Biology subjects

McLean, M. A.

Publications and source records attributed to McLean, M. A..

4 recordsLinked to original sources

bioRxiv2021

Sodium accumulation in breast cancer predicts malignancy and treatment response

Breast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive 23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+ concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models. Ex vivo SBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by 1H diffusion-weighted imaging (DWI). Moreover, combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using 23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.

cancer biology↗

bioRxiv2019

PIP2 Influences the Conformational Dynamics of Membrane bound KRAS4b

KRAS4b is a small GTPase involved in cellular signaling through receptor tyrosine kinases. Activation of KRAS4b is achieved through the interaction with nucleotide exchange factors while inactivation is regulated by through interaction with GTPase activating proteins. The activation of KRAS4b only occurs after recruitment of the regulatory proteins to the plasma membrane thus making the role of the phospholipid bilayer an integral part of the activation mechanism. The phospholipids, primarily with anionic head groups, interact with both the membrane anchoring hypervariable region and the G-domain, thus influencing the orientation of KRAS at the membrane surface. The orientation of the G-domain at the membrane surface is believed to play a role in the regulation of KRAS activation. Much of the research has focused on the role of phosphatidyl serine but little has been done regarding the important signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2). We report here the use of fluorescence anisotropy decay, atomic force microscopy, and molecular dynamic simulations to show that the presence of PIP2 in the bilayer promotes the interaction of the G-domain with the bilayer surface. The stability of these interactions significantly alters the dynamics of KRAS4b bound to the membrane indicating a potential role for PIP2 in the regulation of KRAS4b activity.

cancer biology↗

bioRxiv2017

Multi-Parametric and Multi-Regional Histogram Analysis of MRI: Revealing Imaging Phenotypes of Glioblastoma Correlated with Patient Survival

IntroductionGlioblastoma is characterized by its remarkable heterogeneity and dismal prognosis. Histogram analysis of quantitative magnetic resonance imaging (MRI) is an important in vivo method to study intratumoral heterogeneity. With large amounts of histogram features generated, integrating these modalities effectively for clinical decision remains a challenge.\n\nMethodsA total of 80 patients with supratentorial primary glioblastoma were recruited. All patients received surgery and standard regimen of temozolomide chemoradiotherapy. Diagnosis was confirmed by pathology. Anatomical T2-weighted, T1-weighted post-contrast and FLAIR images, as well as dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI) and chemical shift imaging were acquired preoperatively using a 3T MRI scanner. DTI-p, DTI-q, relative cerebral blood volume (rCBV), mean transit time (MTT) and relative cerebral blood flow (rCBF) maps were generated. Contrast-enhancing (CE) and non-enhancing (NE) regions of interest were manually delineated. Voxel intensity histograms were constructed from the CE and NE regions independently. Patient clustering was performed by the Multi-View Biological Data Analysis (MVDA) approach. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the relevance of the patient clustering to survival. The histogram features selected from MVDA approach were evaluated using receiver operator characteristics (ROC) curve analysis. The metabolic signatures of the patient clusters were analyzed by multivoxel MR spectroscopy (MRS).\n\nResultsThe MVDA approach yielded two final patient clusters, consisting of 53 and 27 patients respectively. The two patient subgroups showed significance for overall survival (p = 0.007, HR = 0.32) and progression-free survival (p < 0.001, HR = 0.33) in multivariate Cox regression analysis. Among the features selected by MVDA, higher mean value of DTI-q in the non-enhancing region contributed to a worse OS (HR = 1.40, p = 0.020) and worse PFS (HR = 1.36, p = 0.031). Multivoxel MRS showed N-acetylaspartate/creatine (NAA/Cr) ratio between the two clusters, both in the CE region (p < 0.001) and NE region (p = 0.013). Glutamate/Cr (Glu/Cr) ratio and glutamate + glutamine/Cr (Glx/Cr) of the cluster 1 was significantly lower than cluster 2 (p = 0.037, and 0.027 respectively) In the NE region.\n\nDiscussionThis study demonstrated that integrating multi-parametric and multi-regional MRI histogram features may help to stratify patients. The histogram features selected from the proposed approach may be used as potential imaging markers in personalized treatment strategy and response determination.

bioinformatics↗

bioRxiv2017

Low Perfusion Compartments in Glioblastoma Quantified by Advanced Magnetic Resonance Imaging: Correlation with Patient Survival

BackgroundGlioblastoma exhibits profound intratumoral heterogeneity in blood perfusion, which may cause inconsistent therapy response. Particularly, low perfusion may create hypoxic microenvironment and induce resistant clones. Thus, developing validated imaging approaches that define low perfusion compartments is crucial for clinical management.\n\nMethodsA total of 112 newly-diagnosed supratentorial glioblastoma patients were prospectively recruited for maximal safe resection. Preoperative MRI included anatomical, dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI) and chemical shift imaging (CSI). The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from DTI and DSC respectively. Using thresholding methods, two low perfusion compartments (ADCH-rCBVL and ADCL-rCBVL) were identified. Volumetric analysis was performed. Lactate and macromolecule/lipid levels were determined from multivoxel spectroscopy. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier and multivariate Cox regression analyses.\n\nResultsTwo compartments displayed higher lactate and macromolecule/lipid levels than normal controls (each P < 0.001), suggesting hypoxic and pro-inflammatory microenvironment. The proportional volume of ADCL-rCBVL compartment was associated with a larger infiltration area (P < 0.001, rho = 0.42). Lower lactate in this compartment was associated with a less invasive phenotype visualized on DTI. Multivariate Cox regression showed higher lactate level in the ADCL-rCBVL compartment was associated with a worse survival (PFS: HR 2.995, P = 0.047; OS: HR 4.974, P = 0.005).\n\nConclusionsThe ADCL-rCBVL compartment represent a treatment resistant sub-region associated with glioblastoma invasiveness. This approach was based on clinically available imaging modalities and could thus provide crucial pretreatment information for clinical decision making.

cancer biology↗