ORCID Profile
0000-0001-8069-090X
Current Organisations
University of Newcastle Australia
,
NSW Health Pathology North, John Hunter Hospital
,
Calvary Mater Newcastle
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Publisher: Elsevier BV
Date: 12-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-03-2023
DOI: 10.1126/SCISIGNAL.ABP9586
Abstract: Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML s les. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in s les from patient subtypes with FLT3 mutations. These s les also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.
Publisher: Wiley
Date: 03-10-2023
DOI: 10.1111/IJLH.14180
Publisher: Wiley
Date: 18-07-2021
DOI: 10.1111/IJLH.13657
Abstract: Digital microscopy systems are beginning to replace traditional light microscopes for morphologic analysis of blood films, but these are geographically restricted to in idual computers and technically limited by manufacturer's constraints. We explored the use of a scanner‐agnostic web‐based artificial intelligence (AI) system to assess the accuracy of white blood cell (WBC) differentials and blast identification in haematological malignancies. Digitized images of 20 normal and 124 abnormal peripheral blood films were uploaded to the web‐based platform (Techcyte©) and WBC differentials performed using the online AI software. Digital images were viewed for accuracy and manual cell reassignment was performed where necessary. Results were correlated to the ‘gold standard’ of manual microscopy for each WBC class, and sensitivity and specificity of blast identification were calculated. The AI digital differential was very strongly correlated to microscopy (r .8) for most normal cell types and did not require any manual reassignment. The AI digital differential was less reliable for abnormal blood films (r = .50‐.87), but could be greatly improved by manual assessment of digital images for most cell types (r .95) with the exception of immature granulocytes (r = .62). For blast identification, initial AI digital differentials showed 96% sensitivity and 25% specificity, which was improved to 99% and 84%, respectively, after manual digital review. The Techcyte platform allowed remote viewing and manual analysis of digitized slides that was comparable to microscopy. The AI software produced adequate WBC differentials for normal films and had high sensitivity for blast identification in malignant films.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 07-02-2019
DOI: 10.1111/VOX.12753
Abstract: Transfusion-associated circulatory overload is a leading cause of transfusion-related adverse events. The frequency and risks for transfusion-associated circulatory overload in ambulatory haematology patients are not known. A retrospective cohort analysis of ambulatory patients transfused in a tertiary haematology centre, using medical records and an electronic transfusion database, was undertaken between January and December 2014. Variables studied included age, gender, diagnosis, heart failure, kidney disease and details of transfusions. Transfusion-associated circulatory overload was defined according to proposed International Society of Blood Transfusion criteria. Patients with clinical evidence of hypervolaemia, not meeting the TACO definition and/or who were prescribed otherwise unscheduled diuretic agent, were collectively deemed to be at 'risk of clinically significant hypervolaemia' (ROCSH). In the study period, 93 ambulatory patients (male = 49, female = 44, mean age = 75·89 ± 11·37 years) attended 715 transfusion encounters, totalling 1536 packed red cell units. No cases of TACO occurred whilst 'ROCSH' events occurred in 57/715 (8%) of transfusion encounters. In a univariate model, age was significantly associated with 'ROCSH', odds ratio = 1·05 (P = 0·017 95%, CI 1·01-1·09) and no factors were significant on multivariate analysis. Transfusion-associated circulatory overload occurs infrequently haematology patients receiving ambulatory blood transfusions. To our knowledge, this is the first study to report on occurrence and risk factors for circulatory overload in ambulatory transfusions. This study provides vital baseline data for future prospective studies on this important aspect of haemovigilance.
Publisher: Cold Spring Harbor Laboratory
Date: 25-03-2021
DOI: 10.1101/2021.03.25.436351
Abstract: Global changes in DNA methylation are observed in developmental and disease contexts, and singlecell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of global DNA methylation levels. By targeting high-copy LINE-1 and SINE Alu elements, we achieve licon bisulphite sequencing with thousands of loci covered in each library. Parallel transcriptome analysis is also performed to link global DNA methylation heterogeneity with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Decitabine treatment of KG1a cells induces global DNA methylation heterogeneity associated with altered expression of immune process genes. We also compare global levels of DNA methylation to expression of transposable elements and find a predominance of negative correlations in both the KG1a and patient cells. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.BCMD.2018.11.001
Abstract: Myelodysplasia (MDS) is characterised by abnormal haematopoiesis and increased risk of bleeding. Microvesicles (MV) play a key role in coagulation and their impact in MDS is unknown. Platelet free plasma from 35 red-cell transfusion-dependent MDS patients and 15 controls were analysed. Pro-coagulant function was assessed by the XaCT assay and by thrombin generation (ETP). Total MV were enumerated by nano-tracking analysis. MV subsets were quantified by flow cytometry after staining with specific antibodies for various endovascular cell types. Small RNA was quantitated and sequenced. The MV measurements were correlated with MDS clinical risk scores and level of transfusion dependence. The pro-coagulant function of MV was significantly lower in MDS. All the MV subtypes, as measured by flow cytometric markers, were also significantly lower. The small RNA and miRNA cargo were significantly higher in MDS. The miRNA profile showed that mir-28 and mir-LETD7 were under expressed whilst mir-584J and mir-4485 were over expressed in MV from MDS. Circulating MV in MDS show reduced pro-coagulant functional activity, reduced subtypes by flow cytometry and significantly different miRNA content. However, the levels or subtypes of MV did not predict the clinical phenotype or level of transfusion dependence.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.THROMRES.2017.04.019
Abstract: Characterization of circulating microvesicles (MV) in healthy subjects in relation to various biological factors is not well studied. We evaluated the influence of age, gender, smoking status, lipid and hormone profiles on circulating MV in healthy subjects. Platelet free plasma from 143 volunteer blood donors (males=80, females=63) was evaluated by standardized flow cytometry for MV expressing CD41 (platelet-derived), CD105 (endothelial-derived), CD235 (red cell-derived), TF (tissue factor) and phosphatidylserine (PS) MV. Procoagulant function was measured by the Xa based assay (XaCT) and endogenous thrombin potential (ETP) using thrombin generation assay. Those ≤29years and ≥60years had higher levels of MV subsets (CD41, CD235, TF and PS) compared to those aged 30-59years. The median CD41, CD105, CD235, TF and PS expressing MV by flow cytometry were similar or lower in females, whilst procoagulant activity by the XaCT assay was higher (p=0.002). In smokers (n=21), certain MV subsets (CD41, TF and PS) and functional activity (ETP) was lower (p<0.05). Regression analysis showed that MV parameters of CD41, CD105, TF and ETP could be predicted independently by age, whilst smoking predicted for CD105, CD235, TF, PS and ETP. Certain MV parameters also correlated with BMI, lipid and hormone levels. The small RNA and miRNA levels did not differ by age group, smoking status or gender. It is important to recognize that differences may arise depending on age, gender, BMI, lipid, hormone levels and smoking status in apparently healthy subjects when evaluating MV for pathogenic potential.
Publisher: Informa UK Limited
Date: 04-2018
Publisher: Wiley
Date: 06-2020
DOI: 10.1111/IJLH.13201
Publisher: Informa UK Limited
Date: 13-12-2012
No related grants have been discovered for Anoop Enjeti.