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1.
J Med Genet ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811135

RESUMO

BACKGROUND: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population. METHODS: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays. RESULTS: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks. CONCLUSION: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

2.
Curr Opin Allergy Clin Immunol ; 21(2): 135-143, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560741

RESUMO

PURPOSE OF REVIEW: Self-management education in asthma can dramatically reduce asthma morbidity, but specific pediatric challenges need to be addressed. The purpose of this review is to discuss the most recent and significant advances regarding self-management interventions in pediatric asthma. RECENT FINDINGS: Recent evidence supports school-based programs including asthma self-management skills for children to significantly improve asthma control. A defined theoretical intervention framework, parent involvement, child satisfaction, and running the intervention outside the child's own free time are suggested drivers of successful implementation. Real-time telemedically delivered asthma education may also improve asthma-related outcomes in children. Moreover, mobile applications supporting self-management are generally welcomed by children and parents. Current evidence supports the use of models of health behaviors change in mobile application design and content development; self-monitoring alone is ineffective but useful when coupled with decision support for proactive care. SUMMARY: School-based and e-health interventions are potential facilitators for the implementation of successful self-management asthma programs, providing access to large numbers of children with asthma. This supports the healthcare practitioners to work together with researchers to promote these interventions, while following current recommendations for the effective transition of children into competent and confident adults to continue to successfully self-manage their asthma.

3.
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
4.
Org Biomol Chem ; 19(9): 1915-1925, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33443278

RESUMO

Enzymes are proteins that catalyse chemical reactions and, as such, have been widely used to facilitate a variety of natural and industrial processes, dating back to ancient times. In fact, the global enzymes market is projected to reach $10.5 billion in 2024. The development of computational and DNA editing tools boosted the creation of artificial enzymes (de novo enzymes) - synthetic or organic molecules created to present abiological catalytic functions. These novel catalysts seek to expand the catalytic power offered by nature through new functions and properties. In this manuscript, we discuss the advantages of combining computational design with directed evolution for the development of artificial enzymes and how this strategy allows to fill in the gaps that these methods present individually by providing key insights about the sequence-function relationship. We also review examples, and respective strategies, where this approach has enabled the creation of artificial enzymes with promising catalytic activity. Such key enabling technologies are opening new windows of opportunity in a variety of industries, including pharmaceutical, chemical, biofuels, and food, contributing towards a more sustainable development.

5.
Acta Med Port ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33241993

RESUMO

INTRODUCTION: Pediatric-onset multiple sclerosis may contrast with adult-onset multiple sclerosis, in terms of disease activity. We aimed to determine differentiating features between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis, at diagnosis and after one year under disease modifying therapies, and analyse the attainment of the status of "No Evidence of Disease Activity" between groups. MATERIAL AND METHODS: We analyzed demographical, laboratory, clinical and imaging features of patients with relapsing-remitting multiple sclerosis diagnosed at our center, according to the McDonald's 2010 criteria, with ≥ 1 year under disease modifying therapies and with available magnetic resonance imaging scans at diagnosis and one year after disease modifying therapies initiation. Patients were paired according to gender and disease modifying therapies in use. "No Evidence of Disease Activity" status was assessed, and differences were studied. RESULTS: Fifteen pediatric-onset multiple sclerosis (aged ≥ 8 and < 18 years) and 15 adult-onset multiple sclerosis (≥ 18 and < 55 years) patients were recruited. We found a statistically significant difference in the number of T2 weighted image diffuse lesions/with poorly defined borders (p = 0.015). The mean expanded disability status scale score after one year under disease modifying therapies was lower in the pediatric-onset multiple sclerosis group (1.6 ± 0.8) compared to the adult-onset multiple sclerosis group (2.3 ± 0.8; p = 0.032). Nevertheless, no differences were found regarding the percentage of cases achieving "No Evidence of Disease Activity" in either group. DISCUSSION: Although there is an empirical impression about the difference in inflammatory activity between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis, it was not possible to corroborate it in our study. Nevertheless, this was an exploratory and retrospective analysis of a small sample of patients, identifying variables in which such differences appear to be most important. CONCLUSION: Extensive studies of children, adolescents and adults with multiple sclerosis will be needed to categorize the clinical and radiological differences that allow the identification of drug response biomarkers in the early stages of the disease.

