable model systems to investigate PNF development. We reprogrammed PNF-derived NF1(-/-) cells, descendants from the tumor originating cell. These NF1(-/-)-induced pluripotent stem cells (iPSCs) captured the genomic status of PNFs and were able to differentiate toward neural crest stem cells and further to SCs. iPSC-derived NF1(-/-) SCs exhibited a continuous high proliferation rate, poor myelination ability, and a tendency to form 3D spheres that expressed the same markers as their PNF-derived primary SC counterparts. They represent a valuable model to study and treat PNFs. PNF-derived iPSC lines were banked for making them available.

9.
Stem Cells Transl Med ; 8(5): 478-489, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30644653

RESUMO

Severe corneal injuries often result in permanent vision loss and remain a clinical challenge. Human bone marrow-derived mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their antiscarring, anti-inflammatory, and antiangiogeneic properties. We aimed to deliver lyophilized MSC secretome (MSC-S) within a viscoelastic gel composed of hyaluronic acid (HA) and chondroitin sulfate (CS) as a way to enhance corneal re-epithelialization and reduce complications after mechanical and chemical injuries of the cornea. We hypothesized that delivering MSC-S within HA/CS would have improved wound healing effects compared the with either MSC-S or HA/CS alone. The results showed that a once-daily application of MSC-S in HA/CS enhances epithelial cell proliferation and wound healing after injury to the cornea. It also reduced scar formation, neovascularization, and hemorrhage after alkaline corneal burns. We found that combining MSC-S and HA/CS increased the expression of CD44 receptors colocalized with HA, suggesting that the observed therapeutic effects between the MSC-S and HA/CS are in part mediated by CD44 receptor upregulation and activation by HA. The results from this study demonstrate a reproducible and efficient approach for delivering the MSC-S to the ocular surface for treatment of severe corneal injuries. Stem Cells Translational Medicine 2019;8:478-489.

10.
Genet Med ; 21(1): 189-194, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29904161

RESUMO

PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.


Assuntos
Azoospermia/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Síndrome de Células de Sertoli/genética , Adulto , Idade de Início , Azoospermia/sangue , Azoospermia/complicações , Azoospermia/patologia , Quebra Cromossômica , Exoma/genética , Anemia de Fanconi/sangue , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/patologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Síndrome de Células de Sertoli/sangue , Síndrome de Células de Sertoli/complicações , Síndrome de Células de Sertoli/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
11.
COPD ; 15(4): 317-325, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30375898

RESUMO

Surveys estimating chronic obstructive pulmonary disease (COPD) prevalence are unevenly distributed in the Americas, which make it difficult to estimate accurately its geographical distribution. The geographic information system inverse distance weighted (IDW) interpolation technique has proved to be an effective tool in spatial distribution estimation of epidemiological variables, even when real data are few or widely spread. We aimed to represent cartographically the COPD prevalence in the Americas by means of a blue to red scale representation of the prevalence data, where different values are represented as different colours, and a population density filtered IDW interpolation mapping, where areas with a population density <0.1 inhabitants/km2 are hidden. We systematically searched for prevalence rates from population surveys of individuals 40 years and older, and a COPD diagnosis confirmed by spirometry. Interpolation maps were obtained for the whole Americas, even from extensive areas lacking real data. Maps showed high prevalence values in the Southeast and Southwest regions of Canada bordering the United States; in several states of the Great Lakes region, and in the lower Missouri, Ohio and Mississippi basins of the United States; in the coastal regions of south-eastern and southern Brazil; Uruguay, and the Argentine Pampas. In general, most of the remaining American regions showed intermediate values of COPD prevalence. IDW interpolation seems to be a suitable tool to visually display estimates of COPD prevalence, and it may be a valuable help to draw attention about the worrying prevalence of this preventable and treatable disease.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , América Central/epidemiologia , Mapeamento Geográfico , Humanos , América do Norte/epidemiologia , Prevalência , América do Sul/epidemiologia , Estados Unidos/epidemiologia , Índias Ocidentais/epidemiologia
12.
Med. clín (Ed. impr.) ; 151(2): 80.e1-80.e10, jul. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-173778

