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1.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
2.
Animals (Basel) ; 10(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271995

RESUMO

A 90-d feeding trial was conducted in which five groups of gilthead seabream (11.96 g initial body weight) were fed with a microalgae-free diet (control group, C) or four diets containing the microalgae Nannochloropsis gaditana at two inclusion levels (2.5% or 5%), either raw (R2.5 and R5 batches) or cellulose-hydrolyzed (H2.5 and H5 batches), to study their effect on the body and muscle growth. At 40 days, the highest values of body length and weight were reached in R5 group, but at 64 and 90 days, these were reached in R2.5. However, feed conversion rate, specific growth, daily intake, and survival (100%) were similar in all the groups. The acquisition of a discoid body shape was accelerated depending on the inclusion level of N. gaditana in the diets. Moreover, H5 diet affected the fish geometric morphology compared to R5 diet. The white muscle transverse area was similar in all groups at 40 days, with the exception of H2.5 group, which showed the lowest area. At day 90, C and R2.5 displayed the highest muscle growth, attributable to increased hyperplasia in C, and higher hypertrophy in R2.5. However, the highest proportion of small and medium fibers was observed in R5 and H5.

3.
Plant J ; 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33219553

RESUMO

The absorption of water and solutes by plant leaves has been recognised since more than two centuries. Given the polar nature of water and solutes, the mechanisms of foliar uptake have been proposed to be similar for water and electrolytes, including nutrient solutions. Research efforts since the XIX Century focussed on characterising the properties of cuticles and applying foliar sprays to crop plants as tool for improving crop nutrition. This was accompanied by the development of hundreds of studies aimed at characterising the chemical and structural nature of plant cuticles from different species and the mechanisms of cuticular and, to a lower extent, stomatal penetration of water and solutes. The processes involved are complex and will be affected by multiple environmental, physico-chemical and physiological factors which are only partially clear to date. During the last decades, there is growing evidence that water transport across leaf surfaces of native species may contribute to water balances (absorption and loss) at an ecosystem level. Given the potential importance of foliar water absorption for many plant species and ecosystems as shown in recent studies, the aim of this review is to first integrate current knowledge on plant surface composition, structure, wettability and physico-chemical interactions with surface-deposited matter. The different mechanisms of foliar absorption of water and electrolytes and experimental procedures for tracing the uptake process are discussed before posing several outstanding questions which should be tackled in future studies.

4.
J Curr Ophthalmol ; 32(3): 281-284, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32775804

RESUMO

Purpose: To evaluate the changes on the position of the lower lid after phacoemulsification surgery using objective methods. Methods: This prospective study evaluated the lower lid position of cataract carriers who underwent to phacoemulsification surgery from January to May 2017. Data were collected on demographics, type of anesthesia, duration of the surgical procedure, and duration of the speculum remained in place. Standardized digital photographs of the patient's face in primary gaze position were obtained preoperatively and 1, 30, 90, and 180 days, postoperatively. The data were analyzed on the distraction test, distance of the lower lacrimal punctum from the inner canthus, and margin reflex distance 2 (MRD2). Comparative and correlation statistical analyses involving preoperative and postoperative measurements were performed. Results: One hundred twelve cataract patients comprised the study sample. There were 68 (60.7%) females with a median age of 74 (interquartile range, 70-81) years old. The mean distraction test value before surgery was 7 ± 2 mm and 6.8 ± 1.8 mm 180 days postoperatively (P = 0.02). The mean lacrimal lower punctum distance changed from 5 ± 1.1 mm preoperatively to 5.4 ± 1 mm at 180 days postoperatively (P = 0.06). The mean MRD2 preoperatively was 5 ± 1 mm and increased to 5.4 ± 0.9 mm 180 days after surgery (P = 0.02). The duration of surgery and the duration that speculum remained in place were not correlated to MRD2 (P = 0.7; P = 0.98). Conclusions: There is a mild lower lid laxity after phacoemulsification reflected by slight increased lacrimal lower punctum distance to the inner canthus and MRD2. Lacrimal lower punctum distance and MRD2 vary along the study and remained altered at 180 days after surgery, while distraction test tends to recover to similar preoperative levels. Although lid laxity is common in elderly cataract carriers, even a short procedure as phacoemulsification can mildly increase flaccidity.

