ORCID Profile
0000-0003-2289-4837
Current Organisation
UNSW Sydney
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Publisher: Springer Science and Business Media LLC
Date: 11-04-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428153.V1
Abstract: SLC7A11 multivariate survival analysis parameters.
Publisher: Wiley
Date: 24-01-2022
DOI: 10.1111/DOM.14639
Abstract: Sodium glucose co‐transporter‐2 inhibitors (SGLT‐2i) improve cardiorenal outcomes in patients with chronic kidney disease (CKD), with and without type 2 diabetes. The molecular mechanisms underlying these pleiotropic effects remain unclear, yet it is speculated that SGLT‐2i elicit a neurohormonal modulation resulting in renin‐angiotensin system (RAS) activation. We hypothesized that combined SGLT‐2 and angiotensin‐converting enzyme inhibition (ACEi) favours RAS regulation towards the beneficial angiotensin‐(1‐7)‐driven axis. This randomized controlled prospective study investigated the effect of 12 weeks treatment with the SGLT‐2i empagliflozin on top of ACEi on the molecular RAS dynamics in 24 diabetic and 24 non‐diabetic patients with CKD. Systemic RAS peptides were quantified by mass spectrometry. In patients with type 2 diabetes, combined SGLT‐2i and ACEi significantly upregulated plasma renin activity [pre‐treatment median and interquartile range 298.0 (43.0‐672.0) pmol/L versus post‐treatment 577.0 (95.0‐1543.0) pmol/L p = .037] and angiotensin I levels [pre‐treatment 289.0 (42.0‐668.0) pmol/L versus post‐treatment 573.0 (93.0‐1522.0) pmol/L p = .037], together with a significant increase of angiotensin‐(1‐7) levels [pre‐treatment 14.0 (2.1‐19.0) pmol/L versus post‐treatment 32.0 (5.7‐99.0) pmol/L p = .012]. Empagliflozin treatment resulted in a 1.5 to 2‐fold increase in main RAS peptides in patients with diabetes compared with placebo. No significant effect of empagliflozin on top of ACEi on RAS peptides was found in patients with CKD without diabetes. A distinct RAS modulation by SGLT‐2i occurs in diabetic kidney disease reflected by enhancement of the beneficial angiotensin‐(1‐7) providing a molecular background for this renoprotective therapeutic approach.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428156.V1
Abstract: SLC7A11 expression in iCAFs, myCAFs and quiescent PSCs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428159
Abstract: Australian Pancreatic Cancer Genome Initiative International Cancer Genome Cohort patient cohort characteristics.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428156
Abstract: SLC7A11 expression in iCAFs, myCAFs and quiescent PSCs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428168
Abstract: SLC7A11 knockdown in PDAC CAFs does not affect glutamate secretion and is maintained in the presence of oxidative stress.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428165
Abstract: Confirmation of SLC7A11 knockdown in KPC tumour cells and CAFs and collagen fibril analysis in tumour sections at therapeutic model endpoint.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428159.V1
Abstract: Australian Pancreatic Cancer Genome Initiative International Cancer Genome Cohort patient cohort characteristics.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428177
Abstract: Anti-proliferative effect of SLC7A11 knockdown in CAFs and the effect of SLC7A11 inhibition in MiaPaCa-2 PDAC cells and normal human pancreatic ductal epithelial (HPDE) cells.
Publisher: American Association for Cancer Research (AACR)
Date: 12-05-2021
DOI: 10.1158/0008-5472.CAN-20-2496
Abstract: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428177.V1
Abstract: Anti-proliferative effect of SLC7A11 knockdown in CAFs and the effect of SLC7A11 inhibition in MiaPaCa-2 PDAC cells and normal human pancreatic ductal epithelial (HPDE) cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428153
Abstract: SLC7A11 multivariate survival analysis parameters.
Publisher: Wiley
Date: 28-11-2022
Abstract: Nanoparticle drug formulations have many advantages for cancer therapy due to benefits in targeting selectivity, lack of systemic toxicity, and increased drug concentration in the tumor microenvironment after delivery. However, the promise of nanomedicine is limited by preclinical models that fail to accurately assess new drugs before entering human trials. In this work a new approach to testing nanomedicine using a microtumor array formed through hydrogel micropatterning is demonstrated. This technique allows partitioning of heterogeneous cell states within a geometric pattern—where boundary regions of curvature prime the stem cell‐like fraction—allowing to simultaneously probe drug uptake and efficacy in different cancer cell fractions with high reproducibility. Using melanoma cells of different metastatic potential, a relationship between stem fraction and nanoparticle uptake is discovered. Deformation cytometry reveals that the stem cell‐like population exhibits a more mechanically deformable cell membrane. Since the stem fraction in a tumor is implicated in drug resistance, recurrence, and metastasis, the findings suggest that nanoparticle drug formulations are well suited for targeting this dangerous cell population in cancer therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428162
Abstract: List of antibodies
Publisher: MDPI AG
Date: 02-2019
Abstract: The anti-inflammatory properties of high-density lipoproteins (HDL) are lost in uremia. These HDL may show pro-inflammatory features partially as a result of changed protein composition. Alterations of polymorphonuclear leukocytes (PMNLs) in chronic kidney disease (CKD) may contribute to chronic inflammation and high vascular risk. We investigated if HDL from uremic patients is related to systemic inflammation by interfering with PMNL function. PMNL apoptosis was investigated by assessing morphological features and DNA content. CD11b surface expression was quantified by flow cytometry. Oxidative burst was measured via cytochrome c reduction assay. Chemotaxis was assessed by using an under-agarose migration assay. We found that HDL from CKD and hemodialysis (HD) patients significantly attenuated PMNL apoptosis, whereas HDL isolated from healthy subjects had no effect on PMNL apoptosis. The use of signal transduction inhibitors indicated that uremic HDL exerts anti-apoptotic effects by activating pathways involving phosphoinositide 3-kinase and extracellular-signal regulated kinase. Healthy HDL attenuated the surface expression of CD11b, whereas HDL from CKD and HD patients had no effect. All tested isolates increased the stimulation of oxidative burst, but did not affect PMNL chemotactic movement. In conclusion, HDL may contribute to the systemic inflammation in uremic patients by modulating PMNL functions.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428162.V1
Abstract: List of antibodies
Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
DOI: 10.1038/S41598-019-46114-X
Abstract: Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the ‘classical’ and ‘alternative’ RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early ( years), intermediate (2–12 years) or late periods after KTx ( years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels ( P 0.01) and higher levels of Ang I ( P 0.05) and Ang-(1–7) ( P 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group ( P 0.005) likely as a consequence of increased allograft chymase activity ( P 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of ‘alternative RAS’ metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428180
Abstract: Validation of SLC7A11 antibodies and SLC7A11 knockdown in CAFs and PDAC cells in vitro.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512931.V1
Abstract: Abstract Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428180.V1
Abstract: Validation of SLC7A11 antibodies and SLC7A11 knockdown in CAFs and PDAC cells in vitro.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428165.V1
Abstract: Confirmation of SLC7A11 knockdown in KPC tumour cells and CAFs and collagen fibril analysis in tumour sections at therapeutic model endpoint.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428168.V1
Abstract: SLC7A11 knockdown in PDAC CAFs does not affect glutamate secretion and is maintained in the presence of oxidative stress.
No related grants have been discovered for Chantal Kopecky.