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BACKGROUND: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. METHODS: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). RESULTS: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10-4 (0.01%)-10-5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. CONCLUSIONS: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.
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Biomarcadores Tumorais/genética , Rearranjo Gênico , Neoplasia Residual/patologia , Neuroblastoma/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Sarcoma de Ewing/patologia , Sequenciamento Completo do Genoma/métodos , Adolescente , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Neoplasia Residual/genética , Neuroblastoma/sangue , Neuroblastoma/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Proto-Oncogênica c-fli-1/genética , Receptores de Antígenos de Linfócitos T/genética , Sarcoma de Ewing/sangue , Sarcoma de Ewing/genética , Regulador Transcricional ERG/genéticaRESUMO
BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.
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Proteínas de Fusão bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Proteínas de Fusão bcr-abl/genética , Humanos , Imunoglobulinas , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
The HLA gene complex on human chromosome 6 is one of the most polymorphic regions in the human genome and contributes in large part to the diversity of the immune system. Accurate typing of HLA genes with short-read sequencing data has historically been difficult due to the sequence similarity between the polymorphic alleles. Here, we introduce an algorithm, xHLA, that iteratively refines the mapping results at the amino acid level to achieve 99-100% four-digit typing accuracy for both class I and II HLA genes, taking only [Formula: see text]3 min to process a 30× whole-genome BAM file on a desktop computer.
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Teste de Histocompatibilidade/métodos , Algoritmos , Benchmarking , HumanosRESUMO
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.
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Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pré-Escolar , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Gradação de Tumores , Proteínas de Fusão Oncogênica/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento , Sequenciamento Completo do GenomaRESUMO
Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.
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Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Criança , Neoplasias/genética , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Feminino , Masculino , Adolescente , Pré-Escolar , Lactente , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
Predicting the impact of coding and noncoding variants on splicing is challenging, particularly in non-canonical splice sites, leading to missed diagnoses in patients. Existing splice prediction tools are complementary but knowing which to use for each splicing context remains difficult. Here, we describe Introme, which uses machine learning to integrate predictions from several splice detection tools, additional splicing rules, and gene architecture features to comprehensively evaluate the likelihood of a variant impacting splicing. Through extensive benchmarking across 21,000 splice-altering variants, Introme outperformed all tools (auPRC: 0.98) for the detection of clinically significant splice variants. Introme is available at https://github.com/CCICB/introme .
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Sítios de Splice de RNA , Splicing de RNA , Humanos , Íntrons , Aprendizado de Máquina , MutaçãoRESUMO
Introduction: Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion. Methods: Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. Results: Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo. Discussion: Others who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.
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Diffuse midline gliomas (DMG) harbouring H3K27M mutation are paediatric tumours with a dismal outcome. Recently, a new subtype of midline gliomas has been described with similar features to DMG, including loss of H3K27 trimethylation, but lacking the canonical H3K27M mutation (H3-WT). Here, we report a cohort of five H3-WT tumours profiled by whole-genome sequencing, RNA sequencing and DNA methylation profiling and combine their analysis with previously published cases. We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation. Affected patients share a similar poor prognosis as patients with H3K27M DMG. Global molecular analysis of H3-WT and H3K27M DMG reveal distinct transcriptome and methylome profiles including differential methylation of homeobox genes involved in development and cellular differentiation. Patients have distinct clinical features, with a trend demonstrating ACVR1 mutations occurring in H3-WT tumours at an older age. This in-depth exploration of H3-WT tumours further characterises this novel DMG, H3K27-altered sub-group, characterised by a specific immunohistochemistry profile with H3K27me3 loss, wild-type H3K27M and positive EZHIP. It also gives new insights into the possible mechanism and pathway regulation in these tumours, potentially opening new therapeutic avenues for these tumours which have no known effective treatment. This study has been retrospectively registered on clinicaltrial.gov on 8 November 2017 under the registration number NCT03336931 ( https://clinicaltrials.gov/ct2/show/NCT03336931 ).
