ORCID Profile
0000-0001-6202-6861
Current Organisations
University of New South Wales
,
Children's Cancer Institute Australia
,
ETH Zurich
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Publisher: Wiley
Date: 27-11-2017
DOI: 10.1111/NPH.14918
Abstract: In nonagricultural systems, the relationship between intrinsic water-use efficiency (WUE
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2023
DOI: 10.1101/2023.07.19.548825
Abstract: No targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors represent attractive therapeutic candidates, however, beyond rare TK-activating fusions or mutations, predictive biomarkers are lacking. RNA overexpression of TKs is more commonly observed in pediatric sarcomas, however, an unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 sarcoma patients from the ZERO Childhood Cancer precision medicine program using whole genomic and transcriptomic sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were also performed in cell lines and patient-derived xenografts (PDXs). Our integrated analysis shows that although novel genomic driver lesions are rare, they are present and therapeutically actionable in selected patients as exemplified by a novel LSM1-FGFR1 fusion identified in an osteosarcoma patient. We further show that in certain contexts, TK expression data can be used to indicate TK pathway activity and predict TK-inhibitor sensitivity. We exemplify the utility of FGFR-inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) mediated by high FGFR4 and FGF8 RNA expression levels, and overt activation of FGFR4 (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single agent FGF401 (FGFR4-specific inhibitor) and single agent lenvatinib (multi-kinase FGFR-inhibitor). Clinical benefit of lenvatinib in a relapsed metastatic FP-RMS patient further exemplifies that FGFR-inhibitors deserve additional investigation in FP-RMS patients. Our multi-omic interrogation of sarcomas in the ZERO Childhood Cancer program illustrates how an RNA-expression biomarker signature ( FGFR4+/FGF8+ ) in association with FGFR4 activation identifies that PAX3-FOXO1 -positive rhabdomyosarcoma patients could benefit from FGFR-inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2018
DOI: 10.1038/S41559-018-0647-7
Abstract: A substantial body of evidence has demonstrated that bio ersity stabilizes ecosystem functioning over time in grassland ecosystems. However, the relative importance of different facets of bio ersity underlying the ersity-stability relationship remains unclear. Here we use data from 39 grassland bio ersity experiments and structural equation modelling to investigate the roles of species richness, phylogenetic ersity and both the ersity and community-weighted mean of functional traits representing the 'fast-slow' leaf economics spectrum in driving the ersity-stability relationship. We found that high species richness and phylogenetic ersity stabilize biomass production via enhanced asynchrony in the performance of co-occurring species. Contrary to expectations, low phylogenetic ersity enhances ecosystem stability directly, albeit weakly. While the ersity of fast-slow functional traits has a weak effect on ecosystem stability, communities dominated by slow species enhance ecosystem stability by increasing mean biomass production relative to the standard deviation of biomass over time. Our in-depth, integrative assessment of factors influencing the ersity-stability relationship demonstrates a more multicausal relationship than has been previously acknowledged.
Publisher: Informa UK Limited
Date: 14-10-2017
Publisher: Wiley
Date: 19-07-2010
DOI: 10.1002/IJC.25172
Abstract: Gab2, a docking-type signaling protein with demonstrated oncogenic potential, is overexpressed in breast cancer, but its prognostic significance and role in disease evolution remain unclear. Immunohistochemical detection of Gab2 in a large cohort of primary human breast cancers of known outcome revealed that while Gab2 expression was positively correlated with increased tumor grade, it did not correlate with disease recurrence or breast cancer-related death in the total cohort or in patients stratified according to lymph node, estrogen receptor (ER) or HER2 status. Interestingly, analysis of a "progression series" that included premalignant and preinvasive breast lesions as well as s les of metastatic disease revealed that Gab2 expression was significantly enhanced in the earliest lesion examined, usual ductal hyperplasia, with a further increase detected in ductal carcinoma in situ (DCIS). Furthermore, expression was less in invasive cancers and lymph node metastases than in DCIS, but still higher than in normal breast. These findings indicate that while Gab2 expression is not prognostic in breast cancer, its role in early disease evolution warrants further analysis, as Gab2 and its effectors may provide targets for novel strategies aimed at preventing breast cancer development.
