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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
Excessive fine sediment (particles <2 mm) deposition in freshwater systems is a pervasive stressor worldwide. However, understanding of ecological response to excess fine sediment in river systems at the global scale is limited. Here, we aim to address whether there is a consistent response to increasing levels of deposited fine sediment by freshwater invertebrates across multiple geographic regions (Australia, Brazil, New Zealand and the UK). Results indicate ecological responses are not globally consistent and are instead dependent on both the region and the facet of invertebrate diversity considered, that is, taxonomic or functional trait structure. Invertebrate communities of Australia were most sensitive to deposited fine sediment, with the greatest rate of change in communities occurring when fine sediment cover was low (below 25% of the reach). Communities in the UK displayed a greater tolerance with most compositional change occurring between 30% and 60% cover. In both New Zealand and Brazil, which included the most heavily sedimented sampled streams, the communities were more tolerant or demonstrated ambiguous responses, likely due to historic environmental filtering of invertebrate communities. We conclude that ecological responses to fine sediment are not generalisable globally and are dependent on landscape filters with regional context and historic land management playing important roles.
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Sedimentos Geológicos , Invertebrados , Animais , Invertebrados/fisiologia , Água Doce , Rios , Nova Zelândia , Ecossistema , Biodiversidade , Monitoramento AmbientalRESUMO
Despite lotic systems demonstrating high levels of seasonal and spatial variability, most research and biomonitoring practices do not consider seasonality when interpreting results and are typically focused at the meso-scale (combined pool/riffle samples) rather than considering habitat patch dynamics. We therefore sought to determine if the sampling season (spring, summer and autumn) influenced observed macroinvertebrate biodiversity, structure and function at the habitat unit scale (determined by substrate composition), and if this in turn influenced the assessment of fine sediment (sand and silt) pressures. We found that biodiversity supported at the habitat level was not seasonally consistent with the contribution of nestedness and turnover in structuring communities varying seasonally. Habitat differences in community composition were evident for taxonomic communities regardless of the season but were not seasonally consistent for functional communities, and, notably, season explained a greater amount of variance in functional community composition than the habitat unit. Macroinvertebrate biodiversity supported by silt habitats demonstrated strong seasonal differences and communities were functionally comparable to sand habitats in spring and to gravel habitats in autumn. Sand communities were impoverished compared to other habitats regardless of the season. Silt habitats demonstrated a strong increase in Ephemeroptera, Plecoptera and Trichoptera (EPT) taxa and functional richness from spring into autumn, while vegetation habitats displayed a peak in EPT abundance in summer. Only silt and sand habitats demonstrated temporal variability in functional evenness suggesting that these habitats are different in terms of their resource partitioning and productivity over time compared to other habitats. Gravel and vegetation habitats appeared to be more stable over time with functional richness and evenness remaining consistent. To accurately evaluate the influence of fine sediment on lotic ecosystems, it is imperative that routine biomonitoring and scientific research discriminate between sand and silt fractions, given they support different biodiversity, particularly during summer and autumn months.
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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
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
The carnivorous pitcher plant Sarracenia purpurea is native to North America, but has been introduced into Europe, where it is now widespread. Understanding of how this species functions in its non-native range is limited. We measured pitcher morphology and prey capture by S. purpurea in its non-native range in Britain and Ireland. Pitchers were removed from different plants at each of six bogs covering the species range in Britain and Ireland (n = 10 pitchers per site). For each pitcher we counted and identified every prey item and took measurements of morphology. We also compiled prey capture data for existing studies in Europe and North America. Prey capture characteristics varied between sites in Britain and Ireland. The amount of prey captured varied 20-fold between sites and was partially explained by differences in pitcher size; larger pitchers caught more prey. The primary prey was Formicidae, Diptera and Coleoptera. At the rank of order, prey composition varied between bogs, some contained mainly Formicidae, some mainly Diptera and some a mix. Prey capture was less evenly distributed at some bogs compared to others, suggesting more specialization. There was no overall difference in prey capture (composition or evenness) at the rank of order between plants in Europe compared to those in North America. At the rank of species, prey capture varied between populations even within the same order. This study demonstrates a large amount of variability between sites in prey capture characteristics. This may reflect different site characteristics and/or plant strategies, which will likely impact plant function, and may impact the inquiline community. In terms of prey capture at the rank of order, S. purpurea functions identically in its non-native range. This supports its use as a model system in a natural experiment for understanding food webs.
