Royal Prince Alfred Hospital

About: Royal Prince Alfred Hospital is a healthcare organization based out in Sydney, New South Wales, Australia. It is known for research contribution in the topics: Population & Transplantation. The organization has 7424 authors who have published 14798 publications receiving 550338 citations. The organization is also known as: RPAH & RPA.

ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

Abstract: Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.

Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center.

Abstract: BACKGROUND The current study was performed to determine whether tumor mitotic rate (TMR) is a useful, independent prognostic factor in patients with localized cutaneous melanoma. METHODS From the Sydney Melanoma Unit database, 3661 patients with complete clinical information and details of primary tumor thickness, ulcerative state, and TMR were studied. TMR was expressed as mitoses per mm2 in the dermal part of the tumor in which most mitoses were seen, as recommended in the 1982 revision of the 1972 Sydney classification of malignant melanoma. To determine which was the more prognostically useful method of grouping TMR, two separate methods (A and B) were used. Factors predicting melanoma-specific survival were analyzed using the Cox proportional hazards regression model. RESULTS Patients with a TMR of 0 mitoses/mm2 had a significantly better survival than those with 1 mitosis/mm2 (P < 0.0001) but no significant survival differences were recorded for the stepwise increases from 1–2, 2–3, 3–4, and 4–5/mm2. Tumor thickness, ulceration, and TMR were closely correlated, whether TMR was grouped using Method A (0, 1–4, 5–10, and ≥ 11 mitoses/mm2) or Method B (0–1, 2–4, and ≥ 5 mitoses/mm2). However, Cox regression analysis indicated that the TMR was a highly significant independent prognostic factor, particularly when grouped according to Method A, in which it was second only to tumor thickness as the most powerful predictor of survival (P < 0.0001). CONCLUSIONS TMR is an important independent predictor of survival for melanoma patients. If confirmed by studies from other centers, it has the potential to further improve the accuracy of melanoma staging, as well as to define more rigidly the risk categories for patients entering clinical trials. Cancer 2003;97:1488–98. © 2003 American Cancer Society. DOI 10.1002/cncr.11196

A sensitive test demonstrating lupus anticoagulant and its behavioural patterns

Abstract: The kaolin clotting time of platelet poor plasma was used as a sensitive test for detecting the lupus anticoagulant in mixtures of normal and patients' plasmas. Platelets were found to decrease the anticoagulant effect of a typical lupus inhibitor. Thus, high sensitivity in this test system was achieved by ensuring low platelet concentrations and omitting platelet lipid substitute. In 17 patients with disseminated lupus erythematosus (DLE), 12 had detectable inhibitor by this method, more than would be detected with routine coagulation tests. Mixing patterns were of four distinct types, representing three different modes of anticoagulant behaviour. The pattern (type 3) of plasma mixtures giving longer kaolin clotting times than the individual components could be reproduced in vitro by adding trace amounts of crude thrombin or platelet fragments to a more typical lupus anticoagulant-containing plasma; formation of such a mixing pattern by the plasma of a patient with DLE may therefore indicate activation of the coagulation pathway. Six patients with idopathic thrombocytopenic purpura (ITP) had no detectable inhibitor indicating that anti-platelet antibodies behave differently from the lupus anticoagulant.