Publisher: Wiley
Date: 07-08-2008
Publisher: American Geophysical Union (AGU)
Date: 26-11-2020
DOI: 10.1029/2020GB006561
Abstract: A potential strategy for mitigating nitrous oxide (N 2 O) emissions from permanent grasslands is the partial substitution of fertilizer nitrogen (N fert ) with symbiotically fixed nitrogen (N symb ) from legumes. The input of N symb reduces the energy costs of producing fertilizer and provides a supply of nitrogen (N) for plants that is more synchronous to plant demand than occasional fertilizer applications. Legumes have been promoted as a potential N 2 O mitigation strategy for grasslands, but evidence to support their efficacy is limited, partly due to the difficulty in conducting experiments across the large range of potential combinations of legume proportions and fertilizer N inputs. These experimental constraints can be overcome by biogeochemical models that can vary legume‐fertilizer combinations and subsequently aid the design of targeted experiments. Using two variants each of two biogeochemical models (APSIM and DayCent), we tested the N 2 O mitigation potential and productivity of full factorial combinations of legume proportions and fertilizer rates for five temperate grassland sites across the globe. Both models showed that replacing fertilizer with legumes reduced N 2 O emissions without reducing productivity across a broad range of legume‐fertilizer combinations. Although the models were consistent with the relative changes of N 2 O emissions compared to the baseline scenario (200 kg N ha −1 yr −1 no legumes), they predicted different levels of absolute N 2 O emissions and thus also of absolute N 2 O emission reductions both were greater in DayCent than in APSIM. We recommend confirming these results with experimental studies assessing the effect of clover proportions in the range 30–50% and ≤150 kg N ha −1 yr −1 input as these were identified as best‐bet climate smart agricultural practices.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BBCAN.2014.02.005
Abstract: Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer. However, despite encouraging in vitro and in vivo results, apart from intriguing results of Insulin-like Growth Factor-1 Receptor (IGF-1R) antibodies in ES, clinical studies are limited or disappointing. Primary resistance to RTK inhibitors is frequently observed in OS and ES patients, and even patients that initially respond well eventually develop acquired resistance. There are, however, a few remarks to make concerning the current set-up of clinical trials and about strategies to improve RTK-based treatments in OS and ES. This review provides an overview concerning current RTK-mediated therapies in OS and ES and discusses the problems observed in the clinic. More importantly, we describe several strategies to overcome resistance to RTK inhibitors which may significantly improve outcome of OS and ES patients.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2021
DOI: 10.1038/S41597-021-00851-9
Abstract: A Correction to this paper has been published: 0.1038/s41597-021-00851-9.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.EJCA.2013.04.009
Abstract: To investigate whether F(ab')₂-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')₂-R1507) can successfully target IGF-1R in Ewing sarcomas (ES). BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8) which previously showed heterogeneous or no uptake of indium-111-labelled R1507 IgG ((111)In-R1507), respectively. Mice were injected with (111)In-F(ab')₂-R1507 or (111)In-R1507 as a reference. Biodistribution and immuno-SPECT/computed tomography (CT) imaging studies were carried out 2, 4, 8 and 24 h post-injection (p.i.) for (111)In-F(ab')₂-R1507 and 24 h p.i. for (111)In-R1507. Biodistribution studies showed specific accumulation of (111)In-F(ab')₂-R1507 in EW-5 xenografts from t=2 h p.i. onwards (3.6 ± 0.2%ID/g at t = 24 h p.i.) and (111)In-F(ab')₂-R1507 immuno-SPECT showed almost homogeneous intratumoural distribution at t=24h p.i. Tumour-to-blood ratios of (111)In-F(ab')₂-R1507 were significantly higher than those of (111)In-R1507 at t=24 h p.i. (2.4 ± 0.4 versus 0.5 ± 0.1, respectively p<0.05). More importantly, (111)In-F(ab')₂-R1507 also specifically accumulated in EW-8 tumours (3.7 ± 0.7%ID/g at t = 24 h p.i). In both EW-5 and EW-8 tumours, there was a good spatial correlation between IGF-1R expression and (111)In-F(ab')₂-R1507 tumour distribution. (111)In-F(ab')₂-R1507 fragments can successfully target IGF-1R in ES models and have superior tumour penetrating and IGF-1R-targeting properties as compared to (111)In-R1507. This suggests that anti-IGF-1R therapies in ES and other tumours may be improved by using smaller therapeutic compounds, although further in vivo studies addressing this topic are warranted.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2016
