ORCID Profile
0000-0001-6847-4980
Current Organisations
Central Queensland University
,
Genome Institute of Singapore
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Quaternary Environments | Ecological Impacts of Climate Change | Physical Geography and Environmental Geoscience | Isotope Geochemistry
Expanding Knowledge in the Earth Sciences | Effects of Climate Change and Variability on Australia (excl. Social Impacts) | Climate Variability (excl. Social Impacts) |
Publisher: Springer Science and Business Media LLC
Date: 28-08-2007
DOI: 10.1007/S00442-007-0832-X
Abstract: The stable isotope composition of spines produced serially from the apex of columnar cacti has the potential to be used as a record of changes in climate and physiology. To investigate this potential, we measured the delta(18)O, delta(13)C and F(14)C values of spines from a long-lived columnar cactus, saguaro (Carnegiea gigantea). To determine plant age, we collected spines at 11 different heights along one rib from the stem apex (3.77 m height) to the base of a naturally occurring saguaro. Fractions of modern carbon (F(14)C) ranged from 0.9679 to 1.5537, which is consistent with ages between 1950 and 2004. We observed a very strong positive correlation (r = 0.997) between the F(14)C age of spines and the age of spines determined from direct and repeated height measurements taken on this in idual over the past 37 years. A series of 96 spines collected from this in idual had delta(18)O values ranging from 38 per thousand to 50 per thousand [Vienna standard mean ocean water (VSMOW)] and delta(13)C values from -11.5 per thousand to -8.5 per thousand [Vienna Peedee belemnite (VPDB)]. The delta(18)O and delta(13)C values of spines were positively correlated (r = 0.45, P < 0.0001) and showed near-annual oscillations over the approximately 15-year record. This pattern suggests that seasonal periods of reduced evaporative demand or greater precipitation input may correspond to increased daytime CO(2) uptake. The lowest delta(18)O and delta(13)C values of spines observed occurred during the 1983 and 1993 El Niño years, suggesting that the stable isotope composition recorded in spine tissue may serve as a proxy for these climate events. We compared empirical models and data from potted experimental cacti to validate these observations and test our hypotheses. The isotopic records presented here are the first ever reported from a chronosequence of cactus spines and demonstrate that tissues of columnar cacti, and potentially other long-lived succulents, may contain a record of past physiological and climatic variation.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1007/S00442-016-3761-8
Abstract: Several previous studies have investigated the use of the stable hydrogen and oxygen isotope compositions in plant materials as indicators of palaeoclimate. However, accurate interpretation relies on a detailed understanding of both physiological and environmental drivers of the variations in isotopic enrichments that occur in leaf water and associated organic compounds. To progress this aim we measured δ
Publisher: Springer Science and Business Media LLC
Date: 06-08-2011
DOI: 10.1007/S00442-011-2021-1
Abstract: Crassulacean acid metabolism (CAM) and the capacity to store large quantities of water are thought to confer high water use efficiency (WUE) and survival of succulent plants in warm desert environments. Yet the highly variable precipitation, temperature and humidity conditions in these environments likely have unique impacts on underlying processes regulating photosynthetic gas exchange and WUE, limiting our ability to predict growth and survival responses of desert CAM plants to climate change. We monitored net CO(2) assimilation (A(net)), stomatal conductance (g(s)), and transpiration (E) rates periodically over 2 years in a natural population of the giant columnar cactus Carnegiea gigantea (saguaro) near Tucson, Arizona USA to investigate environmental and physiological controls over carbon gain and water loss in this ecologically important plant. We hypothesized that seasonal changes in daily integrated water use efficiency (WUE(day)) in this constitutive CAM species would be driven largely by stomatal regulation of nighttime transpiration and CO(2) uptake responding to shifts in nighttime air temperature and humidity. The lowest WUE(day) occurred during time periods with extreme high and low air vapor pressure deficit (D(a)). The diurnal with the highest D(a) had low WUE(day) due to minimal net carbon gain across the 24 h period. Low WUE(day) was also observed under conditions of low D(a) however, it was due to significant transpiration losses. Gas exchange measurements on potted saguaro plants exposed to experimental changes in D(a) confirmed the relationship between D(a) and g(s). Our results suggest that climatic changes involving shifts in air temperature and humidity will have large impacts on the water and carbon economy of the giant saguaro and potentially other succulent CAM plants of warm desert environments.