6.
Ther Adv Neurol Disord ; 13: 1756286420935697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32843900

RESUMO

Background: Although the pathogenesis of myasthenia gravis (MG) is well known, prognostic markers are not yet available. We assessed the utility of anti-acetylcholine receptor (AChR) antibody (AChR-ab) titer and concentration of C3, C4, and C5a as potential severity biomarkers in MG. Methods: Levels of C3, C4, C5a, and AChR-ab were measured in 60 AChR-ab-positive patients with MG. Their relationship with clinical severity was analyzed using the activities of daily living (ADL) and MG composite (MGC) scales. Results: AChR-ab titer correlated with severity of MG according to ADL (p = 0.002) and MGC scales (p = 0.001). When patients were classified according to disease duration, a statistically significant correlation between AChR-ab titer and clinical severity was only found in the subgroup of patients with fewer than 5 years from symptoms onset. C5a levels showed a positive correlation with MG severity according to the ADL scale (p = 0.041; τb = 0.18), although C5a levels were not different from the control group. Discussion: AChR-ab titers and C5a levels could potentially be considered markers of severity in patients with MG.

7.
Glob Chang Biol ; 26(8): 4572-4582, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32520438

RESUMO

Microbial processing of aggregate-unprotected organic matter inputs is key for soil fertility, long-term ecosystem carbon and nutrient sequestration and sustainable agriculture. We investigated the effects of adding multiple nutrients (nitrogen, phosphorus and potassium plus nine essential macro- and micro-nutrients) on decomposition and biochemical transformation of standard plant materials buried in 21 grasslands from four continents. Addition of multiple nutrients weakly but consistently increased decomposition and biochemical transformation of plant remains during the peak-season, concurrent with changes in microbial exoenzymatic activity. Higher mean annual precipitation and lower mean annual temperature were the main climatic drivers of higher decomposition rates, while biochemical transformation of plant remains was negatively related to temperature of the wettest quarter. Nutrients enhanced decomposition most at cool, high rainfall sites, indicating that in a warmer and drier future fertilized grassland soils will have an even more limited potential for microbial processing of plant remains.


Assuntos
Ecossistema , Pradaria , Carbono , Nitrogênio/análise , Nutrientes , Solo
8.
Plant Physiol Biochem ; 152: 232-242, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32449682

RESUMO

Growing conditions at different tree canopy positions may significantly vary and lead to foliar changes even within the same tree. An assessment of foliar anatomy, including also epidermal features, can help us understand how plants respond to environmental factors. Working with two model tree species (i.e., Quercus petraea and Fagus sylvatica) grown at their southernmost European distribution area in Central Spain, the influence of irradiation and canopy height was examined by sampling lower canopy leaves and comparing them with fully irradiated, top canopy leaves and shaded top canopy leaves grown for months within a bag made of shade netting fabric before they sprouted. At the end of the summer, samples were collected, and several parameters were analysed. The results indicate that SLA (specific leaf area) differences are significant both between species and groups. Leaf and cuticle thickness differed significantly between groups while stomatal densities only between species. Regarding mineral concentrations, differences between species were significant for K, Mn, N and N: P ratios. It is concluded that leaf responses to environmental conditions may be variable both within the same tree and between species.


Assuntos
Fagus , Folhas de Planta/anatomia & histologia , Folhas de Planta/fisiologia , Folhas de Planta/efeitos da radiação , Quercus , Escuridão , Fotossíntese , Estômatos de Plantas , Espanha , Luz Solar , Árvores
9.
Front Plant Sci ; 11: 493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411165

RESUMO

Humic substances (HS, fulvic and humic acids) are widely used as fertilizers or plant growth stimulants, although their mechanism of action still remains partially unknown. Humic substances may be applied either directly to the soil or as foliar sprays. Despite both kind of application are commonly used in agricultural practices, most of the studies regarding the elicited response in plants induced by HS are based on the root-application of these substances. The present work aimed at discriminating between the mechanisms of action of foliar application versus root application of a sedimentary humic acid (SHA) on plant development. For this purpose, six markers related to plant phenotype, plant morphology, hormonal balance and root-plasma membrane H+-ATPase were selected. Both application strategies improved the shoot and root growth. Foliar applied- and root applied-SHA shared the capacity to increase the concentration of indole-3-acetic acid in roots and cytokinins in shoots. However, foliar application did not lead to short-term increases in either abscisic acid root-concentration or root-plasma membrane H+-ATPase activity which are, however, two crucial effects triggered by SHA root-application. Both application modes increased the root concentrations of jasmonic acid and jasmonoyl-isoleucine. These hormonal changes caused by foliar application could be a stress-related symptom and connected to the loss of leaves trichomes and the diminution of chloroplasts size seen by scanning electron microscopy. These results support the hypothesis that the beneficial effects of SHA applied to roots or leaves may result from plant adaptation to a mild transient stress caused by SHA application.