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Genes Homeobox , Glioma , Criança , Humanos , Histonas/genética , Metilação , Glioma/genética , Mutação , Receptores ErbB/genética , Receptores de Ativinas Tipo IRESUMO
For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. SIGNIFICANCE: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.
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Antineoplásicos , Neoplasias , Humanos , Criança , Avaliação Pré-Clínica de Medicamentos , Detecção Precoce de Câncer , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios de Triagem em Larga Escala/métodosRESUMO
BACKGROUND: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. METHODS: We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. RESULTS: A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. CONCLUSIONS: Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.
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Antígeno B7-H1 , Neoplasias , Adulto , Humanos , Criança , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias/genética , Linfócitos T CD8-Positivos/metabolismo , Biomarcadores Tumorais/genética , Microambiente Tumoral/genética , MutaçãoRESUMO
The ID proteins are named for their role as inhibitors of DNA binding and differentiation. They contain a helix-loop-helix (HLH) domain but lack a basic DNA-binding domain. In complex with basic HLH (bHLH) transcription factors, gene expression is regulated by DNA-binding inactivation. Although the HLH domain is highly conserved and shares a similar topology, the IDs preferentially bind class I bHLH-group members such as E47 (TCF3) but not the class III bHLH member Myc. A structure of an ID protein could potentially shed light on its mechanism. Owing to their short half-lives in vivo and reported in vitro instability, this paper describes the strategies that went into expressing sufficient soluble and stable ID2 to finally obtain diffraction-quality crystals. A 2.1â Å resolution data set was collected from a crystal belonging to space group P3(1)21 with unit-cell parameters a=b=51.622, c=111.474â Å, α=ß=90, γ=120° that was obtained by hanging-drop vapour diffusion in a precipitant solution consisting of 0.1â M MES pH 6.5, 2.0â M potassium acetate. The solvent content was consistent with the presence of one or two molecules in the asymmetric unit.
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Proteína 2 Inibidora de Diferenciação/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Ligação Competitiva , Cromatografia de Afinidade , Clonagem Molecular , Sequência Conservada , Cristalização , Cristalografia por Raios X , DNA/química , Humanos , Proteína 2 Inibidora de Diferenciação/isolamento & purificação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estabilidade Proteica , Estrutura Quaternária de ProteínaRESUMO
Complex somatic genomic rearrangements and copy number alterations are hallmarks of nearly all cancers. We have developed an algorithm, LINX, to aid interpretation of structural variant and copy number data derived from short-read, whole-genome sequencing. LINX classifies raw structural variant calls into distinct events and predicts their effect on the local structure of the derivative chromosome and the functional impact on affected genes. Visualizations facilitate further investigation of complex rearrangements. LINX allows insights into a diverse range of structural variation events and can reliably detect pathogenic rearrangements, including gene fusions, immunoglobulin enhancer rearrangements, intragenic deletions, and duplications. Uniquely, LINX also predicts chained fusions that we demonstrate account for 13% of clinically relevant oncogenic fusions. LINX also reports a class of inactivation events that we term homozygous disruptions that may be a driver mutation in up to 9% of tumors and may frequently affect PTEN, TP53, and RB1.