6.
Ann Hematol ; 99(5): 937-945, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32166377

RESUMO

Hydroxyurea (HU) is used as a therapy in sickle cell anemia (SCA). Many studies have established that HU improves patient quality of life by reducing symptoms. However, the effect of HU on erythrocytes is not well-described. We evaluated several parameters related to oxidative stress and total lipid content of erythrocytes in patients with SCA. The patient cohort consisted of 7 SCA patients treated with HU, 17 untreated SCA patients, and 15 healthy subjects. Erythrocytes from patients with SCA displayed increased oxidative stress relative to the control group, including higher thiobarbituric acid reactive substances (TBARS), Fe3+ content, and osmotic fragility, and decreased total cholesterol. We observed that treatment of SCA patients with HU increased Fe3+ content and activity of glutathione peroxidase, and decreased glutathione reductase activity, glutathione levels, total cholesterol, and phospholipid content comaperaded to patients untreated with HU. Thus, HU alters biochemical characteristics of erythrocytes; future studies will determine whether they are beneficial or not.


Assuntos
Anemia Falciforme , Eritrócitos Anormais/metabolismo , Hidroxiureia/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Colesterol/sangue , Feminino , Humanos , Masculino , Fragilidade Osmótica/efeitos dos fármacos , Fosfolipídeos/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
BMC Endocr Disord ; 20(1): 21, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028936

RESUMO

BACKGROUND: Adrenal hypoplasia congenita (AHC) is an X-linked disorder that affects the adrenal cortex and hypothalamus-pituitary-gonadal axis (HPG), leading to primary adrenocortical insufficiency (PAI) and hypogonadotropic hypogonadism. AHC is caused by a mutation in the DAX-1 gene (NR0B1). More commonly, this disease is characterized by early-onset PAI, with symptoms in the first months of life. However, a less severe phenotype termed late-onset AHC has been described, as PAI signs and symptoms may begin in adolescence and adulthood. Here we describe a family report of a novel mutation within NR0B1 gene and variable reproductive phenotypes, including spontaneous fertility, in a very late-onset X-linked AHC kindred. CASE PRESENTATION: Three affected maternal male relatives had confirmed PAI diagnosis between 30 y and at late 64 y. The X-linked pattern has made the endocrinology team to AHC suspicion. Regarding the HPG axis, all males presented a distinct degree of testosterone deficiency and fertility phenotypes, varying from a variable degree of hypogonadism, oligoasthenoteratozoospermia to spontaneous fertility. Interestingly, the other five maternal male relatives unexpectedly died during early adulthood, most likely due to undiagnosed PAI/adrenal crisis as the probable cause of their premature deaths. Sequencing analysis of the NR0B1 gene has shown a novel NR0B1 mutation (p.Tyr378Cys) that segregated in three AHC family members. CONCLUSIONS: NR0B1 p.Tyr378Cys segregates in an AHC family with a variable degree of adrenal and gonadal phenotypes, and its hemizygous trait explains the disease in affected family members. We recommend that NR0B1 mutation carriers, even those that are allegedly asymptomatic, be carefully monitored while reinforcing education to prevent PAI and consider early sperm banking when spermatogenesis still viable.


Assuntos
Insuficiência Adrenal/genética , Insuficiência Adrenal/patologia , Receptor Nuclear Órfão DAX-1/genética , Fertilidade , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Reprodução , Adulto , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Prognóstico
8.
Mol Psychiatry ; 25(8): 1876-1900, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-29950682

RESUMO

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

9.
J. investig. allergol. clin. immunol ; 30(5): 340-345, 2020. tab, graf
Artigo em Inglês | IBECS-Express | IBECS | ID: ibc-ET1-6897