RESUMO

El diagnóstico genético de los síndromes de cáncer hereditario ofrece la oportunidad de establecer unas medidas de predicción/prevención eficaces en el paciente y sus familiares que se traducen en una disminución de la morbimortalidad por cáncer en las familias de alto riesgo genético. La secuenciación masiva (NGS) ofrece una considerable mejora de la eficiencia del diagnóstico genético, permitiendo un aumento del rendimiento diagnóstico con una reducción sustancial del tiempo de respuesta y costes económicos. En consecuencia, la implementación de esta nueva tecnología es una gran oportunidad de mejora en el manejo clínico de las familias afectas. El objetivo de la presente guía es establecer un marco de recomendaciones útiles para una implementación planificada y controlada de la NGS en el contexto de la predisposición hereditaria a cáncer, que permita potenciar las fortalezas y oportunidades que ofrece dicha tecnología y minimizar las debilidades y amenazas que puedan derivarse de su uso. Está inspirada en las recomendaciones de sociedades internacionales, habiendo sido adaptada a nuestro entorno, y teniendo en cuenta aspectos coyunturales a nivel organizativo y biojurídico. Se aportan 41 declaraciones agrupadas en 6 apartados: utilidad clínica y diagnóstica, consentimiento informado y asesoramiento genético pretest y postest, validación de los procedimientos analíticos, informe de resultados, gestión de la información y distinción entre ámbito de investigación y ámbito asistencial. Esta guía ha sido elaborada por la Asociación Española de Genética Humana (AEGH), la Sociedad Española de Medicina de Laboratorio (SEQC-ML) y la Sociedad Española de Oncología Médica (SEOM)


Genetic diagnosis of hereditary cancer syndromes offers the opportunity to establish more effective predictive and preventive measures for the patient and their families. The ultimate objective is to decrease cancer morbidity and mortality in high genetic risk families. Next Generation Sequencing (NGS) offers an important improvement in the efficiency of genetic diagnosis, allowing an increase in diagnostic yield with a substantial reduction in response times and economic costs. Consequently, the implementation of this new technology is a great opportunity for improvement in the clinical management of affected families. The aim of these guidelines is to establish a framework of useful recommendations for planned and controlled implementation of NGS in the context of hereditary cancer. These will help to consolidate the strengths and opportunities offered by this technology, and minimise the weaknesses and threats which may derive from its use. The recommendations of international societies have been adapted to our environment, taking the Spanish context into account at organisational and juridical levels. Forty-one statements are grouped under six headings: clinical and diagnostic utility, informed consent and genetic counselling pre-test and post-test, validation of analytical procedures, results report, management of information and distinction between research and clinical context. This guide has been developed by the Spanish Association of Human Genetics (AEGH), the Spanish Society of Laboratory Medicine (SEQC-ML) and the Spanish Society of Medical Oncology (SEOM)


Assuntos
Neoplasias/genética , Análise de Sequência/métodos , Neoplasias/diagnóstico , Testes Genéticos/métodos , Guias de Prática Clínica como Assunto
13.
Psicooncología (Pozuelo de Alarcón) ; 15(1): 23-26, ene.-jun. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-171935

RESUMO

Objetivo: Analizar la validez y la fiabilidad de la adaptación de la escala Perceived Personal Control (PPC) en el contexto español para pacientes portadoras de mutación en los genes BRCA1/2 responsables del cáncer de mama y ovario hereditario (CMOH). Método: Adaptación transcultural y validación de la escala Perceived Personal Control (PPC) desarrollada por Shiloh y colaboraradores mediante traducción, retrotraducción y validación a través de un análisis factorial exploratorio con rotación Oblimin en una muestra de 176 mujeres portadoras de genes BRCA 1/2 para CMOH. Resultados: La versión española de la PPC reduce a seis los nueve ítems de la escala original, dado que esta estructura es la que ofrece una solución factorial más satisfactoria. El análisis factorial mostró un solo factor que explica el 51,07% de la varianza, en el que todos los ítems tenían cargas factoriales por encima de 0,4. El coeficiente α de Cronbach fue de 0,84 para el conjunto de la escala, la cual permite obtener valores que oscilan entre 0 (bajo grado de percepción de control) y 2 (alto grado de percepción de control). Conclusiones: La adaptación española de la Escala de Percepción de Control (PPC6) posee propiedades psicométricas satisfactorias en la versión de 6 ítems con un solo factor, por lo que su utilización en contexto español Consejo Genético para cáncer hereditario parece adecuada (AU)


Purpose: The aim of this study was to analyze the reliability and validity of the spanish adaptation of the Perceived Personal Control (PPC) scale in women who were positive for BRCA1/2 genes, which are related with hereditary ovarian and breast cancer (HOBC). Method: PPC original items developed by Shiloh and co-workers were translated and back-translated in order to develop an spanish version which was analyzed by an exploratory factor analysis with Oblimin rotation. Answers to the spanish version were provided by a sample of 176 women who were positive for BRCA1/2 for HOBC. Results: Spanish version contains only six items of the nine original items, since this structure provided the optimal solution to the exploratory factor analysis. This version is a one-factor scale (51.07% of variance explained) and all items had factor loading values >0.4. The scale has good reliability (Cronbach's Alpha =0.84) and gives a range of values between 0 (low perceived control) and 2 (high perceived control). Conclusions: Spanish adaptation (PPC6) of the original 9-items version has enough reliability and psychometric properties, and it seems to be useful to be applied in Genetic Counseling at spanish cultural settings (AU)