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Gymnemic-acids (GA) block lingual sweet taste receptors, thereby reducing pleasantness and intake of sweet food. Objective: To examine whether a 14-day gymnema-based intervention can reduce sweet foods and discretionary sugar intake in free-living adults. Healthy adults (n = 58) were randomly allocated to either the intervention group (INT) or control group (CON). The intervention comprised of consuming 4 mg of Gymnema sylvestre containing 75% gymnema acids, a fibre and vitamin supplement, and an associated healthy-eating guide for 14 days; participants in the CON group followed the same protocol, replacing the GA with a placebo mint. Amount of chocolate bars eaten and sensory testing were conducted before and after the 14-day intervention (post-GA or placebo dosing on days zero and 15, respectively). Food frequency questionnaires were conducted on days zero, 15 and after a 28-day maintenance period to examine any changes in intake of sweet foods. A range of statistical procedures were used to analyse the data including Chi square, t-test and two-way analysis of variance. Post dosing, INT consumed fewer chocolates (2.65 ± 0.21 bars) at day zero than CON (3.15 ± 0.24 bars; p = 0.02); there were no differences between groups at day 15 (INT = 2.77 ± 0.22 bars; CON = 2.78 ± 0.22 bars; p = 0.81). At both visits, a small substantive effect (r < 0.3) was observed in the change in pleasantness and desire ratings, with INT showing a slight increase while CON showed a small decrease over the 14-day period. No differences were found in the intake of 9 food categories between groups at any timepoint. There were no differences in consumption of low sugar healthy foods between visits, or by group. The 14-day behavioural intervention reduced pleasantness and intake of chocolate in a laboratory setting. There was no habituation to the mint over the 14-day period. This study is the first to investigate the effect of longer-term gymnema acid consumption on sweet food consumption outside of a laboratory setting; further research is needed to assess how long the effect of the 14-day intervention persists.
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Gymnema sylvestre , Gymnema , Humanos , Adulto , Açúcares , Fissura , Preferências Alimentares , PaladarRESUMO
Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.
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Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Criança , Modelos Animais de Doenças , Genômica/métodos , Humanos , Neoplasias/patologia , Medicina de Precisão/métodos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Salmon provides long-chain (LC) n-3 PUFA and Se, which are well recognised for their health benefits. The n-3 and Se status of the New Zealand population is marginal. The objective of the present study was to compare the effects of consuming salmon v. supplementation with salmon oil on LC n-3 and Se status. Healthy volunteers (n 44) were randomly assigned to one of four groups consuming 2 × 120 g servings of salmon/week or 2, 4 or 6 salmon oil capsules/d for 8 weeks. Linear regression analysis predictive models were fitted to the capsule data to predict changes in erythrocyte LC n-3 levels with intakes of LC n-3 from capsules in amounts equivalent to that consumed from salmon. Changes in Se status (plasma Se and whole-blood glutathione peroxidase) were compared between the groups consuming salmon and capsules (three groups combined). Salmon, 2, 4 and 6 capsules provided 0·82, 0·24, 0·47 and 0·69 g/d of LC n-3 fatty acids. Salmon provided 7 µg/d and capsules < 0·02 µg/d of Se. The predictive model (r(2) 0·31, P = 0·001) showed that increases in erythrocyte LC n-3 levels were similar when intakes of 0·82 g/d LC n-3 from salmon or capsules (1·92 (95 % CI 1·35, 2·49) v. 2·32 (95 % 1·76, 2·88) %) were consumed. Plasma Se increased significantly more with salmon than with capsules (12·2 (95 % CI 6·18, 18·12) v. 1·57 (95 % CI - 2·32, 5·45) µg/l, P = 0·01). LC n-3 status was similarly improved with consumption of salmon and capsules, while consuming salmon had the added benefit of increasing Se status. This is of particular relevance to the New Zealand population that has marginal LC n-3 and Se status.
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Ácidos Graxos Ômega-3/sangue , Óleos de Peixe/administração & dosagem , Salmão , Selênio/sangue , Adulto , Animais , Suplementos Nutricionais , Ingestão de Alimentos , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Nova Zelândia , Adulto JovemRESUMO
BACKGROUND: Nitrate (NO3 -)-rich beetrAs BR juice can naturally contain both NO3 In four separate treatments, 11 healthy adults consumed 250 mL of BR containing one of the following: (i) high NO3 Ingestion of the HL and MM BR increased plasma [NO2 Inorganic NO3 - consumptio
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Beta vulgaris , Suplementos Nutricionais , Sucos de Frutas e Vegetais , Nitratos/sangue , Nitritos/sangue , Adolescente , Adulto , Pressão Arterial , Placa de Sangue Epidural , Débito Cardíaco , Estudos Cross-Over , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Nitratos/farmacocinética , Nitritos/farmacocinética , Adulto JovemRESUMO
Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.