10.
J Sci Food Agric ; 100(12): 4643-4650, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32399984

RESUMO

BACKGROUND: The mechanisms of calcium (Ca) absorption and transport in plants are still poorly understood. This study focused on assessing the absorption and distribution of Ca in different plant organs after root (soil), foliar, or fruit application to 6-year-old 'Clemenules' mandarin trees, grown in pots, using 45 Ca as a tracer. RESULTS: The rate of 45 Ca absorption and transportation in plant tissues varied according to the treatment method. The fruit and shoot Ca supply led to a rate of 97% to 98% 45 Ca retention in such organs. In Ca-treated fruits, 22% of the applied 45 Ca moved to the pulp and 78% remained in the flavedo and albedo. The fruit peel was examined by scanning electron microscopy and transmission electron microscopy (SEM and TEM) and variations were observed during fruit development. Following 45 Ca soil treatment, approximately 56% of 45 Ca activity was measured in the soil, with 19.5% determined in the roots, 14.6% in the trunks (90% in bark and sapwood and only 10% in heartwood), 9.6% in shoots, and 0.3% in fruits. CONCLUSION: Calcium mobility in 'Clemenules' mandarin trees is limited and depends on the mode of Ca fertilizer application. The distribution of Ca to and within the fruits may be limited during development because of structural and functional constraints. © 2020 Society of Chemical Industry.

12.
Front Hum Neurosci ; 14: 73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265672

RESUMO

The acquisition and evolution of speech production, discourse and communication can be negatively impacted by brain malformations. We describe, for the first time, a case of developmental dynamic dysphasia (DDD) in a right-handed adolescent boy (subject D) with cortical malformations involving language-eloquent regions (inferior frontal gyrus) in both the left and the right hemispheres. Language evaluation revealed a markedly reduced verbal output affecting phonemic and semantic fluency, phrase and sentence generation and verbal communication in everyday life. Auditory comprehension, repetition, naming, reading and spelling were relatively preserved, but executive function was impaired. Multimodal neuroimaging showed a malformed cerebral cortex with atypical configuration and placement of white matter tracts bilaterally and abnormal callosal fibers. Dichotic listening showed right hemisphere dominance for language, and functional magnetic resonance imaging (fMRI) additionally revealed dissociated hemispheric language representation with right frontal activation for phonology and bilateral dominance for semantic processing. Moreover, subject D also had congenital mirror movements (CMM), defined as involuntary movements of one side of the body that mirror intentional movements of the other side. Transcranial magnetic stimulation and fMRI during voluntary unimanual (left and right) hand movements showed bilateral motor cortex recruitment and tractography revealed a lack of decussation of bilateral corticospinal tracts. Genetic testing aimed to detect mutations that disrupt the development of commissural tracts correlating with CMM (e.g., Germline DCC mutations) was negative. Overall, our findings suggest that DDD in subject D resulted from the underdevelopment of the left inferior frontal gyrus with limited capacity for plastic reorganization by its homologous counterpart in the right hemisphere. Corpus callosum anomalies probably contributed to hinder interhemispheric connectivity necessary to compensate language and communication deficits after left frontal involvement.