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Rivers are among the most threatened ecosystems worldwide and are experiencing rapid biodiversity loss. Flow alteration due to climate change, water abstraction and augmentation is a severe stressor on many aquatic communities. Macroinvertebrates are widely used for biomonitoring river ecosystems although current taxonomic approaches used to characterise ecological responses to flow have limitations in terms of generalisation across biogeographical regions. A new macroinvertebrate trait-based index, Flow-T, derived from ecological functional information (flow velocity preferences) currently available for almost 500 invertebrate taxa at the European scale is presented. The index was tested using data from rivers spanning different biogeographic and hydro-climatic regions from the UK, Cyprus and Italy. The performance of Flow-T at different spatial scales and its relationship with an established UK flow assessment tool, the Lotic-invertebrate Index for Flow Evaluation (LIFE), was assessed to determine the transferability of the approach internationally. Flow-T was strongly correlated with the LIFE index using both presence-absence and abundance weighted data from all study areas (r varying from 0.46 to 0.96). When applied at the river reach scale, Flow-T was effective in identifying communities associated with distinct mesohabitats characterised by their hydraulic characteristics (e.g., pools, riffles, glides). Flow-T can be derived using both presence/absence and abundance data and can be easily adapted to varying taxonomic resolutions. The trait-based approach facilitates research using the entire European invertebrate fauna and can potentially be applied in regions where information on taxa-specific flow velocity preferences is not currently available. The inter-regional and continental scale transferability of Flow-T may help water resource managers gauge the effects of changes in flow regime on instream communities at varying spatial scales.
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Ecossistema , Rios , Animais , Biodiversidade , Mudança Climática , Monitoramento Ambiental , Invertebrados/fisiologiaRESUMO
Globally, excessive fine sediment (particles <2 mm) deposition is acknowledged to have deleterious effects on aquatic biodiversity. However, the impacts are often equivocal possibly reflecting landscape context, although this is rarely considered. To address this, we examined the temporal response of macroinvertebrate taxonomic and functional diversity to experimental fine sediment clogging in a prealpine (Italy) and lowland setting (UK). Colonisation devices were installed insitu with either clean or clogged substrates and examined for short (7-14 days), medium (21-28 days) and long (56-63 days) timescales. Clogging resulted in altered taxonomic community composition in both the lowland and prealpine rivers and modified functional community composition in the prealpine river. Nestedness was consistently found to be the dominant process driving differences in taxonomic composition between the clean and clogged substrates in the prealpine environment, with clogged substrates forming a nested community. No dominant component structured lowland taxonomic communities. Functional community composition was driven by nestedness in both environments but was heavily dominant in the case of the prealpine river, possibly reflecting low functional redundancy. Widely employed community richness metrics (EPT, taxa and functional richness) only displayed a response to fine sediment loading in the prealpine environment but taxa characterized as sensitive to fine sediment as well as some functional feeding groups did exhibit differences in both settings. In the prealpine environment, the effects of fine sediment intensified over time for several community metrics. Although further research is required to corroborate our findings and extend our observations across more rivers and typologies, excessive fine sediment is a pervasive stressor affecting macroinvertebrate communities in prealpine and lowland environments. However, the biodiversity facets that responded to clogging differed between the two landscape settings probably reflecting wider environmental filtering. Monitoring and managing fine sediment loading likely requires context specific approaches to maximise ecological benefits.
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Ecossistema , Invertebrados , Animais , Biodiversidade , Monitoramento Ambiental/métodos , Invertebrados/fisiologia , Itália , Rios/químicaRESUMO
Soil - water pollution resulting from anthropogenic activities is a growing concern internationally. Effective monitoring techniques play a crucial role in the detection, prevention, and remediation of polluted sites. Current pollution monitoring practices in many geographical locations are primarily based on physico-chemical assessments which do not always reflect the potential toxicity of contaminant 'cocktails' and harmful chemicals not screened for routinely. Biomonitoring provides a range of sensitive techniques to characterise the eco-toxicological effects of chemical contamination. The bioavailability of contaminants, in addition to their effects on organisms at the molecular, cellular, individual, and community level allows the characterisation of the overall health status of polluted sites and ecosystems. Quantifying bioaccumulation, changes to community structure, faunal morphology, behavioural, and biochemical responses are standard procedures employed in biomonitoring studies in many High-Income Countries (HICs). This review highlights the need to integrate biomonitoring tools alongside physico-chemical monitoring techniques by using 'effect-based' tools to provide more holistic information on the ecological impairment of soil-water systems. This paper considers the wider implementation of biomonitoring methods in Low to Middle Income Countries (LMICs) and their significance in pollution investigations and proposes an integrated monitoring framework that can identify toxicity drivers by utilising 'effect-based' and 'risk-based' monitoring approaches.