RESUMO

BACKGROUND: The prevalence of fish allergy has increased in recent years. The parvalbumin Gad c 1 is a major cod allergen that is used as a follow-up marker in patients with fish allergy. OBJECTIVES: To determine the clinical and laboratory characteristics of a population of patients with fish allergy. To analyze the role of the specific IgE (sIgE) of recombinant Gad c 1 (rGad c 1) and skin prick tests (SPTs) in confirming the acquisition of tolerance to fish. METHODS: We performed a retrospective study of patients with fish allergy from July 1, 2005 to December 31, 2016. The population was characterized according to demographic data, species of fish associated with allergic reactions, and symptoms. The SPT wheal diameter and sIgE for fish and rGad c 1 were evaluated before acquisition of tolerance (T0) and afterwards (T1). RESULTS: The study population comprised 81 patients (68% male). Most reactions were triggered by hake (51%), mackerel (30%), and cod (26%). The most frequent manifestations were urticaria/angioedema (72%), gastrointestinal symptoms (35%), and eczema (33%); 42% of patients experienced anaphylaxis. At T0, the average sIgE values were as follows: cod, 32.2 kUA/L; sardine, 18.4 kUA/L; hake, 17.5 kUA/L; salmon, 13.9 kUA/L; tuna, 4.5 kUA/L; and rGad c 1, 22.9 kUA/L. In patients who acquired tolerance to at least 1 fish species (n=60; 74%), the mean value of rGad c 1 at T1 (5.1 kUA/L) was significantly lower than at T0 (16.8 kUA/L) (P=.001). Significant values were also recorded for the average diameter of the SPT wheal and the evaluations at T0 and T1 for hake (9.42 mm/3.79 mm) and salmon (7.8 mm/2.8 mm) (P=.002 and P=.026, respectively). CONCLUSION: The decrease in sIgE to rGad c 1 and the mean wheal diameter of SPT for hake and salmon can be used as markers of prognosis in the acquisition of tolerance by fish-allergic patients


ANTECEDENTES: La prevalencia de alergia al pescado ha aumentado en los últimos años. Gad c 1 es una parvalbúmina y un importante alérgeno del bacalao, utilizado como marcador de seguimiento en pacientes con alergia a pescado. OBJETIVOS: Caracterización clínica y de laboratorio de una población de pacientes con alergia a pescados. Analizar la contribución de la IgE específica (sIgE) a parvalbúmina recombinante (rGad c 1) y las pruebas cutáneas (SPT) para confirmar la aparición de tolerancia al pescado. MÉTODOS: Estudio retrospectivo de pacientes con alergia a pescados, desde julio de 2005 hasta diciembre de 2016. Se recogieron datos demográficos, reacciones alérgicas y síntomas con los pescados; el diámetro total de la SPT y el valor de la IgE a rGad c 1 antes (T0) y después de la adquisición de tolerancia (T1). RESULTADOS: Se evaluaron 81 pacientes (68% hombres). La merluza (51%), caballa (30%) y bacalao (26%) desencadenaron la mayoría de las reacciones. Las manifestaciones más frecuentes fueron urticaria/angioedema (72%), síntomas gastrointestinales (35%) eccema (33%) y el 42% de los pacientes tuvieron anafilaxia. En (T0), los valores medios de sIgE fueron: bacalao (32,2 kUA/L), sardina (18,4 kUA/L), merluza (17,5 kUA/L), salmón (13,9 kUA/L), atún (4,5 kUA/L) y rGad c 1 (22,9 kUA/L). En pacientes que adquirieron tolerancia a al menos una especie de pescado (n= 60; 74%), el valor medio de rGad c 1 en T1 (5,1 kUA/L) fue significativamente más bajo que T0 (16,8 kUA/L) (p= 0,001). Los valores del diámetro medio de la SPT en T0 y T1 para merluza (9,42 mm/3,79 mm) y salmón (7,8 mm/2,8 mm) también fueron significativos p= 0,002 y p= 0,026, respectivamente. CONCLUSIÓN: La disminución de la sIgE a rGad c 1 y el diámetro medio de la SPT para merluza y salmón se pueden utilizar como marcadores de pronóstico en la adquisición de tolerancia de alergia a pescados