Publisher: Elsevier BV
Date: 04-1970
Publisher: Missouri Botanical Garden Press
Date: 28-09-2009
DOI: 10.3417/2008019
Publisher: American Society for Clinical Investigation
Date: 04-05-2020
DOI: 10.1172/JCI126726
Publisher: Elsevier BV
Date: 06-2015
Publisher: MDPI AG
Date: 29-11-2019
DOI: 10.3390/JMSE7120434
Abstract: Maintenance dredging for shipping channels is required to maintain safe and efficient navigational channels and berths in ports around the world. Sediment that refills dredged channels can enter ports via alluvial transport of eroded materials from upstream and adjacent catchments, from marine transport due to tidal currents and wind driven currents and from longshore drift. Identifying the provenance of sediment infilling navigational channels allows port operators to mitigate and manage sediment transport, potentially reducing dredging requirements and costs. Further, understanding sediment sources can inform options for beneficial reuse or disposal of dredged sediments. A multi-faceted approach was used to assess whether sediment provenance in the Port of Gladstone could be characterized. A combination of particle size analysis, rare earth element composition, carbon stable isotope ratios, strontium isotopes, and beryllium-7 radioisotopes was employed. S les were collected at accumulation locations within the navigational channel. Potential sediment sources were s led from sites of longshore drift to the south of the Port of Gladstone, and intertidal sand and mud representative of transport from currents. Fluvial sediment s les were collected during dry and wet season conditions and from the three main local catchments. Potential source sediment s les yielded identifiable differences with respect to rare earth elements, while beryllium-7 isotope analysis indicated recent deposition of sediments from mudflats or catchment within the channels. The approach used here provided insights into the source of recently deposited sediments to the dredged channels, enabling managers to make informed decisions on mitigation and management strategies.
Publisher: Cold Spring Harbor Laboratory
Date: 09-03-2011
DOI: 10.1261/RNA.2387911
Publisher: Proceedings of the National Academy of Sciences
Date: 25-09-2001
Abstract: Between A.D. 900 and 1150, more than 200,000 conifer trees were used to build the prehistoric great houses of Chaco Canyon, New Mexico, in what is now a treeless landscape. More than one-fifth of these timbers were spruce ( Picea ) or fir ( Abies ) that were hand-carried from isolated mountaintops 75–100 km away. Because strontium from local dust, water, and underlying bedrock is incorporated by trees, specific logging sites can be identified by comparing 87 Sr/ 86 Sr ratios in construction beams from different ruins and building periods to ratios in living trees from the surrounding mountains. 87 Sr/ 86 Sr ratios show that the beams came from both the Chuska and San Mateo (Mount Taylor) mountains, but not from the San Pedro Mountains, which are equally close. Incorporation of logs from two sources in the same room, great house, and year suggest stockpiling and intercommunity collaboration at Chaco Canyon. The use of trees from both the Chuska and San Mateo mountains, but not from the San Pedro Mountains, as early as A.D. 974 suggests that selection of timber sources was driven more by regional socioeconomic ties than by a simple model of resource depletion with distance and time.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 30-11-2000
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.SCITOTENV.2016.08.096
Abstract: Dendroclimatology can be used to better understand past climate in regions such as Australia where instrumental and historical climate records are sparse and rarely extend beyond 100years. Here we review 36 Australian dendroclimatic studies which cover the four major climate zones of Australia temperate, arid, subtropical and tropical. We show that all of these zones contain tree and shrub species which have the potential to provide high quality records of past climate. Despite this potential only four dendroclimatic reconstructions have been published for Australia, one from each of the climate zones: A 3592year temperature record for the SE-temperate zone, a 350year rainfall record for the Western arid zone, a 140year rainfall record for the northern tropics and a 146year rainfall record for SE-subtropics. We report on the spatial distribution of tree-ring studies, the environmental variables identified as limiting tree growth in each study, and identify the key challenges in using tree-ring records for climate reconstruction in Australia. We show that many Australian species have yet to be tested for dendroclimatological potential, and that the application of newer techniques including isotopic analysis, carbon dating, wood density measurements, and anatomical analysis, combined with traditional ring-width measurements should enable more species in each of the climate zones to be used, and long-term climate records to be developed across the entire continent.