Assuntos
Humanos , Feminino , Neoplasias da Mama/psicologia , Neoplasias Ovarianas/psicologia , Aconselhamento Genético/psicologia , Psicometria/instrumentação , Autocontrole/psicologia , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Reprodutibilidade dos Testes , Doenças Genéticas Inatas/psicologia , Genes Neoplásicos
14.
Psicooncología (Pozuelo de Alarcón) ; 15(1): 37-48, ene.-jun. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-171936

RESUMO

Objetivo: En este estudio se realiza una revisión de la literatura sobre el impacto psicológico y emocional que conlleva la Neurofibromatosis tipo 1 (NF1) en los pacientes adultos. Método: Se realizó una revisión bibliográfica en PubMed (Medline) entre enero del 2007 y abril del 2017 de artículos publicados en el idioma inglés. Se encontraron un total de 75 artículos de los cuales se seleccionaron 23 con base en los criterios de inclusión y exclusión definidos para esta revisión. Resultados: Prácticamente todos los estudios vienen a concluir que los cambios y/o desfiguración en la imagen corporal o apariencia física, la visibilidad, el dolor y la gravedad de la enfermedad son el eje central sobre el cual gira el deterioro en la calidad de vida de las personas con NF1, debido a las dificultades que tienen los enfermos para adaptarse a los cambios físicos y para hacer frente a los problemas de ansiedad y el estrés psicológico que genera la carga de la enfermedad. Conclusiones: Conocer el impacto psicológico y emocional que tiene la NF1 permitirá desarrollar e implementar intervenciones psicoterapéuticas y psicosociales específicas para este grupo de población con el objetivo de facilitarles que puedan afrontar las consecuencias y los retos que trae asociada la enfermedad (AU)


Objective: This study was done to conduct a review of the literature on the psychological and emotional impact of NF1 in adult patients. Method: A literature review in PubMed (Medline) of articles published in the English languaje was conducted between January 2007 and April 2017. A total of 75 articles were found, of which 23 were selected based on the inclusion and exclusion criteria defined for this review. Results: Almost all studies conclude that changes and/or disfigurement in the corporal image or physical appearance, the visibility, the pain and the severity of the disease are the central axes on which the deterioration in the quality of life of the people with NF1; due to the difficulties that patients have to adapt to the physical changes and to cope the problems of anxiety and psychological stress generated by the burden of the disease. Conclusions: Knowing the psychological and emotional impact of NF1 will allow the development and implementation of specific psychotherapeutic and psychosocial interventions for this population group with the aim of facilitating them to face the consequences and challenges associated with the disease (AU)


Assuntos
Humanos , Neurofibromatose 1/psicologia , Estresse Psicológico , Transtornos de Ansiedade/psicologia , Depressão/psicologia , Qualidade de Vida , Perfil de Impacto da Doença , Adaptação Psicológica , Autoimagem , Estigma Social , Relações Interpessoais
15.
Hum Mutat ; 39(8): 1112-1125, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29774626

RESUMO

Plexiform neurofibromas (PNFs) are benign peripheral nerve sheath tumors involving large nerves present in 30%-50% Neurofibromatosis type 1 (NF1) patients. Atypical neurofibromas (ANF) are distinct nodular lesions with atypical features on histology that arise from PNFs. The risk and timeline of malignant transformation in ANF is difficult to assess. A recent NIH workshop has stratified ANFs and separated a subgroup with multiple atypical features and higher risk of malignant transformation termed atypical neurofibromatous neoplasms with uncertain biological potential (ANNUBP). We performed an analysis of intratumor heterogeneity on eight PNFs to link histological and genomic findings. Tumors were homogeneous although histological and molecular heterogeneity was identified. All tumors were 2n, almost mutation-free and had a clonal NF1(-/-) origin. Two ANFs from the same patient showed atypical features on histology and deletions of CDKN2A/B. One of the ANFs exhibited different areas in which the degree of histological atypia correlated with the heterozygous or homozygous loss of the CDKN2A/B loci. CDKN2A/B deletions in different areas originated independently. Results may indicate that loss of a single CDKN2A/B copy in NF1(-/-) cells is sufficient to start ANF development and that total inactivation of both copies of CDKN2A/B is necessary to form an ANNUBP.