10.
Acta Med Port ; 32(7-8): 514-519, 2019 Aug 01.
Artigo em Português | MEDLINE | ID: mdl-31445531

RESUMO

INTRODUCTION: Children with DiGeorge syndrome/chromosome 22q11.2 deletion syndrome might have a variable degree of immunodeficiency, which may limit the use of live vaccines. The aim of this study was to review the adverse effects of live vaccines and possible relation with immune status in patients with DiGeorge Syndrome/partial 22q11.2 deletion syndrome. MATERIAL AND METHODS: Retrospective study with analysis of the clinical records of children with chromosome 22q11.2 deletion syndrome and DiGeorge syndrome phenotype, followed in a Primary Immunodeficiency center. Data were collected on: demographic characteristics; medical and vaccination history with live vaccines; T-CD4+ lymphocyte counts and lymphocyte proliferative responses to antigens and mitogens; adverse reactions; vaccine failure. RESULTS: Twenty three children with DiGeorge syndrome/22q11.2 deletion syndrome were included, 65.2% male, with average age at diagnosis of 11.3 months. Eighteen children (78%) received bacillus Calmette-Guérin vaccine: all with evidence of thymic activity; three presented moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses; one had abnormal lymphocyte proliferative responses for mitogens, four for purified protein derivative and one for tetanus toxoid. Measles, mumps and rubella vaccine was administered to 15 children, three of them with moderate immunosuppression and abnormal lymphocyte proliferative responses. Live attenuated polio vaccine was administered to 4 children without immunosuppression and the rotavirus vaccine to three children, one with moderate immunosuppression. No significant adverse reactions were reported. DISCUSSION: These data are in line with the findings of other international studies. CONCLUSION: In our sample, live vaccines were well-tolerated, even in children with moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses to antigens/mitogens.


Assuntos
Síndrome de DiGeorge/imunologia , Tolerância Imunológica , Adjuvantes Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Linfócitos T CD4-Positivos , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Linfopenia/imunologia , Masculino , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Fenótipo , Vacina Antipólio de Vírus Inativado/administração & dosagem , Estudos Retrospectivos , Vacinas contra Rotavirus/administração & dosagem , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
11.
G3 (Bethesda) ; 9(9): 2811-2821, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278175

RESUMO

Partial selfing, whereby self- and cross- fertilization occur in populations at intermediate frequencies, is generally thought to be evolutionarily unstable. Yet, it is found in natural populations. This could be explained if populations with partial selfing are able to reduce genetic loads and the possibility for inbreeding depression while keeping genetic diversity that may be important for future adaptation. To address this hypothesis, we compare the experimental evolution of Caenorhabditis elegans populations under partial selfing, exclusive selfing or predominant outcrossing, while they adapt to osmotically challenging conditions. We find that the ancestral genetic load, as measured by the risk of extinction upon inbreeding by selfing, is maintained as long as outcrossing is the main reproductive mode, but becomes reduced otherwise. Analysis of genome-wide single-nucleotide polymorphisms (SNPs) during experimental evolution and among the inbred lines that survived enforced inbreeding indicates that populations with predominant outcrossing or partial selfing maintained more genetic diversity than expected with neutrality or purifying selection. We discuss the conditions under which this could be explained by the presence of recessive deleterious alleles and/or overdominant loci. Taken together, our observations suggest that populations evolving under partial selfing can gain some of the benefits of eliminating unlinked deleterious recessive alleles and also the benefits of maintaining genetic diversity at partially dominant or overdominant loci that become associated due to variance of inbreeding levels.