13.
Acta Neurol Belg ; 120(3): 565-572, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30182259

RESUMO

Autoimmune encephalitis (AE) is a common cause of noninfectious acute encephalitis. We aimed to provide the first review of immune therapy regimens used for patients with AE in Latin America, as well as the safety and efficacy associated with them, by reviewing the medical records of Argentine patients with AE treated between 2013 and 2018. Data included clinical symptoms, laboratory tests, electroencephalography, magnetic resonance imaging, cerebral spinal fluid, and neoplasm screenings. We examined ten AE patients who received first-line immunotherapy at a median of 2.5 months following symptom onset. Among these patients, five required second-line treatment: three received therapy at a median of 4 months (2-112) after symptom onset and were treated with rituximab, while two received therapy at a median of 4.5 (4-5) months after onset and received methylprednisolone for 6 months and initiated chronic treatment with azathioprine. By the last follow-up, their respective outcomes improved significantly. On the modified Rankin Scale, the median score decreased from 5 to 1 (p ≤ 0.05). Only two of the ten patients in our series experienced relapses; both had been treated with a combination of methylprednisolone and IVIG. The regimen after recurrence included rituximab and corticoids plus azathioprine. Neither patient had experienced another relapse by their last follow-up. Our findings demonstrate the importance of early and aggressive immunosuppressive therapy to achieve a good clinical outcome and a fast recovery without relapses.

14.
Ethn Health ; 25(5): 679-685, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29463112

RESUMO

Background: The Mayas of the State of Yucatan in Mexico are the only aboriginal group with obesity and diabetes data before 1997. Objective: To analyze socioeconomic trends associated with the increase in obesity and diabetes seen in rural Yucatan from 1962 to 2000. Methods: Body weight, height and venous Fasting Blood Glucose (FBG) were measured in 263 rural Maya adults participating in a 2000 nutrition survey. Results: Diabetes (FBG > 125 mg/dL) and obesity (BMI ≥ 30 kg/m2) were 10.6% and 35.7%, respectively. These results contrast with those of a 1962 survey where diabetic prevalence was 2.3% and 0% in women and men respectively, with widespread adult pellagra and malnutrition. An important socioeconomic transition that took place in Yucatan during this lapse appeared to be associated to the obesity and diabetes increase. Conclusions: Rural Yucatan evolved from malnutrition conditions to high prevalence of obesity and diabetes in less than 40 years. This change was associated with the transition from an agroindustry-based economy, characterized by high-energy expenditure and low protein intake, to lower energy requirements of a Government-subsidized economy with larger food supply.

15.
Mol Neurobiol ; 57(1): 105-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31494826

RESUMO

Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2-/- mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2-/-, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2-/-, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.


Assuntos
Antioxidantes/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Panax , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Fumarato de Dimetilo/farmacologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neuroproteção/efeitos dos fármacos
16.
Front Plant Sci ; 10: 1542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827482

RESUMO

Nutrient resorption is crucial for mineral element conservation and efficiency of forest species, but knowledge on its significance and the mechanisms involved is still limited for most species and habitats. Focusing on the harsh conditions for plant growth and survival of southern Patagonia, a field study for comparing the rate of foliar resorption of macro-, micro-nutrients, and trace elements in coexisting Nothofagus pumilio and Nothofagus antarctica forests was performed. Forests located in three contrasting productivity sites (with different soil and climatic conditions) were selected, and mature, functional versus senescent leaves of both species were collected at two different dates of the growing season. Macro- (N, P, Ca, K, S, and Mg), micronutrients (B, Cu, Fe, Mn, Zn, and Ni), and trace elements (Al, Li, Pb, Rb, Sr, Ti, and Tl) were determined in foliar tissues. The mineral element concentrations of mature and senescent leaves were used for calculating the nutrient resorption efficiency (NuR). In general, and making an average of all sites and species, macro-nutrient resorption showed a decreasing trend for N > S = K > P > Mg, being Ca the only macro-nutrient with negative values (i.e., no resorption). Resorption of the majority of the elements did not vary between species in any of the evaluated sites. Variation across sites in nutrient resorption efficiency for most macronutrients, some micronutrients, and trace elements was observed for N. antarctica, whereas N. pumilio had a similar NuR for all experimental sites. On the other hand, regardless of the site or the species, some elements were not resorbed (e.g., B, Cu, Fe, Mn, Al, and Ti). It is concluded that both Nothofagus species performed similarly concerning their nutrient conservation strategy, when coexisting in the same mixed forest. However, no evidence was gained for an increased rate of foliar NuR in association with the sites subjected to more limiting soil and climatic conditions for plant growth.