Publisher: Wiley
Date: 25-04-2006
DOI: 10.1111/J.1469-8137.2006.01732.X
Abstract: The influences of prior monsoon-season drought (PMSD) and the seasonal timing of episodic rainfall ('pulses') on carbon and water exchange in water-limited ecosystems are poorly quantified. *In the present study, we estimated net ecosystem exchange of CO(2) (NEE) and evapotranspiration (ET) before, and for 15 d following, experimental irrigation in a semi-arid grassland during June and August 2003. Rainout shelters near Tucson, Arizona, USA, were positioned on contrasting soils (clay and sand) and planted with native (Heteropogon contortus) or non-native invasive (Eragrostis lehmanniana) C4 bunchgrasses. Plots received increased ('wet') or decreased ('dry') monsoon-season (July-September) rainfall during 2002 and 2003. Following a June 2003 39-mm pulse, species treatments had similar NEE and ET dynamics including 15-d integrated NEE (NEE(pulse)). Contrary to predictions, PMSD increased net C uptake during June in plots of both species. Greater flux rates after an August 2003 39-mm pulse reflected biotic activity associated with the North American Monsoon. Furthermore, August NEE(pulse) and ecosystem pulse-use efficiency (PUE(e) = NEE(pulse)/ET(pulse)) was greatest in Heteropogon plots. PMSD and rainfall seasonal timing may interact with bunchgrass invasions to alter NEE and ET dynamics with consequences for PUE(e) in water-limited ecosystems.
Publisher: Oxford University Press (OUP)
Date: 2015
Publisher: American Geophysical Union (AGU)
Date: 06-05-2010
DOI: 10.1029/2009JG001008
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2022
DOI: 10.1200/PO.22.00278
Abstract: HER2-altered non–small-cell lung cancer (NSCLC) represents a erse subgroup, including mutations, lifications, and overexpression. However, HER2 exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of HER2-altered NSCLC in an Asian tertiary cancer center. We identified patients with HER2-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 ( HER2)–mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. HER2 lification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of HER2 mutations was 3.1%—exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with HER2-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was HER2 Y772_A775dup in 30 (75%), followed by HER2 G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of HER2 exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature—similar to EGFR-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) HER2-mutated tumors resembled EGFR wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with HER2 RNA expression and HER2 lification. The incidence of HER2 mutations is 3.1% in East Asian nonsquamous NSCLC. HER2 exon 20 insertion–mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) HER2 mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of HER2-mutated NSCLC warrant further investigation.