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Ecossistema , Poluentes Químicos da Água , Efeitos Antropogênicos , Monitoramento Biológico , Monitoramento Ambiental , Solo , Poluentes Químicos da Água/análise , Poluição da ÁguaRESUMO
The current erosion of biodiversity is a major concern that threatens the ecological integrity of ecosystems and the ecosystem services they provide. Due to global change, an increasing proportion of river networks are drying and changes from perennial to non-perennial flow regimes represent dramatic ecological shifts with potentially irreversible alterations of community and ecosystem dynamics. However, there is minimal understanding of how biological communities respond functionally to drying. Here, we highlight the taxonomic and functional responses of aquatic macroinvertebrate communities to flow intermittence across river networks from three continents, to test predictions from underlying trait-based conceptual theory. We found a significant breakpoint in the relationship between taxonomic and functional richness, indicating higher functional redundancy at sites with flow intermittence higher than 28%. Multiple strands of evidence, including patterns of alpha and beta diversity and functional group membership, indicated that functional redundancy did not compensate for biodiversity loss associated with increasing intermittence, contrary to received wisdom. A specific set of functional trait modalities, including small body size, short life span and high fecundity, were selected with increasing flow intermittence. These results demonstrate the functional responses of river communities to drying and suggest that on-going biodiversity reduction due to global change in drying river networks is threatening their functional integrity. These results indicate that such patterns might be common in these ecosystems, even where drying is considered a predictable disturbance. This highlights the need for the conservation of natural drying regimes of intermittent rivers to secure their ecological integrity.
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Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.
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A greater understanding and effective management of biological invasions is a priority for biodiversity conservation globally. Many freshwater ecosystems are experiencing the colonization and spread of multiple co-occurrent alien species. Here the implications of both the relative abundance and richness of alien invaders on aquatic macroinvertebrate taxonomic and functional richness, ecosystem quality, and functional redundancy are assessed using long-term data from rivers in England. Based on the most common aquatic invaders, results indicated that their richness, rather than abundance, was the most important factor negatively affecting aquatic macroinvertebrate biodiversity. However, the response of functional redundancy was negatively affected by invader abundance at the river basin scale. The response of communities varied as the number of invading taxa increased, with the most marked reductions following the colonization of the first few invaders. Results indicate that different facets of multiple biological invasions influence distinct aspects of aquatic biodiversity. Preventing the establishment of new invaders and limiting invader taxa richness within a community should therefore be a conservation priority. These findings will assist river scientists in understanding mechanisms driving changes in biodiversity and facilitate the testing of ecological theories while also ensuring environmental managers and regulators can prioritize conservation / management opportunities.
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Ecossistema , Rios , Animais , Biodiversidade , Espécies Introduzidas , InvertebradosRESUMO
The use of pesticides has historically helped improve agricultural productivity, although their continued use may have unforeseen effects upon the natural environment when not applied appropriately. Metaldehyde is a commercial pesticide widely used to reduce crop losses resulting from terrestrial mollusc damage. However, following precipitation and runoff it frequently enters waterbodies with largely unknown consequences for aquatic fauna. This study represents one of the first attempts to examine its potential effects on aquatic macroinvertebrate communities at sites known to have experienced elevated metaldehyde concentrations alongside unaffected control sites. In addition, a series of laboratory exposures specifically examined the effects of metaldehyde on the survivorship of non-target aquatic mollusc species. When the entire aquatic macroinvertebrate community and aquatic mollusc community were considered, limited differences were observed between metaldehyde affected and control sites based on field data. Laboratory exposures highlighted that for the molluscs examined, gastropods (Bithynia tentaculata, Planorbis planorbis, Radix balthica and Potamopyrgus antipodarum) had a greater tolerance to metaldehyde than bivalves (Sphaerium corneum and Corbicula fluminea). However, the concentrations required to reduce survivorship of all species were much greater than those ever recorded historically under field conditions. The results suggest that the differences in the community composition recorded between sites exposed to elevated metaldehyde concentrations and control sites were probably due to nutrient loading (N and P from agricultural fertilizers) rather than metaldehyde. However, these results do not negate wider concerns regarding metaldehyde use, particularly issues caused when ingested by vertebrate wildlife, livestock or children and pets in domestic settings.