Assuntos
Neurofibroma Plexiforme/genética , Neurofibroma/genética , Neurofibromatose 1/genética , Adulto , Idoso , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genômica/métodos , Humanos , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética
16.
Int J Chron Obstruct Pulmon Dis ; 13: 1001-1007, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29615836

RESUMO

Background: The clinical course of alpha-1 antitrypsin deficiency (AATD) is very heterogeneous. It is estimated that 60% of individuals with severe AATD (Pi*ZZ) develop emphysema. The main objective of this study was to describe the outcomes of long-term lung function in individuals with AATD-associated emphysema after at least 8 years of follow-up. Materials and methods: We performed a retrospective analysis of longitudinal follow-up data of AATD PiZZ patients from the Spanish registry (AATD Spanish Registry [REDAAT]). The main follow-up outcome was the annual rate of decline in forced expiratory volume in 1 second (FEV1) calculated using the FEV1 values at baseline and in the last post-bronchodilator spirometry available. Results: One hundred and twenty-two AATD PiZZ patients were analyzed. The median follow-up was 11 years (interquartile range =9-14). The mean FEV1 decline was 28 mL/year (SD=54), with a median of 33 mL/year. Tobacco consumption (ß=19.8, p<0.001), previous pneumonia (ß=27.8, p=0.026) and higher baseline FEV1% (ß=0.798, p=0.016) were independently related to a faster FEV1 decline. Conclusion: In this large cohort with a long follow-up, we observed a very variable decline of FEV1. However, the mean FEV1 decline was similar to that observed in large cohorts of smoking-related COPD. Tobacco consumption, previous pneumonia and better lung function at baseline were related to a faster decline in FEV1. These results highlight the importance of early diagnosis and effective treatment.


Assuntos
Pulmão/fisiopatologia , Enfisema Pulmonar/etiologia , Deficiência de alfa 1-Antitripsina/complicações , Adulto , Idoso , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Pneumonia/complicações , Prognóstico , Enfisema Pulmonar/diagnóstico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Espanha , Espirometria , Fatores de Tempo , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/fisiopatologia
19.
Pest Manag Sci ; 74(8): 1925-1937, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29479817

RESUMO

BACKGROUND: In perennial crops, the most common method of weed control is to spray herbicides, and glyphosate has long been the first choice of farmers. Three species of the genus Conyza are among the most problematic weeds for farmers, exhibiting resistance to glyphosate. The objectives of this study were to evaluate resistance levels and mechanisms, and to test chemical control alternatives in putative resistant (R) populations of Conyza bonariensis, Conyza canadensis and Conyza sumatrensis. RESULTS: Plants from the three R populations of Conyza spp. survived high doses of glyphosate compared with plants from susceptible (S) populations. The rate of movement of 14 C glyphosate out of treated leaves in plants from S populations was higher than in plants from R populations. Only plants from the R population of C. sumatrensis contained the known target site 5-enolpyruvylshikimate-3-phosphate synthase mutation Pro106-Thr. Field responses to the different alternative herbicide treatments tested indicated injury and high effectiveness in most cases. CONCLUSIONS: The results indicate that non-target site resistant (NTSR) mechanisms explain resistance in C. bonariensis and C. canadensis, whereas both NTSR and target site resistant (TSR) mechanisms contribute to resistance in C. sumatrensis. The results obtained in the field trials suggest that the resistance problem can be solved through integrated weed management. © 2018 Society of Chemical Industry.


Assuntos
3-Fosfoshikimato 1-Carboxiviniltransferase/genética , Conyza/efeitos dos fármacos , Glicina/análogos & derivados , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Proteínas de Plantas/genética , 3-Fosfoshikimato 1-Carboxiviniltransferase/química , 3-Fosfoshikimato 1-Carboxiviniltransferase/metabolismo , Sequência de Aminoácidos , Conyza/genética , Glicina/farmacologia , Filogenia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/genética , Espanha , Controle de Plantas Daninhas
20.
Semin Arthritis Rheum ; 48(1): 22-27, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422324

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA. METHODS: National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA. RESULTS: 63 patients (36 women) with RA-associated ILD undergoing ABA therapy were studied. The mean ± standard deviation age at the time of the study was 63.2 ± 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 ± 3.2 months, two-thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events. CONCLUSION: ABA appears to be an effective in RA-associated ILD.


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Idoso , Artrite Reumatoide/complicações , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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