Publisher: Elsevier BV
Date: 12-2003
Publisher: Springer Science and Business Media LLC
Date: 14-10-2003
DOI: 10.1007/S00442-003-1389-Y
Abstract: Physiological activity and structural dynamics in arid and semi-arid ecosystems are driven by discrete inputs or "pulses" of growing season precipitation. Here we describe the short-term dynamics of ecosystem physiology in experimental stands of native (Heteropogon contortus) and invasive (Eragrostis lehmanniana) grasses to an irrigation pulse across two geomorphic surfaces with distinctly different soils: a Pleistocene-aged surface with high clay content in a strongly horizonated soil, and a Holocene-aged surface with low clay content in homogenously structured soils. We evaluated whole-ecosystem and leaf-level CO2 and H2O exchange, soil CO2 efflux, along with plant and soil water status to understand potential constraints on whole-ecosystem carbon exchange during the initiation of the summer monsoon season. Prior to the irrigation pulse, both invasive and native grasses had less negative pre-dawn water potentials (Psipd), greater leaf photosynthetic rates (Anet) and stomatal conductance (gs), and greater rates of net ecosystem carbon exchange (NEE) on the Pleistocene surface than on the Holocene. Twenty-four hours following the experimental application of a 39 mm irrigation pulse, soil CO2 efflux increased leading to all plots losing CO2 to the atmosphere over the course of a day. Invasive species stands had greater evapotranspiration rates (ET) immediately following the precipitation pulse than did native stands, while maximum instantaneous NEE increased for both species and surfaces at roughly the same rate. The differential ET patterns through time were correlated with an earlier decline in NEE in the invasive species as compared to the native species plots. Plots with invasive species accumulated between 5% and 33% of the carbon that plots with the native species accumulated over the 15-day pulse period. Taken together, these results indicate that system CO2 efflux (both the physical displacement of soil CO2 by water along with plant and microbial respiration) strongly controls whole-ecosystem carbon exchange during precipitation pulses. Since CO2 and H2O loss to the atmosphere was partially driven by species effects on soil microclimate, understanding the mechanistic relationships between the soil characteristics, plant ecophysiological responses, and canopy structural dynamics will be important for understanding the effects of shifting precipitation and vegetation patterns in semi-arid environments.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.20.00261
Abstract: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the In idualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. In idualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2005
DOI: 10.1007/S00442-005-0078-4
Abstract: Plant metabolic activity in arid and semi-arid environments is largely tied to episodic precipitation events or "pulses". The ability of plants to take up and utilize rain pulses during the growing season in these water-limited ecosystems is determined in part by pulse timing, intensity and amount, and by hydrological properties of the soil that translate precipitation into plant-available soil moisture. We assessed the sensitivity of an invasive woody plant, velvet mesquite (Prosopis velutina Woot.), to large (35 mm) and small (10 mm) isotopically labeled irrigation pulses on two contrasting soil textures (sandy-loam vs. loamy-clay) in semi-desert grassland in southeastern Arizona, USA. Predawn leaf water potential (psi(pd)), the isotopic abundance of deuterium in stem water (deltaD), the abundance of 13C in soluble leaf sugar (delta13C), and percent volumetric soil water content (theta(v)) were measured prior to irrigation and repeatedly for 2 weeks following irrigation. Plant water potential and the percent of pulse water present in the stem xylem indicated that although mesquite trees on both coarse- and fine-textured soils quickly responded to the large irrigation pulse, the magnitude and duration of this response substantially differed between soil textures. After reaching a maximum 4 days after the irrigation, the fraction of pulse water in stem xylem decreased more rapidly on the loamy-clay soil than the sandy-loam soil. Similarly, on both soil textures mesquite significantly responded to the 10-mm pulse. However, the magnitude of this response was substantially greater for mesquite on the sandy-loam soil compared to loamy-clay soil. The relationship between psi(pd) and delta13C of leaf-soluble carbohydrates over the pulse period did not differ between plants at the two sites, indicating that differences in photosynthetic response of mesquite trees to the moisture pulses was a function of soil water availability within the rooting zone rather than differences in plant biochemical or physiological constraints. Patterns of resource acquisition by mesquite during the dynamic wetting-drying cycle following rainfall pulses is controlled by a complex interaction between pulse size and soil hydraulic properties. A better understanding of how this interaction affects plant water availability and photosynthetic response is needed to predict how grassland structure and function will respond to climate change.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2012
DOI: 10.1038/NATURE11252
Publisher: Elsevier BV
Date: 10-2005