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Praguicidas , Poluentes Químicos da Água/análise , Acetaldeído/análogos & derivados , Agricultura , Animais , Criança , HumanosRESUMO
River impoundment constitutes one of the most important anthropogenic impacts on the World's rivers. An increasing number of studies have tried to quantify the effects of river impoundment on riverine ecosystems over the past two decades, often focusing on the effects of individual large reservoirs. This study is one of the first to use a large-scale, multi-year diatom dataset from a routine biomonitoring network to analyse sample sites downstream of a large number of water supply reservoirs (n = 77) and to compare them with paired unregulated control sites. We analysed benthic diatom assemblage structure and a set of derived indices, including ecological guilds, in tandem with multiple spatio-temporal variables to disclose patterns of ecological responses to reservoirs beyond the site-specific scale. Diatom assemblage structure at sites downstream of water supply reservoirs was significantly different to control sites, with the effect being most evident at the regional scale. We found that regional influences were important drivers of differences in assemblage structure at the national scale, although this effect was weaker at downstream sites, indicating the homogenising effect of river impoundment on diatom assemblages. Sites downstream of reservoirs typically exhibited a higher taxonomic richness, with the strongest increases found within the motile guild. In addition, Trophic Diatom Index (TDI) values were typically higher at downstream sites. Water quality gradients appeared to be an important driver of diatom assemblages, but the influence of other abiotic factors could not be ruled out and should be investigated further. Our results demonstrate the value of diatom assemblage data from national-scale biomonitoring networks to detect the effects of water supply reservoirs on instream communities at large spatial scales. This information may assist water resource managers with the future implementation of mitigation measures such as setting environmental flow targets.
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Freshwater ecosystems face many threats in the form of reduced water quantity, poor water quality and the loss of biodiversity. As a result, aquatic biomonitoring tools are required to enable the evaluation of these critical changes. Currently, macroinvertebrate-based indices are globally the most widely used biomonitoring tools in fluvial ecosystems. However, very little is known about the potential effects of changes in taxonomic understanding (updating of classification and nomenclature) or the presence of new non-native species for biotic indices calculation. This is especially relevant given that errors, incorrect classification or exclusion of new/updated nomenclature may affect ecological status evaluations and have direct consequences for the management and conservation of freshwater systems. In this discussion paper the main constraints, challenges and implications of these issues are outlined and case studies from a range of European countries are discussed. However, similar challenges affect rivers and managers globally and will potentially be amplified further in the future. Bioassessment science needs to be open to improvements, and current tools and protocols need to be flexible so that they can be updated and revised rapidly to allow new scientific developments to be integrated. This discussion highlights specific examples and new ideas that may contribute to the future development of aquatic biomonitoring using macroinvertebrates and other faunal and floral groups in riverine ecosystems.
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Biodiversidade , Monitoramento Ambiental/métodos , Espécies Introduzidas , Invertebrados , Rios , Animais , Organismos Aquáticos/classificação , Ecossistema , Europa (Continente) , Invertebrados/classificaçãoRESUMO
River impoundment by the construction of dams potentially modifies a wide range of abiotic and biotic factors in lotic ecosystems and is considered one of the most significant anthropogenic impacts on rivers globally. The past two decades have witnessed a growing body of research centred on quantifying the effects of river impoundment, with a focus on mitigating and managing the effects of individual large dams. This study presents a novel multi-scale comparison of paired downstream and control sites associated with multiple water supply reservoirs (nâ¯=â¯80) using a spatially extensive multi-year dataset. Macroinvertebrate community structure and indices were analysed in direct association with spatial (e.g. region) and temporal variables (e.g. season) to identify consistent patterns in ecological responses to impoundment. Macroinvertebrate communities at monitoring sites downstream of water supply reservoirs differed significantly from those at control sites at larger spatial scales, both in terms of community structure and taxa richness. The effect was most significant at the regional scale, while biogeographical factors appeared to be important drivers of community differences at the national scale. Water supply reservoirs dampened natural seasonal patterns in community structure at sites downstream of impoundments. Generally, taxonomic richness was higher and %EPT richness lower at downstream sites. Biomonitoring indices used for river management purposes were able to detect community differences, demonstrating their sensitivity to river regulation activities. The results presented improve our understanding of the spatially extensive and long-term effects of water supply reservoirs on instream communities and provide a basis for the future implementation of mitigation measures on impounded rivers and heavily modified waterbodies.
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Biota , Monitoramento Ambiental , Invertebrados/fisiologia , Movimentos da Água , Abastecimento de Água , Animais , Inglaterra , Rios , Estações do AnoRESUMO
PURPOSE: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. METHODS: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. RESULTS: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. CONCLUSION: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.