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Pentanos/síntese química , Aldeídos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
Prolonged exercise in the heat elicits a number of physiological changes as glycogen stores are low and water and electrolytes are lost through sweat. However, it is unclear whether these changes provoke an increase in liking of saltiness and, therefore, palatability of an oral rehydration solution (ORS). Twenty-seven recreationally active participants (n = 13 males; n = 14 females) completed sensory analysis of an ORS, a traditional sports drink (TS), and a flavored water placebo (PL) at rest and during 60 min (3 × 20-min bouts) of cycling exercise at 70% age-predicted maximum heart rate (HRmax) at 35.3 ± 1.4 °C and 41 ± 6% relative humidity. Before and after every 20 min of exercise, drinks were rated (using 20-mL beverage samples) based on liking of sweetness, liking of saltiness, thirst-quenching ability, and overall liking on a nine-point hedonic scale. Hydration status was assessed by changes in semi-nude body mass, saliva osmolality (SOsm), and saliva total protein concentration (SPC). After 60 min of exercise, participants lost 1.36 ± 0.39% (mean ± SD) of body mass and there were increases in SOsm and SPC. At all time points, liking of sweetness, saltiness, thirst-quenching ability, and overall liking was higher for the TS and PL compared to the ORS (p < 0.05). However, the saltiness liking and thirst-quenching ability of the ORS increased after 60 min of exercise compared to before exercise (p < 0.05). There was also a change in predictors of overall liking with pre-exercise ratings mostly determined by liking of sweetness, saltiness, and thirst-quenching ability (p < 0.001), whereas only liking of saltiness predicted overall liking post-exercise (R2 = 0.751; p < 0.001). There appears to be a hedonic shift during exercise in which the perception of saltiness becomes the most important predictor of overall liking. This finding supports the potential use of an ORS as a valuable means of hydration during the latter stages of prolonged and/or intense exercise in the heat.
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Exercício Físico/fisiologia , Temperatura Alta , Percepção , Soluções para Reidratação/administração & dosagem , Soluções para Reidratação/farmacologia , Sensação , Administração Oral , Adulto , Feminino , Humanos , Masculino , Percepção/efeitos dos fármacos , Sensação/efeitos dos fármacos , Paladar/efeitos dos fármacos , Paladar/fisiologia , Sede/efeitos dos fármacos , Sede/fisiologiaRESUMO
INTRODUCTION: Markers of oxidative and psychological stress are elevated during high-intensity exercise. Additionally, when energy intake does not match expenditure, women who actively participate in sports and exercise are at risk of developing menstrual dysfunction, infertility, and osteoporosis. Vitamin C is known to reduce exercise-induced stress. Here, this study investigates the efficacy of consuming vitamin C from SunGold kiwifruit compared to in isolation, in ameliorating exercise-induced stress in recreationally active women. METHODS AND RESULTS: Ten eumenorrheic women are recruited in this crossover study and attended three exercise and one rest trial. In the exercise trials, participants consumed 300 mg vitamin C from kiwifruit or drink, or have a placebo drink, followed by 30-min exercise on a cycle ergometer at 60% power. During rest visit, participants sat quietly and consumed a placebo drink. Salivary uric acid (oxidative stress) and cortisol (psychological stress) are measured before and immediately after exercise for 2 h. Both vitamin C and kiwifruit reduced exercise-induced uric acid, immediately after exercise. Vitamin C drink continued to decrease uric acid for a further 30 min and slightly attenuated exercise-induced cortisol. CONCLUSIONS: Consuming liquid vitamin C prior to high-intensity cycling appears more effective than eating kiwifruit, in ameliorating exercise-induced stress in recreationally active women of reproductive age.
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Actinidia , Ácido Ascórbico/administração & dosagem , Exercício Físico/fisiologia , Frutas , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Adulto , Ciclismo , Estudos Cross-Over , Feminino , Humanos , Hidrocortisona/análise , Placebos , Saliva/química , Adulto JovemRESUMO
Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.