Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies.

Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared with their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues.

Resolution of Cellular Heterogeneity in Human Prostate Cancers: Implications for Diagnosis and Treatment.

Prostate cancers have a justified reputation as one of the most heterogeneous human tumours. Indeed, there are some who consider that advanced and castration-resistant prostate cancers are incurable, as a direct result of this heterogeneity. However, tumour heterogeneity can be defined in different ways.

Efficacy and Cardiotoxic Safety Profile of Raltitrexed in Fluoropyrimidines-Pretreated or High-Risk Cardiac Patients With GI Malignancies: Large Single-Center Experience.

Background: Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from raltitrexed-based therapy.

Patients And Methods: Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving raltitrexed were included in this analysis.

Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity.

Methylation at the 5 position of cytosine in DNA (5meC) is a key epigenetic mark in eukaryotes. Once introduced, 5meC can be maintained through DNA replication by the activity of 'maintenance' DNA methyltransferases (DNMTs). Despite their ancient origin, DNA methylation pathways differ widely across animals, such that 5meC is either confined to transcribed genes or lost altogether in several lineages.

Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers.

Radiation therapy is a major primary treatment option for both localized early stage prostate cancer, and for advanced, regionally un-resectable, cancer. However, around 30% of patients still experience biochemical recurrence after radiation therapy within 10 years. Thus, identification of better biomarkers and new targets are urgently required to improve current therapeutic strategies.

Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia.

Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming.

Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors.

Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition.

Telomerase Activity and Telomere Length in Human Benign Prostatic Hyperplasia Stem-like Cells and Their Progeny Implies the Existence of Distinct Basal and Luminal Cell Lineages.

Unlabelled: Benign prostatic hyperplasia (BPH) treatments have changed little over many years and do not directly address the underlying cause. Because BPH is characterised by uncontrolled cell growth, the chromosomal telomeres should be eroded in the reported absence or low levels of telomerase activity, but this is not observed. We investigated the telomere biology of cell subpopulations from BPH patients undergoing transurethral resection of prostate (TURP).

Construction of therapeutically relevant human prostate epithelial fate map by utilising miRNA and mRNA microarray expression data.

Background: Objective identification of key miRNAs from transcriptomic data is difficult owing to the inherent inconsistencies within miRNA target-prediction algorithms and the promiscuous nature of miRNA-mRNA target relationship.

Methods: An integrated database of miRNAs and their 'relevant' mRNA targets was generated from validated miRNA and mRNA microarray data sets generated from patient-derived prostate epithelial normal and cancer stem-like cells (SCs) and committed basal (CB) cells. The effect of miR-542-5p inhibition was studied to provide proof-of-principle for database utility.

CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations.

Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target.

Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy.

Androgen deprivation therapy induces apoptosis or cell cycle arrest in prostate cancer (PCa) cells. Here we set out to analyze whether MCL1, a known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin.

Bio-inspired surfactants capable of generating plant volatiles.

Plants are able to synthesize, store and release lipophilic organic molecules known as plant volatiles (PVs) utilizing specific biological pathways and different enzymes which play vital roles in the plant's defence and in dealing with biotic and abiotic stress situations. The process of generation, storage and release of PVs by plants acquired during the course of evolution is a very complex phenomenon. Bio-inspired molecular design of farnesol-based surfactants facilitates similar production, storage and release of PVs.

Asphaltene-laden interfaces form soft glassy layers in contraction experiments: a mechanism for coalescence blocking.

In previous studies, the adsorption kinetics of asphaltenes at the water-oil interface were interpreted utilizing a Langmuir equation of state (EOS) based on droplet expansion experiments.1-3 Long-term adsorption kinetics followed random sequential adsorption (RSA) theory predictions, asymptotically reaching ∼85% limiting surface coverage, which is similar to limiting random 2D close packing of disks. To extend this work beyond this slow adsorption process, we performed rapid contractions and contraction-expansions of asphaltene-laden interfaces using the pendant drop experiment to emulate a Langmuir trough.

MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets.

Unlabelled: MicroRNA (miRNA) expression profiles were generated from prostate epithelial subpopulations enriched from patient-derived benign prostatic hyperplasia (n=5), Gleason 7 treatment-naive prostate cancer (PCa) (n=5), and castration-resistant PCa (CRPC) (n=3). Microarray expression was validated in an independent patient cohort (n=10). Principal component analysis showed that miRNA expression is clustered by epithelial cell phenotype, regardless of pathologic status.

Long-term adsorption kinetics of asphaltenes at the oil-water interface: a random sequential adsorption perspective.

Previous studies indicated that asphaltenes adsorbed as monomers on oil-water interfaces and the early stage kinetics of the process was controlled by diffusion and hence dependent on oil viscosity. By measuring interfacial tension (IFT) as a function of surface coverage during droplet expansions in pendant drop experiments, it was also concluded that the IFT data could be interpreted with a Langmuir equation of state (EoS), which was independent of oil viscosity, time of adsorption, and bulk asphaltenes concentration. The surface excess coverage was calculated to be ∼0.

Conserved two-step regulatory mechanism of human epithelial differentiation.

Human epithelia are organized in a hierarchical structure, where stem cells generate terminally differentiated cells via intermediate progenitors. This two-step differentiation process is conserved in all tissues, but it is not known whether a common gene set contributes to its regulation. Here, we show that retinoic acid (RA) regulates early human prostate epithelial differentiation by activating a tightly coexpressed set of 80 genes (e.

Interfacial rheology of asphaltenes at oil-water interfaces and interpretation of the equation of state.

In an earlier study, oil-water interfacial tension was measured by the pendant drop technique for a range of oil-phase asphaltene concentrations and viscosities. The interfacial tension was found to be related to the relative surface coverage during droplet expansion. The relationship was independent of aging time and bulk asphaltenes concentration, suggesting that cross-linking did not occur at the interface and that only asphaltene monomers were adsorbed.

Advanced prostate cancer--a case for adjuvant differentiation therapy.

The development of novel therapies such as abiraterone acetate and sipuleucel-T has improved the outlook for patients with advanced-stage and castration-resistant prostate cancer. However, the beneficial effects of these drugs are only measured in months. Moreover, the National Institute for Health and Clinical Excellence in the UK had ruled that the use of abiraterone acetate was not cost-effective before cost revision by the manufacturers.

Adsorption kinetics of asphaltenes at the oil-water interface and nanoaggregation in the bulk.

Asphaltenes constitute high molecular weight constituents of crude oils that are insoluble in n-heptane and soluble in toluene. They contribute to the stabilization of the water-in-oil emulsions formed during crude oil recovery and hinder drop-drop coalescence. As a result, asphaltenes unfavorably impact water-oil separation processes and consequently oil production rates.