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Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias/tratamento farmacológico , Panobinostat/administração & dosagem , Acetilação , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Western Blotting , Neoplasias do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Citometria de Fluxo , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/sangue , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Neoplasias/sangue , Panobinostat/efeitos adversos , Panobinostat/sangueRESUMO
There is growing recognition of the essential services provided to humanity by functionally intact ecosystems. Freshwater ecosystems are found throughout agricultural and urban landscapes and provide a wide range of ecosystem services, but globally they are also amongst the most vulnerable. In particular, ponds (lentic waters typically less than 2 ha), provide natural flood management, sequester carbon and hold significant cultural value. However, to inform their management it is important to understand (1) how functional diversity varies in response to disturbance and (2) the link between biodiversity conservation and ecosystem function. In this study, a meta-analysis of seven separate pond studies from across England and Wales was carried out to explore the effect of urban and agricultural land-use gradients, shading, emergent vegetation, surface area and pH upon groups of functionally similar members of the macroinvertebrate fauna. Functional effect groups were first identified by carrying out a hierarchical cluster analysis using body size, voltinism and feeding habits (18 categories) that are closely related to biogeochemical processes (e.g. nutrient and carbon recycling). Secondly, the influence of the gradients upon effect group membership (functional redundancy-FR) and the breadth of traits available to aid ecosystem recovery (response diversity) was assessed using species counts and functional dispersion (FDis) using 12 response traits. The effect of land-use gradients was unpredictable, whilst there was a negative response in both FR and FDis to shading and positive responses to increases in emergent vegetation cover and surface area. An inconsistent association between FDis and FR suggested that arguments for taxonomic biodiversity conservation to augment ecosystem functioning are too simplistic. Thus, a deeper understanding of the response of functional diversity to disturbance could have greater impact with decision-makers who may relate better to the loss of ecosystem function in response to environmental degradation than species loss alone.
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Biodiversidade , Água Doce , Agricultura , Animais , Mudança Climática , Inglaterra , Recuperação e Remediação Ambiental , Lagoas , País de GalesRESUMO
Intermittent rivers comprise a significant proportion of river networks globally and their spatial extent is predicted to increase with rising water abstraction pressures. Despite this, the ecological implications of hydrological modifications within intermittent rivers have received limited research attention. This paper examines macroinvertebrate assemblages across intermittent and perennial sections of headwater streams within the Hampshire Avon catchment (United Kingdom) over a five-year period. The composition of faunal assemblages was quantified in relation to four hydrological metrics: the duration of flowing conditions, the geographical proximity to the nearest perennial source along each watercourse (two observed flow parameters) and two modelled groundwater abstraction influences. The results highlight that macroinvertebrate communities inhabiting sites which dry periodically and are positioned at greater distances (>c. 2.5km) above the perennial source (the most upstream point of permanent flow within a given year) possessed the highest conservation values. These sites supported species that are rare in many areas of Europe (e.g. Ephemeroptera: Paraletophlebia werneri) or with limited geographical distribution across the United Kingdom (e.g. Trichoptera: Limnephilus bipunctatus). A range of faunal community diversity indices were found to be more sensitive to the antecedent flow duration and distance from the perennial source, rather than any effects of groundwater abstraction. Taxonomic richness responded most strongly to these observed flow parameters and varied more markedly with the distance from the perennial source compared to the antecedent flow duration. Several taxa were significantly associated with the observed flow parameters, particularly those predominantly inhabiting perennially flowing systems. However, the distance that such fauna could migrate into intermittent reaches varied between taxa. This research demonstrates the overriding importance of antecedent flow durations and the geographical proximity to perennial sources on macroinvertebrate communities within intermittent and perennial headwater streams.
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Monitoramento Ambiental , Água Subterrânea/química , Invertebrados/fisiologia , Movimentos da Água , Animais , Ecossistema , Hidrologia , Rios , Reino UnidoRESUMO
Deposition of fine sediment that fills interstitial spaces in streambed substrates is widely acknowledged to have significant negative effects on macroinvertebrate communities, but the temporal consistency of clogging effects is less well known. In this study the effects of experimentally enhanced fine sediment content on aquatic invertebrates were examined over 126days in two lowland UK streams. Taxonomic approaches indicated significant differences in macroinvertebrate community structure associated with sediment treatment (clean or sedimented substrates), although the effects were variable on some occasions. The degree of separation between clean and sedimented communities was strong within seven of the nine sampling periods with significant differences in community composition being evident. EPT taxa and taxon characterised as sensitive to fine sediment demonstrated strong responses to enhanced fine sediment loading. Faunal traits also detected the effects of enhanced fine sediment loading but the results were not as consistent or marked. More widely, the study highlights the temporal dynamics of sedimentation effects upon macroinvertebrate communities and the need to consider faunal life histories when examining the effects of fine sediment loading pressures on lotic ecosystems.