Publisher: Springer Science and Business Media LLC
Date: 11-04-2020
DOI: 10.1007/S00432-020-03211-Z
Abstract: Desmoplastic small round cell tumors (DSRCTs) are highly malignant and very rare soft tissue sarcomas with a high unmet need for new therapeutic options. Therefore, we examined poly(ADP-ribose) polymerase 1 (PARP1) and Schlafen-11 (SLFN11) expression in DSRCT tumor tissue and the combination of PARP inhibitor olaparib with the alkylating agent temozolomide (TMZ) in a preclinical DSRCT model. PARP1 and SLFN11 have been described as predictive biomarkers for response to PARP inhibition. Expression of PARP1 and SLFN11 was assessed in 16 and 12 DSRCT tumor tissue s les, respectively. Effects of single-agent olaparib, and olaparib and TMZ combination treatment were examined using the preclinical JN-DSRCT-1 model. In vitro, single-agent and combination treatment effects on cell viability, the cell cycle, DNA damage and apoptosis were examined. Olaparib and TMZ combination treatment was also assessed in vivo. PARP1 and SLFN11 expression was observed in 100% and 92% of DSRCT tumor tissues, respectively. Olaparib treatment reduced cell viability and cell migration in a dose-dependent manner in vitro. Drug synergy between olaparib and TMZ was observed in vitro and in vivo. Combination treatment led to a cell-cycle arrest and induction of DNA damage and apoptosis, even when combined at low dosages. We show high PARP1 and SLFN11 expression in DSRCT tumor material and antitumor effects following olaparib and TMZ combination treatment in a preclinical DSRCT model. This suggests that olaparib and TMZ combination treatment could be a potential treatment option for DSRCTs.
Publisher: Wiley
Date: 05-05-2014
DOI: 10.1002/IJC.28933
Abstract: Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3'-Deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2020
DOI: 10.1038/S41597-020-0534-3
Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.
Publisher: Wiley
Date: 11-02-2022
DOI: 10.1111/GCB.16060
Abstract: Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km
Publisher: MDPI AG
Date: 20-09-2021
Abstract: Sarcomas are a erse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.
Publisher: Frontiers Media SA
Date: 13-03-2023
DOI: 10.3389/FONC.2023.1013359
Abstract: Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer that predominantly affect the young. Despite aggressive multimodal treatment, survival has not improved significantly over the past four decades. Clinical efficacy has historically been observed for some mono-Receptor Tyrosine Kinase (RTK) inhibitors, albeit in small subsets of OS and ES patients. Clinical efficacy in larger groups of OS or ES patients was reported recently with several newer generation multi-RTK inhibitors. All these inhibitors combine a strong anti-angiogenic (VEGFRs) component with simultaneous inhibition of other key RTKs implicated in OS and ES progression (PDGFR, FGFR, KIT and/or MET). However, despite interesting clinical data, none of these agents have obtained a registration for these indications and are thus difficult to implement in routine OS and ES patient care. It is at present also unclear which of these drugs, with largely overlapping molecular inhibition profiles, would work best for which patient or subtype, and treatment resistance almost uniformly occurs. Here, we provide a critical assessment and systemic comparison on the clinical outcomes to the six most tested drugs in this field in OS and ES to date, including pazopanib, sorafenib, regorafenib, anlotinib, lenvatinib and cabozantinib. We pay special attention to clinical response evaluations in bone sarcomas and provide drug comparisons, including drug-related toxicity, to put these drugs into context for OS and ES patients, and describe how future trials utilizing anti-angiogenic multi-RTK targeted drugs could be designed to ultimately improve response rates and decrease toxicity.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
Publisher: Springer Science and Business Media LLC
Date: 29-01-2016
DOI: 10.1038/NRC.2015.18
Abstract: Over the past decade, rapid advances in genomics, proteomics and functional genomics technologies that enable in-depth interrogation of cancer genomes and proteomes and high-throughput analysis of gene function have enabled characterization of the kinome 'at large' in human cancers, providing crucial insights into how members of the protein kinase superfamily are dysregulated in malignancy, the context-dependent functional role of specific kinases in cancer and how kinome remodelling modulates sensitivity to anticancer drugs. The power of these complementary approaches, and the insights gained from them, form the basis of this Analysis article.
Publisher: Hindawi Limited
Date: 12-05-2022
DOI: 10.1155/2022/3089424
Abstract: Desmoplastic small round cell tumors (DSRCTs), Ewing sarcoma (ES), and alveolar and embryonal rhabdomyosarcoma (ARMS and ERMS) are malignant sarcomas typically occurring at young age, with a poor prognosis in the metastatic setting. New treatment options are necessary. Src family kinase inhibitor dasatinib single-agent treatment has been investigated in a phase 2 study in patients with advanced sarcomas including ES and RMS but failed as a single agent in these subtypes. Since previous studies demonstrated high FAK and Src activities in RMS and ES tissue and cell lines, and dasatinib treatment was shown to upregulate activated FAK, we hypothesized that FAK-Src combination treatment could potentially be an interesting treatment option for these tumor types. We examined the effects of targeting the FAK-Src complex by addressing (p)FAK and (p)Src expressions in tumor sections of DSRCT (n = 13), ES (n = 68), ARMS (n = 21), and ERMS (n = 39) and by determining the antitumor effects of single and combined treatment with FAK inhibitor defactinib and multikinase (Abl/SFK) inhibitor dasatinib in vitro on cell lines of each subtype. In vivo effects were assessed in DSRCT and ERMS models. Concurrent pFAK and pSrc expressions (H-score ) were observed in DSRCT (67%), ES (6%), ARMS (35%), and ERMS (19%) s les. Defactinib treatment decreased pFAK expression and reduced cell viability in all subtypes. Dasatinib treatment decreased pSrc expression and cell viability in each subtype. Combination treatment led to a complete reduction in pFAK and pSrc in each cell line and showed enhanced cell viability reduction, drug synergy, DNA damage induction, and a trend toward higher apoptosis induction in DSRCT, ERMS, and ARMS but not in ES cells. These promising in vitro results unfortunately do not translate into promising in vivo results as we did not observe a significant effect on tumor volume in vivo, and the combination did not show superior effects compared to dasatinib single-agent treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2017
DOI: 10.1158/0008-5472.CAN-17-2056
Abstract: Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18–SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in & non–SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18–SSX family fusion genes are known to alter the composition of the BAF chromatin–remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18–SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18–SSX1 Δ71–78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res 77(24) 7014–26. ©2017 AACR.
Publisher: Walter de Gruyter GmbH
Date: 12-2018
Abstract: Research infrastructures play a key role in launching a new generation of integrated long-term, geographically distributed observation programmes designed to monitor climate change, better understand its impacts on global ecosystems, and evaluate possible mitigation and adaptation strategies. The pan-European Integrated Carbon Observation System combines carbon and greenhouse gas (GHG CO 2 , CH 4 , N 2 O, H 2 O) observations within the atmosphere, terrestrial ecosystems and oceans. High-precision measurements are obtained using standardised methodologies, are centrally processed and openly available in a traceable and verifiable fashion in combination with detailed metadata. The Integrated Carbon Observation System ecosystem station network aims to s le climate and land-cover variability across Europe. In addition to GHG flux measurements, a large set of complementary data (including management practices, vegetation and soil characteristics) is collected to support the interpretation, spatial upscaling and modelling of observed ecosystem carbon and GHG dynamics. The applied s ling design was developed and formulated in protocols by the scientific community, representing a trade-off between an ideal dataset and practical feasibility. The use of open-access, high-quality and multi-level data products by different user communities is crucial for the Integrated Carbon Observation System in order to achieve its scientific potential and societal value.
Publisher: Wiley
Date: 09-2018
DOI: 10.1111/GEB.12764
Publisher: MDPI AG
Date: 30-11-2021
DOI: 10.3390/BIOMEDICINES9121798
Abstract: Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2009
Publisher: Springer Science and Business Media LLC
Date: 02-05-2023
DOI: 10.1038/S41388-023-02705-7
Abstract: Rare but recurrent mutations in the fibroblast growth factor receptor (FGFR) pathways, most commonly in one of the four FGFR receptor tyrosine kinase genes, can potentially be targeted with broad-spectrum multi-kinase or FGFR selective inhibitors. The complete spectrum of these mutations in paediatric cancers is emerging as precision medicine programs perform comprehensive sequencing of in idual tumours. Identification of patients most likely to benefit from FGFR inhibition currently rests on identifying activating FGFR mutations, gene fusions, or gene lification events. However, the expanding use of transcriptome sequencing (RNAseq) has identified that many tumours overexpress FGFRs, in the absence of any genomic aberration. The challenge now presented is to determine when this indicates true FGFR oncogenic activity. Under-appreciated mechanisms of FGFR pathway activation, including alternate FGFR transcript expression and concomitant FGFR and FGF ligand expression, may mark those tumours where FGFR overexpression is indicative of a dependence on FGFR signalling. In this review, we provide a comprehensive and mechanistic overview of FGFR pathway aberrations and their functional consequences in paediatric cancer. We explore how FGFR over expression might be associated with true receptor activation. Further, we discuss the therapeutic implications of these aberrations in the paediatric setting and outline current and emerging therapeutic strategies to treat paediatric patients with FGFR-driven cancers.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2017
Publisher: Wiley
Date: 31-12-2019
DOI: 10.1111/GCB.14904
Abstract: Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to bio ersity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on in idual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.TPLANTS.2018.02.009
Abstract: Biological nitrogen fixation (BNF) by crop legumes reduces demand for industrial nitrogen fixation (INF). Nonetheless, rates of BNF in agriculture remain low, with strong negative feedback to BNF from reactive soil nitrogen (N) and drought. We show that breeding for yield has resulted in strong relationships between photosynthesis and leaf N in non-leguminous crops, whereas grain legumes show strong relations between leaf N and water use efficiency (WUE). We contrast these understandings with other studies that draw attention to the water costs of grain legume crops, and their potential for polluting the biosphere with N. We propose that breeding grain legumes for reduced stomatal conductance can increase WUE without compromising production or BNF. Legume crops remain a better bet than relying on INF.