Assuntos
Caenorhabditis elegans/genética , Carga Genética , Variação Genética , Endogamia , Animais , Evolução Molecular , Feminino , Depressão por Endogamia , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Autofertilização
12.
PLoS One ; 14(6): e0217536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158263

RESUMO

BACKGROUND: Prognostic models based on individual patient characteristics can improve treatment decisions and outcome in the future. In many (radiomic) studies, small size and heterogeneity of datasets is a challenge that often limits performance and potential clinical applicability of these models. The current study is example of a retrospective multi-centric study with challenges and caveats. To highlight common issues and emphasize potential pitfalls, we aimed for an extensive analysis of these multi-center pre-treatment datasets, with an additional 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan acquired during treatment. METHODS: The dataset consisted of 138 stage II-IV non-small cell lung cancer (NSCLC) patients from four different cohorts acquired from three different institutes. The differences between the cohorts were compared in terms of clinical characteristics and using the so-called 'cohort differences model' approach. Moreover, the potential prognostic performances for overall survival of radiomic features extracted from CT or FDG-PET, or relative or absolute differences between the scans at the two time points, were assessed using the LASSO regression method. Furthermore, the performances of five different classifiers were evaluated for all image sets. RESULTS: The individual cohorts substantially differed in terms of patient characteristics. Moreover, the cohort differences model indicated statistically significant differences between the cohorts. Neither LASSO nor any of the tested classifiers resulted in a clinical relevant prognostic model that could be validated on the available datasets. CONCLUSION: The results imply that the study might have been influenced by a limited sample size, heterogeneous patient characteristics, and inconsistent imaging parameters. No prognostic performance of FDG-PET or CT based radiomics models can be reported. This study highlights the necessity of extensive evaluations of cohorts and of validation datasets, especially in retrospective multi-centric datasets.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Bases de Dados Factuais , Fluordesoxiglucose F18/administração & dosagem , Neoplasias Pulmonares , Modelos Biológicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
13.
Chem Commun (Camb) ; 54(28): 3524-3527, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29565075

RESUMO

We demonstrate that fluorinated ionic liquids reduce the impact of the addition of water upon the ionic liquid's H-bond acceptance ability. This is a key factor to obtain functionalized materials to be used e.g. in the dissolution of biomolecules, extraction processes or material engineering.

14.
PLoS One ; 13(3): e0192859, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29494598

RESUMO

BACKGROUND: Lymph node stage prior to treatment is strongly related to disease progression and poor prognosis in non-small cell lung cancer (NSCLC). However, few studies have investigated metabolic imaging features derived from pre-radiotherapy 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) of metastatic hilar/mediastinal lymph nodes (LNs). We hypothesized that these would provide complementary prognostic information to FDG-PET descriptors to only the primary tumor (tumor). METHODS: Two independent cohorts of 262 and 50 node-positive NSCLC patients were used for model development and validation. Image features (i.e. Radiomics) including shape and size, first order statistics, texture, and intensity-volume histograms (IVH) (http://www.radiomics.io/) were evaluated by univariable Cox regression on the development cohort. Prognostic modeling was conducted with a 10-fold cross-validated least absolute shrinkage and selection operator (LASSO), automatically selecting amongst FDG-PET-Radiomics descriptors from (1) tumor, (2) LNs or (3) both structures. Performance was assessed with the concordance-index. Development data are publicly available at www.cancerdata.org and Dryad (doi:10.5061/dryad.752153b). RESULTS: Common SUV descriptors (maximum, peak, and mean) were significantly related to overall survival when extracted from LNs, as were LN volume and tumor load (summed tumor and LNs' volumes), though this was not true for either SUV metrics or tumor's volume. Feature selection exclusively from imaging information based on FDG-PET-Radiomics, exhibited performances of (1) 0.53 -external 0.54, when derived from the tumor, (2) 0.62 -external 0.56 from LNs, and (3) 0.62 -external 0.59 from both structures, including at least one feature from each sub-category, except IVH. CONCLUSION: Combining imaging information based on FDG-PET-Radiomics features from tumors and LNs is desirable to achieve a higher prognostic discriminative power for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Fluordesoxiglucose F18/análise , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
15.
Genetics ; 207(4): 1663-1685, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29066469

RESUMO

Understanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity, and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty can be problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here, we report an advanced recombinant inbred line (RIL) quantitative trait locus mapping panel for the hermaphroditic nematode Caenorhabditis elegans, the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs at present, was created by hybridization of 16 wild isolates, experimental evolution for 140-190 generations, and inbreeding by selfing for 13-16 generations. The panel contains 22% of single-nucleotide polymorphisms known to segregate in natural populations, and complements existing C. elegans mapping resources by providing fine resolution and high nucleotide diversity across > 95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad-sense heritability in the CeMEE. While simulations show that we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits do not feature such alleles. We instead find that a significant fraction of trait variance, approaching 40% for fertility, can be explained by sign epistasis with main effects below the detection limit. In congruence, phenotype prediction from genomic similarity, while generally poor ([Formula: see text]), requires modeling epistasis for optimal accuracy, with most variance attributed to the rapidly evolving chromosome arms.


Assuntos
Evolução Molecular , Aptidão Genética , Herança Multifatorial/genética , Seleção Genética/genética , Alelos , Animais , Caenorhabditis elegans/genética , Cruzamentos Genéticos , Epistasia Genética , Hibridização Genética , Endogamia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
16.
Life Sci ; 187: 42-49, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28823565

RESUMO

AIM: Investigate to what extent low-intensity swim training for six weeks counterbalances the adverse remodeling due to the advance of pathological hypertrophy in the left ventricle (LV) structural and mechanical properties in the early compensated phase of hypertension in male SHR. MAIN METHODS: Four-month-old male SHR and Wistar rats were randomly divided into Sed (sedentary) and Ex (exercised) groups. The exercised rats were submitted to a swimming protocol (1h/day, 5times/week, no additional load) for six weeks. LV tissue and isolated myocytes were used to assess structural and mechanical properties. Myocytes were stimulted at frequencies (F) of 1 and 3Hz at 37°C. KEY FINDINGS: Exercised SHR showed improvement in cardiovascular parameters compared to sedentary SHR (mean arterial pressure: 13.22%; resting HR: 14.28.%). About structural and mechanical properties, swim training induced a decrease in LV myocyte thickness (10.85%), number of inflammatory cells (21.24%); collagen type III (74.23%) and type I (85.6%) fiber areas; amplitude of single myocyte shortening (47% to F1 and 28.46% to F3), timecourses of shortening (16.5% to F1 and 7.55% to F3) and relaxation (15.31% to F3) compared to sedentary SHR. SIGNIFICANCE: Six weeks of swim training attenuates the adverse remodeling of LV structural and mechanical properties in the early compensated phase of hypertension in male SHR.


Assuntos
Ventrículos do Coração/patologia , Hipertensão/patologia , Hipertensão/terapia , Modalidades de Fisioterapia , Natação , Remodelação Ventricular/fisiologia , Animais , Pressão Sanguínea/fisiologia , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Estimulação Elétrica , Frequência Cardíaca/fisiologia , Ventrículos do Coração/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertrofia , Masculino , Contração Muscular/fisiologia , Relaxamento Muscular/fisiologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Condicionamento Físico Animal , Ratos
17.
Adv Drug Deliv Rev ; 109: 131-153, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-26774327

RESUMO

A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models 'learn' using advanced and innovative information technologies (ideally in a distributed fashion - please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi-faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Neoplasias/radioterapia , Medicina de Precisão/métodos , Radioterapia (Especialidade)/métodos , Humanos , Neoplasias/diagnóstico , Resultado do Tratamento
18.
J Chromatogr A ; 1472: 55-65, 2016 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-27773392

RESUMO

A common strategy for the production and purification of recombinant proteins is to fuse a tag to the protein terminal residues and employ a "tag-specific" ligand for fusion protein capture and purification. In this work, we explored the effect of two tryptophan-based tags, NWNWNW and WFWFWF, on the expression and purification of Green Fluorescence Protein (GFP) used as a model fusion protein. The titers obtained with the expression of these fusion proteins in soluble form were 0.11mgml-1 and 0.48mgml-1 for WFWFWF and NWNWNW, respectively. A combinatorial library comprising 64 ligands based on the Ugi reaction was prepared and screened for binding GFP-tagged and non-tagged proteins. Complementary ligands A2C2 and A3C1 were selected for the effective capture of NWNWNW and WFWFWF tagged proteins, respectively, in soluble forms. These affinity pairs displayed 106M-1 affinity constants and Qmax values of 19.11±2.60ugg-1 and 79.39ugg-1 for the systems WFWFWF AND NWNWNW, respectively. GFP fused to the WFWFWF affinity tag was also produced as inclusion bodies, and a refolding-on column strategy was explored using the ligand A4C8, selected from the combinatorial library of ligands but in presence of denaturant agents.