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.EJCA.2022.10.012
Abstract: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. 455 patients were included (267 EGFR-mutated, EGFR-M+ 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2012
Publisher: Elsevier BV
Date: 08-2000
Publisher: Wiley
Date: 23-03-2016
DOI: 10.1111/PCE.12703
Abstract: Leaf water contains naturally occurring stable isotopes of oxygen and hydrogen in abundances that vary spatially and temporally. When sufficiently understood, these can be harnessed for a wide range of applications. Here, we review the current state of knowledge of stable isotope enrichment of leaf water, and its relevance for isotopic signals incorporated into plant organic matter and atmospheric gases. Models describing evaporative enrichment of leaf water have become increasingly complex over time, reflecting enhanced spatial and temporal resolution. We recommend that practitioners choose a model with a level of complexity suited to their application, and provide guidance. At the same time, there exists some lingering uncertainty about the biophysical processes relevant to patterns of isotopic enrichment in leaf water. An important goal for future research is to link observed variations in isotopic composition to specific anatomical and physiological features of leaves that reflect differences in hydraulic design. New measurement techniques are developing rapidly, enabling determinations of both transpired and leaf water δ(18) O and δ(2) H to be made more easily and at higher temporal resolution than previously possible. We expect these technological advances to spur new developments in our understanding of patterns of stable isotope fractionation in leaf water.
Publisher: CSIRO Publishing
Date: 02-09-2020
DOI: 10.1071/ES19034
Abstract: It is well known that severe storms result in some of the costliest natural disasters for New South Wales (NSW), Australia. However, it is not widely acknowledged that some of these events are, in fact, a result of landfalling tropical cyclones (TCs). Indeed, the intense focus of TC research within the tropics generally disregards landfalling TC events in the mid-latitude regions of Australia. This is likely due to the perceived infrequency of these events compared to other more susceptible regions. Therefore, in this study, we review this assumption by developing a 150-year record of TC activity, based on a range of digitised and analogue historical datasets and identify 30 in idual landfalling TCs that have impacted NSW. Periods of enhanced and reduced TC activity are observed, with a defined hiatus (absence of landfalling TCs) after approximately 1980. The recent decrease in TC activity is subsequently linked to an increase in El Niño activity and warming of north-west Australian sea-surface temperatures during this time. Importantly, it is possible that a return to enhanced TC activity could occur again in the future if the Pacific conditions align. We also propose that pre-instrumental data on TC activity need to be developed to appropriately quantify TC risk for the study region via the development of local palaeoclimate archives. This study provides a significant contribution to understanding the risks of NSW landfalling TCs and expands upon our knowledge of environmental conditions that influence landfalling TCs in NSW.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2021
DOI: 10.1158/1078-0432.CCR-20-4607
Abstract: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M−) disease. Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M− tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M− tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M− and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2010
Publisher: Springer Science and Business Media LLC
Date: 18-09-2017
DOI: 10.1038/NM.4401
Abstract: Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.
Publisher: Elsevier BV
Date: 10-2005
Publisher: Public Library of Science (PLoS)
Date: 21-01-2010
Publisher: Wiley
Date: 11-2018
DOI: 10.1002/ECS2.2498
Publisher: Wiley
Date: 23-03-2023
DOI: 10.1002/JQS.3514
Abstract: Our understanding of land‐based cool season temperature variability over the past millennium is limited by the relative lack of annually resolved temperature proxies, especially in the Southern Hemisphere. Here, we develop the first earlywood (EW) and latewood (LW) width chronologies from Australia based on the Tasmanian endemic conifer Athrotaxis s elaginoides in the far southeast of Australia. We also develop total ring width (RW), EW and LW chronologies from a new site in the far south. We compare the climate responses of RW, EW and adjusted LW chronologies of three A. selagnoides sites near the southern extent of the species with three sites of the species near the northern extent of the species. RW and EW at the southern sites are strongly and positively related to cool season temperature (July–October), but in the north, RW and EW are more strongly and positively related with summer (December–February) temperatures. Once adjusted for the influence of the same growing season EW, LW in the north is very strongly negatively correlated with January–February temperatures across southeastern Australia. The new southern RW and EW chronologies can be used to extend one of only two annually resolved regional cool season temperature reconstructions in the Southern Hemisphere back a further 180 years.