Publisher: Wiley
Date: 30-08-2009
DOI: 10.1002/RCM.4088
Abstract: Starch and soluble sugars are the major photosynthetic products, and their carbon isotope signatures reflect external versus internal limitations of CO(2) fixation. There has been recent renewed interest in the isotope composition of carbohydrates, mainly for use in CO(2) flux partitioning studies at the ecosystem level. The major obstacle to the use of carbohydrates in such studies has been the lack of an acknowledged method to isolate starch and soluble sugars for isotopic measurements. We here report on the comparison and evaluation of existing methods (acid and enzymatic hydrolysis for starch ion-exchange purification and compound-specific analysis for sugars). The selectivity and reproducibility of the methods were tested using three approaches: (i) an artificial leaf composed of a mixture of isotopically defined compounds, (ii) a C(4) leaf spiked with C(3) starch, and (iii) two natural plant s les (root, leaf). Starch preparation methods based on enzymatic or acid hydrolysis did not yield similar results and exhibited contaminations by non-starch compounds. The specificity of the acidic hydrolysis method was especially low, and we therefore suggest terming these preparations as HCl-hydrolysable carbon, rather than starch. Despite being more specific, enzyme-based methods to isolate starch also need to be further optimized to increase specificity. The analysis of sugars by ion-exchange methods (bulk preparations) was fast but produced more variable isotope compositions than compound-specific methods. Compound-specific approaches did not in all cases correctly reproduce the target values, mainly due to unsatisfactory separation of sugars and background contamination. Our study demonstrates that, despite their wide application, methods for the preparation of starch and soluble sugars for the analysis of carbon isotope composition are not (yet) reliable enough to be routinely applied and further research is urgently needed to resolve the identified problems.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2016
Publisher: Springer Science and Business Media LLC
Date: 02-2018
Publisher: Springer Science and Business Media LLC
Date: 22-09-2021
DOI: 10.1038/S41586-021-03939-9
Abstract: The leaf economics spectrum 1,2 and the global spectrum of plant forms and functions 3 revealed fundamental axes of variation in plant traits, which represent different ecological strategies that are shaped by the evolutionary development of plant species 2 . Ecosystem functions depend on environmental conditions and the traits of species that comprise the ecological communities 4 . However, the axes of variation of ecosystem functions are largely unknown, which limits our understanding of how ecosystems respond as a whole to anthropogenic drivers, climate and environmental variability 4,5 . Here we derive a set of ecosystem functions 6 from a dataset of surface gas exchange measurements across major terrestrial biomes. We find that most of the variability within ecosystem functions (71.8%) is captured by three key axes. The first axis reflects maximum ecosystem productivity and is mostly explained by vegetation structure. The second axis reflects ecosystem water-use strategies and is jointly explained by variation in vegetation height and climate. The third axis, which represents ecosystem carbon-use efficiency, features a gradient related to aridity, and is explained primarily by variation in vegetation structure. We show that two state-of-the-art land surface models reproduce the first and most important axis of ecosystem functions. However, the models tend to simulate more strongly correlated functions than those observed, which limits their ability to accurately predict the full range of responses to environmental changes in carbon, water and energy cycling in terrestrial ecosystems 7,8 .
Publisher: Wiley
Date: 25-02-2013
DOI: 10.1002/IJC.28047
Abstract: Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 s les) and 36 (59 s les) ES patients, respectively. S les included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 μmol/L), NVP-TAE684 (IC50 0.15-0.79 μmol/L) and cabozantinib (IC50 2.69-8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.BBCAN.2021.188613
Abstract: Rapid advances in genomic technologies have enabled in-depth interrogation of cancer genomes, revealing novel and unexpected therapeutic targets in many cancer types. Identifying actionable dependencies in the erse and heterogeneous group of sarcomas, particularly those that occur in children or adolescents and young adults (AYAs), remains especially challenging. These patients rarely harbor actionable genomic aberrations, no targeted agent is approved, and outcomes have remained poor for the past decades. This underlines a clear need to refine our methods for target identification. Phosphoproteomics studies in sarcoma showed the power of such analyses to capture novel actionable drivers that are not accompanied by mutational events or gene lifications. This Review makes the case that incorporating phosphoproteomic molecular profiling alongside (functional) genomics technologies can significantly expand therapeutic target identification, and pinpoint drug mechanisms of action, in pediatric and AYA sarcoma patients. We explore the utility and prospects of phosphoproteomics in personalized medicine.