Assuntos
Cromatografia de Afinidade/métodos , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/isolamento & purificação , Ligantes , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Triptofano/química , Triptofano/isolamento & purificação , Sequência de Aminoácidos , Proteínas de Fluorescência Verde/biossíntese , Corpos de Inclusão/metabolismo , Desnaturação Proteica , Redobramento de Proteína , Proteínas Recombinantes de Fusão/biossíntese , Solubilidade
19.
Evolution ; 70(10): 2357-2369, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27501095

RESUMO

Hermaphroditic organisms are key models in sex allocation research, yet the developmental processes by which hermaphrodite sex allocation can evolve remain largely unknown. Here we use experimental evolution of hermaphrodite-male (androdioecious) Caenorhabditis elegans populations to quantify the developmental changes underlying adaptive shifts in hermaphrodite sex allocation. We show that the experimental evolution of increased early-life self-fertility occurred through modification of a suite of developmental traits: increased self-sperm production, accelerated oogenesis and ovulation, and increased embryo retention. The experimental evolution of increased self-sperm production delayed entry into oogenesis-as expected, given the sequentially coupled production of self-spermatogenesis and oogenesis. Surprisingly, however, delayed oogenesis onset did not delay reproductive maturity, nor did it trade-off with gamete or embryo size. Comparing developmental time dynamics of germline and soma indicates that the evolution of increased sperm production did not delay reproductive maturity due to a globally accelerated larval development during the period of self-spermatogenesis. Overall, heterochrony in gametogenesis and soma can explain adaptive shifts in hermaphrodite sex allocation.


Assuntos
Caenorhabditis elegans/genética , Evolução Molecular , Organismos Hermafroditas/genética , Maturidade Sexual/genética , Adaptação Fisiológica , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Organismos Hermafroditas/crescimento & desenvolvimento , Oogênese , Autofertilização , Espermatogênese
20.
Radiother Oncol ; 119(3): 487-94, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27139126

RESUMO

AIM: Improve the prognostic prediction of clinical variables for non-small cell lung cancer (NSCLC), by selecting from blood-biomarkers, non-invasively describing hypoxia, inflammation and tumour load. METHODS: Model development and validation included 182 and 181 inoperable stage I-IIIB NSCLC patients treated radically with radiotherapy (55.2%) or chemo-radiotherapy (44.8%). Least absolute shrinkage and selection operator (LASSO), selected from blood-biomarkers related to hypoxia [osteopontin (OPN) and carbonic anhydrase IX (CA-IX)], inflammation [interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP)], and tumour load [carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1 (Cyfra 21-1)]. Sequent model extension selected from alpha-2-macroglobulin (α2M), serum interleukin-2 receptor (sIL2r), toll-like receptor 4 (TLR4), and vascular endothelial growth factor (VEGF). Discrimination was reported by concordance-index. RESULTS: OPN and Cyfra 21-1 (hazard ratios of 3.3 and 1.7) significantly improved a clinical model comprising gender, World Health Organization performance-status, forced expiratory volume in 1s, number of positive lymph node stations, and gross tumour volume, from a concordance-index of 0.66 to 0.70 (validation=0.62 and 0.66). Extension of the validated model yielded a concordance-index of 0.67, including α2M, sIL2r and VEGF (hazard ratios of 4.6, 3.1, and 1.4). CONCLUSION: Improvement of a clinical model including hypoxia and tumour load blood-biomarkers was validated. New immunological markers were associated with overall survival. Data and models can be found at www.cancerdata.org (http://dx.doi.org/10.17195/candat.2016.04.1) and www.predictcancer.org.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Hipóxia Celular , Inflamação/sangue , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Queratina-19/sangue , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Osteopontina/sangue , Prognóstico , Carga Tumoral
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