Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis.

Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration.

Multiclass cancer classification in fresh frozen and formalin-fixed paraffin-embedded tissue by DigiWest multiplex protein analysis.

Histomorphology and immunohistochemistry are the most common ways of cancer classification in routine cancer diagnostics, but often reach their limits in determining the organ origin in metastasis. These cancers of unknown primary, which are mostly adenocarcinomas or squamous cell carcinomas, therefore require more sophisticated methodologies of classification. Here, we report a multiplex protein profiling-based approach for the classification of fresh frozen and formalin-fixed paraffin-embedded (FFPE) cancer tissue samples using the digital western blot technique DigiWest.

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures.

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors.

Regenerative potential of adipocytes in hypertrophic scars is mediated by myofibroblast reprogramming.

Abnormal scarring is a major challenge in modern medicine. The central role of myofibroblasts and TGF-β signaling in scarring is widely accepted, but effective treatment options are missing. Autologous fat grafting is a novel approach that has led to significant improvements in the functionality and appearance of scar tissue.

A spray-coating process for highly conductive silver nanowire networks as the transparent top-electrode for small molecule organic photovoltaics.

We present a novel top-electrode spray-coating process for the solution-based deposition of silver nanowires (AgNWs) onto vacuum-processed small molecule organic electronic solar cells. The process is compatible with organic light emitting diodes (OLEDs) and organic light emitting thin film transistors (OLETs) as well. By modifying commonly synthesized AgNWs with a perfluorinated methacrylate, we are able to disperse these wires in a highly fluorinated solvent.

Color in the corners: ITO-free white OLEDs with angular color stability.

High-efficiency white OLEDs fabricated on silver nanowire-based composite transparent electrodes show almost perfectly Lambertian emission and superior angular color stability, imparted by electrode light scattering. The OLED efficiencies are comparable to those fabricated using indium tin oxide. The transparent electrodes are fully solution-processable, thin-film compatible, and have a figure of merit suitable for large-area devices.

Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines.

Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines.

miR-196 is an essential early-stage regulator of tail regeneration, upstream of key spinal cord patterning events.

Salamanders have the remarkable ability to regenerate many body parts following catastrophic injuries, including a fully functional spinal cord following a tail amputation. The molecular basis for how this process is so exquisitely well-regulated, assuring a faithful replication of missing structures every time, remains poorly understood. Therefore a study of microRNA expression and function during regeneration in the axolotl, Ambystoma mexicanum, was undertaken.

A viral microRNA functions as an orthologue of cellular miR-155.

All metazoan eukaryotes express microRNAs (miRNAs), roughly 22-nucleotide regulatory RNAs that can repress the expression of messenger RNAs bearing complementary sequences. Several DNA viruses also express miRNAs in infected cells, suggesting a role in viral replication and pathogenesis. Although specific viral miRNAs have been shown to autoregulate viral mRNAs or downregulate cellular mRNAs, the function of most viral miRNAs remains unknown.

Genome-wide resources of endoribonuclease-prepared short interfering RNAs for specific loss-of-function studies.

RNA interference (RNAi) has become an important technique for loss-of-gene-function studies in mammalian cells. To achieve reliable results in an RNAi experiment, efficient and specific silencing triggers are required. Here we present genome-wide data sets for the production of endoribonuclease-prepared short interfering RNAs (esiRNAs) for human, mouse and rat.

High-throughput RNA interference strategies for target discovery and validation by using synthetic short interfering RNAs: functional genomics investigations of biological pathways.

During the past five years, RNA interference (RNAi) has emerged as arguably the best functional genomics tool available to date, providing direct, causal links between individual genes and loss-of-function phenotypes through robust, broadly applicable, and readily upscalable methodologies. Originally applied experimentally in C. elegans and Drosophila, RNAi is now widely used in mammalian cell systems also.

Oncology studies using siRNA libraries: the dawn of RNAi-based genomics.

High-throughput, human cell-based applications of RNA-mediated interference (RNAi) have emerged in recent years as perhaps the most powerful of a 'second wave' of functional genomics technologies. The available reagents and methodologies for RNAi screening studies now enable a wide range of different scopes and scales of investigation, from single-parameter assays applied to focused subsets of genes, to comprehensive genome-wide surveys based on rich, multiparameter readouts. As such, RNAi-based screens are offering important new avenues for the discovery and validation of novel therapeutic targets for several disease areas, including oncology.

Vegetable, fruit and meat consumption and potential risk modifying genes in relation to colorectal cancer.

Epidemiological evidence shows high red meat consumption to increase the risk of colorectal cancer, while the consumption of fruit and vegetables has been shown to be protective. Many genes have been identified that encode for enzymes involved in the metabolism of dietary carcinogens or anti-carcinogens. A study of 500 incident colorectal cancer cases and population controls, matched for age, sex and general practitioner, was conducted in the United Kingdom to investigate whether 6 such genes (CYP1A1, GSTT1, GSTM1, GSTP1, EPHX1 and NQO1) modify the relationship between diet and disease risk.

Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism.

Aims: Several single nucleotide polymorphisms (SNPs) of the cytochrome P450 enzyme 1A2 gene (CYP1A2) have been reported. Here, frequencies, linkage disequilibrium and phenotypic consequences of six SNPs are described.

Methods: From genomic DNA, 114 British Caucasians (49 colorectal cancer cases and 65 controls) were genotyped for the CYP1A2 polymorphisms -3858G-->A (allele CYP1A2*1C), -2464T-->delT (CYP1A2*1D), -740T-->G (CYP1A2*1E and *1G), -164A-->C (CYP1A2*1F), 63C-->G (CYP1A2*2), and 1545T-->C (alleles CYP1A2*1B, *1G, *1H and *3), using polymerase chain reaction-restriction fragment length polymorphism assays.

A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer.

Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility.

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment.

Objectives: The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.

Methods: Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission.