Min Ru Qiu

Bio: Min Ru Qiu is an academic researcher from St. Vincent's Health System. The author has contributed to research in topics: Cancer & Transplantation. The author has an hindex of 15, co-authored 27 publications receiving 1339 citations. Previous affiliations of Min Ru Qiu include Garvan Institute of Medical Research & University of New South Wales.

PI3K pathway activation in breast cancer is associated with the basal‐like phenotype and cancer‐specific mortality

Abstract: Breast cancer is a common malignancy with current biological therapies tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may contribute to therapeutic resistance. We undertook an integrative study of mutational, copy number and expression analyses of key regulators of the PI3K pathway in a cohort of 292 invasive breast cancer patients with known treatment outcomes. The alterations identified in this cohort included PIK3CA mutations (12/168, i.e. 7%), PIK3CA copy number gain (28/209, i.e. 14%), PTEN loss (73/258, i.e. 28%) and AKT activation (62/258, i.e. 24%). Overall at least 1 parameter was altered in 72% (139/193) of primary breast cancers. PI3K pathway activation was significantly associated with ER negative (p = 0.0008) and PR negative (p = 0.006) status, high tumor grade (p = 0.032) and a "basal-like" phenotype (p = 0.01), where 92% (25/27) of tumors had an altered pathway. In univariate analysis, PI3K pathway aberrations were associated with death from breast cancer; however, this relationship was not maintained in multivariate analysis. No association was identified between an activated pathway and outcome in tamoxifen- or chemotherapy-treated patients. We concluded that >70% of breast cancers have an alteration in at least 1 component of the PI3K pathway and this might be exploited to therapeutic advantage especially in "basal-like" cancers.

Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Abstract: Hedgehog (Hh) signaling plays an important role in several malignancies but its clinical significance in breast cancer is unclear. In a cohort of 279 patients with invasive ductal carcinoma of the breast, expression of Hh ligand was significantly associated with increased risk of metastasis, breast cancer-specific death, and a basal-like phenotype. A paracrine signature, encompassing high epithelial Hh ligand and high stromal Gli1, was an independent predictor for overall survival in multivariate analysis. In 2 independent histological progression series (n = 301), Hh expression increased with atypia. Hh ligand overexpression in a mouse model of basal breast cancer increased growth, induced a poorly differentiated phenotype, accelerated metastasis, and reduced survival. A stromal requirement for these effects was supported by the lack of similar Hh-mediated changes in vitro, and by stromal-specific expression of Hh target genes in vivo. Furthermore, inhibition of Hh ligand with a monoclonal antibody (5E1) inhibited tumor growth and metastasis. These data suggest that epithelial-stromal Hh signaling, driven by ligand expression in carcinoma cells, promotes breast cancer growth and metastasis. Blockade of Hh signaling to peritumoral stromal cells may represent a novel therapeutic approach in some basal-like breast cancers.

The nuclear chloride ion channel NCC27 is involved in regulation of the cell cycle.

Abstract: 1NCC27 is a nuclear chloride ion channel, identified in the PMA-activated U937 human monocyte cell line. NCC27 mRNA is expressed in virtually all cells and tissues and the gene encoding NCC27 is also highly conserved. Because of these factors, we have examined the hypothesis that NCC27 is involved in cell cycle regulation. 2Electrophysiological studies in Chinese hamster ovary (CHO-K1) cells indicated that NCC27 chloride conductance varied according to the stage of the cell cycle, being expressed only on the plasma membrane of cells in G2/M phase. 3We also demonstrate that Cl− ion channel blockers known to block NCC27 led to arrest of CHO-K1 cells in the G2/M stage of the cell cycle, the same stage at which this ion channel is selectively expressed on the plasma membrane. 4These data strongly support the hypothesis that NCC27 is involved, in some as yet undetermined manner, in regulation of the cell cycle.

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development

Abstract: Objective To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. Methods Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. Results Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. Conclusions The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Patient-derived xenograft models: an emerging platform for translational cancer research.

Abstract: Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. Significance: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field. Cancer Discov; 4(9); 998–1013. ©2014 AACR .

Quantitative reactivity profiling predicts functional cysteines in proteomes

Abstract: Cysteine is the most intrinsically nucleophilic amino acid in proteins, where its reactivity is tuned to perform diverse biochemical functions The absence of a consensus sequence that defines functional cysteines in proteins has hindered their discovery and characterization Here we describe a proteomics method to profile quantitatively the intrinsic reactivity of cysteine residues en masse directly in native biological systems Hyper-reactivity was a rare feature among cysteines and it was found to specify a wide range of activities, including nucleophilic and reductive catalysis and sites of oxidative modification Hyper-reactive cysteines were identified in several proteins of uncharacterized function, including a residue conserved across eukaryotic phylogeny that we show is required for yeast viability and is involved in iron-sulphur protein biogenesis We also demonstrate that quantitative reactivity profiling can form the basis for screening and functional assignment of cysteines in computationally designed proteins, where it discriminated catalytically active from inactive cysteine hydrolase designs

Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system.

Abstract: Most cells contain high levels of glutathione and multiple glutaredoxins, which utilize the reducing power of glutathione to catalyze disulfide reductions in the presence of NADPH and glutathione reductase (the glutaredoxin system). Glutaredoxins, like thioredoxins, may operate as dithiol reductants and are involved as alternative pathways in cellular functions such as formation of deoxyribonucleotides for DNA synthesis (by reducing the essential enzyme ribonucleotide reductase), the generation of reduced sulfur (via 3′-phosphoadenylylsulfate reductase), signal transduction, and the defense against oxidative stress. The three dithiol glutaredoxins of E. coli with the active-site sequence CPYC and a glutathione binding site in a thioredoxin/glutaredoxin fold display surprisingly different properties. These include the inducible OxyR-regulated 10-kDa Grx1 or the highly abundant 24-kDa glutathione S-transferase-like Grx2 (with Grx3 it accounts for 1% of total protein). Glutaredoxins uniquely reduce mixed dis...