17.
Semin Ophthalmol ; 34(6): 442-445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314625

RESUMO

Purpose: To objectively measure the upper eyelid position following phacoemulsification cataract surgery and to identify the determinants of postoperative transient ptosis. Methods: This is a single arm prospective study of patients who underwent cataract surgery from January to May 2017 at a tertiary Eye Hospital in Spain. Data comprised of: the type of anesthesia, the duration that the speculum remained in place and the total surgical time (duration of the procedure). The total surgical time was defined as, the time from the beginning of the paracentesis to the closure of the wounds (incision time). Digital photographs were obtained of: the face with the eye in primary gaze, looking inferiorly and superiorly, preoperatively, and 1, 30, 90 and 180 days postoperatively. Measurements for eyelid crease, levator function, and marginal reflex distance 1 (MRD1) were performed using ImageJ. Statistical analysis was performed of the difference between the preoperative and postoperative measurements. Results: The study consisted of 112 patients. The median lid crease was 9.0 mm [IQR (interquartile range) 7.5; 10.0] both preoperatively and at 180 days postoperatively (IQR 8.0; 10.8). No statistical difference was determined in the lid crease measurements between these two times (P = .17). The median levator function differed significantly preoperatively, at day 1 and 30, 60 and 180 days postoperatively (P < .01). MRD1 decreased significantly from a median of 3.01 mm preoperatively to 2.7 mm at 30 days postoperatively (P = .05) but was similar at preoperative and after 180 days (P = .7). The correlation of MRD1 to the duration of the speculum in place (P = .2) and the incision time (P = .57) was not significant. Conclusions: Ptosis, following phacoemulsification cataract surgery, is mild and transient, occurring only in the early postoperative period.


Assuntos
Blefaroplastia/métodos , Blefaroptose/etiologia , Piscadela/fisiologia , Pálpebras/fisiopatologia , Facoemulsificação/efeitos adversos , Complicações Pós-Operatórias/cirurgia , Idoso , Idoso de 80 Anos ou mais , Blefaroptose/fisiopatologia , Blefaroptose/cirurgia , Pálpebras/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Prospectivos , Reoperação , Fatores de Tempo
18.
Hum Mutat ; 40(5): 566-577, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817846

RESUMO

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Predisposição Genética para Doença , RecQ Helicases/genética , RecQ Helicases/metabolismo , Processamento Alternativo , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Perda de Heterozigosidade , Família Multigênica , Linhagem , Sequenciamento Completo do Exoma
19.
Mol Oncol ; 13(5): 1110-1120, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30747491

RESUMO

Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil-DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA2/genética , Predisposição Genética para Doença , Mutação , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Uracila-DNA Glicosidase/genética , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
20.
Free Radic Biol Med ; 131: 98-114, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30458277

RESUMO

The transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation that are tightly linked to the development and progression of cerebral ischemia pathology, plays a vital role in inducing the endogenous neuroprotective process. Here, hypoxic-ischemia (HI) was performed in adult Nrf2 knockout and wildtype mice that were orally pretreated either with standardized Korean red ginseng extract (Ginseng) or dimethyl fumarate (DMF), two candidate Nrf2 inducers, to determine whether the putative protection was through an Nrf2-dependent mechanism involving the attenuation of reactive gliosis. Results show that Nrf2 target cytoprotective genes were distinctly elevated following HI. Pretreatment with Ginseng or DMF elicited robust neuroprotection against the deterioration of acute cerebral ischemia damage in an Nrf2-dependent manner as revealed by the reductions of neurological deficits score, infarct volume and brain edema, as well as enhanced expression levels of Nrf2 target antioxidant proteins and anti-inflammation mediators. In both ischemic striatum and cortex, the dynamic pattern of attenuated reactive gliosis in astrocytes and microglia, including affected astrocytic dysfunction in glutamate metabolism and water homeostasis, correlated well with the Nrf2-dependent neuroprotection by Ginseng or DMF. Furthermore, such neuroprotective benefits extended to the late phase of ischemic brain damage after HI, as evidenced by improvements in neurobehavioral outcomes, infarct volume and brain edema. Overall, pretreatment with Ginseng or DMF identically attenuates reactive gliosis and confers long-lasting neuroprotective efficacy against ischemic brain damage through an Nrf2-dependent mechanism. This study also provides new insight into the profitable contribution of reactive gliosis in the Nrf2-dependent neuroprotection in acute brain injury.


Assuntos
Fumarato de Dimetilo/farmacologia , Gliose/tratamento farmacológico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Panax/química , Animais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Artérias Carótidas/cirurgia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Transtornos Cerebrovasculares/cirurgia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/genética , Gliose/metabolismo , Gliose/fisiopatologia , Humanos , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Extratos Vegetais/farmacologia
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