Overview of Cancer Stem Cells (CSCs) and Mechanisms of Their Regulation: Implications for Cancer Therapy.

Overview of Cancer Stem Cells (CSCs) and Mechanisms of Their Regulation: Implications for Cancer Therapy.

Curr Protoc Pharmacol. 2013 Jun; Chapter 14: Unit14.25
Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH

The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression, since they appear to be involved in cell migration, invasion, metastasis, and treatment resistance-all of which lead to poor clinical outcomes. The identification of CSC-specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provide a novel opportunity for cancer research. This overview describes the potential implications of several common CSC markers in the identification of CSC subpopulations that are restricted to common malignant diseases, e.g., leukemia, and breast, prostate, pancreatic, and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics.Curr. Protoc. Pharmacol. 61:14.25.1-14.25.14 © 2013 by John Wiley & Sons, Inc. HubMed – drug


Predicting Drug-Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures.

Curr Protoc Pharmacol. 2013 Jun; Chapter 10: Unit10.16
Townsend C, Brown BS

Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single-cell, tissue, and whole-animal level, including for example the well-established action potential to the more recent beat-to-beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans. Curr. Protoc. Pharmacol. 61:10.16.1-10.16.19 © 2013 by John Wiley & Sons, Inc. HubMed – drug


Patterns of Brain Structural Changes in First-Contact, Antipsychotic Drug-Naive Patients with Schizophrenia.

AJNR Am J Neuroradiol. 2013 Jun 6;
Filippi M, Canu E, Gasparotti R, Agosta F, Valsecchi P, Lodoli G, Galluzzo A, Comi G, Sacchetti E

BACKGROUND AND PURPOSE:Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naïve patients with schizophrenia.MATERIALS AND METHODS:A total of 43 first-contact, drug-naïve, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms.RESULTS:Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico-cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms.CONCLUSIONS:First-contact, drug-naïve, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia. HubMed – drug


Estimating conditional probabilities for the detection of unfavorable copy number alterations in targeted therapy.

IEEE Trans Biomed Eng. 2013 Jun 5;
Hsu FH, Dougherty E, Chen Y, Serpedin E

Emerging targeted therapies have shown benefits such as less toxicity and higher effectiveness in specific types of cancer treatment; however, the accessibility of these advantages may rely on correct identification of suitable patients, which remains highly immature. We assume that copy number profiles, being accessible genomic data via microarray techniques, can provide useful information regarding drug response and shed light on personalized therapy. Based on the mechanism of action (MOA) of trastuzumab in the HER2 signaling pathway, a Bayesian network model in which copy number alterations (CNAs) serve as latent parents modifying signal transduction is applied. Two model parameters, M-score and R-value, which stand for the qualitative and quantitative effects of CNAs on drug effectiveness and are functions of conditional probabilities (CPs), are defined. An expectation-maximization (EM) algorithm is developed for estimating CPs, M-scores, and R-values from continuous measures, such as microarray data. We show through simulations that the EM algorithm can outperform classical threshold-based methods in the estimation of CPs and thereby provide improved performance for the detection of unfavorable CNAs. Several candidates of unfavorable CNAs to the trastuzumab therapy in breast cancer are provided in a real data example. HubMed – drug