Publisher: Copernicus GmbH
Date: 28-11-2011
Abstract: Abstract. The terrestrial carbon (C) cycle has received increasing interest over the past few decades, however, there is still a lack of understanding of the fate of newly assimilated C allocated within plants and to the soil, stored within ecosystems and lost to the atmosphere. Stable carbon isotope studies can give novel insights into these issues. In this review we provide an overview of an emerging picture of plant-soil-atmosphere C fluxes, as based on C isotope studies, and identify processes determining related C isotope signatures. The first part of the review focuses on isotopic fractionation processes within plants during and after photosynthesis. The second major part elaborates on plant-internal and plant-rhizosphere C allocation patterns at different time scales (diel, seasonal, interannual), including the speed of C transfer and time lags in the coupling of assimilation and respiration, as well as the magnitude and controls of plant-soil C allocation and respiratory fluxes. Plant responses to changing environmental conditions, the functional relationship between the physiological and phenological status of plants and C transfer, and interactions between C, water and nutrient dynamics are discussed. The role of the C counterflow from the rhizosphere to the aboveground parts of the plants, e.g. via CO2 dissolved in the xylem water or as xylem-transported sugars, is highlighted. The third part is centered around belowground C turnover, focusing especially on above- and belowground litter inputs, soil organic matter formation and turnover, production and loss of dissolved organic C, soil respiration and CO2 fixation by soil microbes. Furthermore, plant controls on microbial communities and activity via exudates and litter production as well as microbial community effects on C mineralization are reviewed. A further part of the paper is dedicated to physical interactions between soil CO2 and the soil matrix, such as CO2 diffusion and dissolution processes within the soil profile. Finally, we highlight state-of-the-art stable isotope methodologies and their latest developments. From the presented evidence we conclude that there exists a tight coupling of physical, chemical and biological processes involved in C cycling and C isotope fluxes in the plant-soil-atmosphere system. Generally, research using information from C isotopes allows an integrated view of the different processes involved. However, complex interactions among the range of processes complicate or currently impede the interpretation of isotopic signals in CO2 or organic compounds at the plant and ecosystem level. This review tries to identify present knowledge gaps in correctly interpreting carbon stable isotope signals in the plant-soil-atmosphere system and how future research approaches could contribute to closing these gaps.
Publisher: Wiley
Date: 21-03-2014
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2550
Abstract: Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were in idually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res 77(16) 4279–92. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1535-7163.MCT-17-1131
Abstract: Targeted therapies have revolutionized cancer treatment however, progress lags behind in alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly occurring at pediatric and young adult age. Insulin-like growth factor 1 receptor (IGF1R)-directed targeted therapy is one of the few single-agent treatments with clinical activity in these diseases. However, clinical effects only occur in a small subset of patients and are often of short duration due to treatment resistance. Rational selection of combination treatments of either multiple targeted therapies or targeted therapies with chemotherapy could hypothetically circumvent treatment resistance mechanisms and enhance clinical efficacy. Simultaneous targeting of distinct mechanisms might be of particular interest in this regard, as this affects multiple hallmarks of cancer at once. To determine the most promising and clinically relevant targeted therapy–based combination treatments for ARMS and ERMS, we provide an extensive overview of preclinical and (early) clinical data concerning a variety of targeted therapy–based combination treatments. We concentrated on the most common classes of targeted therapies investigated in rhabdomyosarcoma to date, including those directed against receptor tyrosine kinases and associated downstream signaling pathways, the Hedgehog signaling pathway, apoptosis pathway, DNA damage response, cell-cycle regulators, oncogenic fusion proteins, and epigenetic modifiers. Mol Cancer Ther 17(7) 1365–80. ©2018 AACR.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2020
Publisher: Proceedings of the National Academy of Sciences
Date: 30-03-2016
Abstract: Leaf traits are used to drive models of global carbon fluxes and understand plant evolution. Many syntheses have highlighted relationships between plant leaf nitrogen and photosynthesis as evidence of a strong evolutionary drive to “intercept light and capture CO 2 .” Different from previous studies, we compiled a global dataset constrained to sites and studies where nitrogen-fixing plants (N 2 FP) and nonfixing species [other plants (OP)] could be directly compared. We show that photosynthesis is not related to leaf nitrogen for N 2 FP, irrespective of climate or growth form. N 2 FP have clear advantages in water use efficiency over OP. These findings contribute to a more complete explanation of global distributions of N 2 FP and can help improve models of global carbon and nitrogen cycles.
Location: United Kingdom of Great Britain and Northern Ireland
Location: Netherlands
No related grants have been discovered for Emmy Fleuren.