Publisher: American Association for Cancer Research (AACR)
Date: 05-02-2021
DOI: 10.1158/0008-5472.CAN-20-2352
Abstract: This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Cold Spring Harbor Laboratory
Date: 08-11-2019
DOI: 10.1101/835512
Abstract: Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumorigenesis yet challenging to decipher from tumor transcriptomes. Here, we report an unbiased, data-driven approach to deconvolute bulk tumor transcriptomes and predict crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. Our approach recovers known transcriptional hallmarks of cancer and stromal cells and is concordant with single-cell and immunohistochemistry data, underlining its robustness. Pan-cancer analysis reveals previously unrecognized features of cancer-stromal crosstalk. We find that autocrine cancer cell cross-talk varied between tissues but often converged on known cancer signaling pathways. In contrast, many stromal cross-talk interactions were highly conserved across tumor types. Interestingly, the immune checkpoint ligand PD-L1 was overexpressed in stromal rather than cancer cells across all tumor types. Moreover, we predicted and experimentally validated aberrant ligand and receptor expression in cancer cells of basal and luminal breast cancer, respectively. Collectively, our findings validate a data-driven method for tumor transcriptome deconvolution and establishes a new resource for hypothesis generation and downstream functional interrogation of the TME in tumorigenesis and disease progression.
Publisher: Elsevier BV
Date: 06-2005
Publisher: Wiley
Date: 05-03-2023
DOI: 10.1002/JOC.8032
Abstract: East coast cyclones (ECCs) provide an essential reprieve from dry periods across eastern Australia. They also deliver flood‐producing rains with significant economic, social and environmental impacts. Assessing and comparing the influence of different types of cyclones is hindered by an incomplete understanding of ECC typology, given their widely variable spatial and temporal characteristics. This study employs a track‐clustering method (probabilistic, curve‐aligned regression model) to identify key cyclonic pathways for ECCs from 1950 to 2019. Six spatially independent clusters were successfully distinguished and further sub‐classified (coastal, continental and tropical) based on their genesis location. The seasonality and long‐term variability, intensity (maximum Laplacian value ± 2 days) and event‐based rainfall were then evaluated for each cluster to quantify the impact of these lows on Australia. The highest quantity of land‐based rainfall per event is associated with the tropical cluster (Cluster 6), whereas widespread rainfall was also found to occur in the two continental clusters (clusters 4 and 5). Cyclone tracks orientated close to the coast (clusters 1, 2 and 3) were determined to be the least impactful in terms of rainfall and intensity, despite being the most common cyclone type. In terms of interannual variability, sea surface temperature anomalies suggest an increased cyclone frequency for clusters 1 (austral winter) and 4 (austral spring) during a central Pacific El Niño. Furthermore, cyclone incidence during IOD‐negative conditions was more pronounced in winter for clusters 1, 2, 3— and clusters 4 and 5 in spring. All cyclones also predominantly occurred in SAM‐positive conditions. However, winter ECCs for clusters 1 and 3 had a higher frequency in SAM‐negative. This new typology of ECCs via spatial clustering provides crucial insights into the systems that produce extreme rainfall across eastern Australia and should be used to inform future hazard management of cyclone events.
Publisher: Springer Science and Business Media LLC
Date: 05-2013
DOI: 10.1038/NATURE12113
Publisher: American Society for Clinical Investigation
Date: 07-2022
DOI: 10.1172/JCI145099
Publisher: Elsevier BV
Date: 07-2010
Publisher: Wiley
Date: 12-09-2021
DOI: 10.1111/NPH.16864
Location: United States of America
Start Date: 2013
End Date: 12-2019
Amount: $373,679.00
Funder: Australian Research Council
View Funded Activity