Bringing Greater Accuracy to Europe's Healthcare Systems: The Unexploited Potential of Biomarker Testing in Oncology.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption.

Bringing Onco-Innovation to Europe's Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine.

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions-notably testing in ovarian, breast, pancreatic and prostate cancers.

A European survey on the insights of patients living with metastatic colorectal cancer: the patient journey before, during and after diagnosis - an Eastern European perspective.

Background: Despite being highly preventable and treatable if diagnosed early, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Europe. Limited information is available from the patient perspective on the persisting unmet needs of the journey of the patient with CRC.

Objective: To capture European metastatic CRC (mCRC) patients' insights during the patient journey (prediagnosis; diagnosis; postdiagnosis) through a patient survey.

The Transcription Factor Foxg1 Promotes Optic Fissure Closure in the Mouse by Suppressing Wnt8b in the Nasal Optic Stalk.

During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma.

Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators.

Glioblastoma multiforme (GBM) is an aggressive brain tumor driven by cells with hallmarks of neural stem (NS) cells. GBM stem cells frequently express high levels of the transcription factors FOXG1 and SOX2. Here we show that increased expression of these factors restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative NS cell state.

The molecular and cellular signatures of the mouse eminentia thalami support its role as a signalling centre in the developing forebrain.

The mammalian eminentia thalami (EmT) (or thalamic eminence) is an embryonic forebrain structure of unknown function. Here, we examined the molecular and cellular properties of the mouse EmT. We first studied mRNA expression of signalling molecules and found that the EmT is a structure, rich in expression of secreted factors, with Wnts being the most abundantly detected.

Loss of functional Dicer in mouse radial glia cell-autonomously prolongs cortical neurogenesis.

Radial glia of the mouse cerebral cortex emerge from neuroepithelial stem cells around embryonic day 11 and produce excitatory cortical neurons until a few days before birth. The molecular mechanisms that regulate the end of cortical neurogenesis remain largely unknown. Here we investigated if the Dicer-dependent microRNA (miRNA) pathway is involved.

Foxg1 is required to limit the formation of ciliary margin tissue and Wnt/β-catenin signalling in the developing nasal retina of the mouse.

The ciliary margin (CM) develops in the peripheral retina and gives rise to the iris and the ciliary body. The Wnt/β-catenin signalling pathway has been implicated in ciliary margin development. Here, we tested the hypothesis that in the developing mouse retina Foxg1 is responsible for suppressing the Wnt/β-catenin pathway and restricting CM development.

MicroRNA-92b regulates the development of intermediate cortical progenitors in embryonic mouse brain.

Cerebral cortical neurons arise from radial glia (direct neurogenesis) or from intermediate progenitors (indirect neurogenesis); intriguingly, the sizes of intermediate progenitor populations and the cortices they generate correlate across species. The generation of intermediate progenitors is regulated by the transcription factor Tbr2, whose expression marks these cells. We investigated how this mechanism might be controlled.

Wnt/β-catenin signaling is disrupted in the extra-toes (Gli3(Xt/Xt) ) mutant from early stages of forebrain development, concomitant with anterior neural plate patterning defects.

The zinc finger transcription factor Gli3 is essential for normal development of the forebrain. Mutant mice with no functional Gli3 (extra-toes, Gli3(Xt/Xt) mutants) display a massive reduction in the size of the telencephalic lobes and absence of dorsomedial telencephalic structures, including the cortical hem, which normally expresses a number of Wnt molecules essential for patterning the hippocampus. Dorsomedial telencephalic Wnt activity, transduced through the Wnt/β-catenin signaling pathway, is also required for hippocampal specification and dorsoventral telencephalic patterning.

Loss of Wnt8b has no overt effect on hippocampus development but leads to altered Wnt gene expression levels in dorsomedial telencephalon.

Wnt signalling proteins regulate many aspects of animal development. We have investigated the function of mouse Wnt8b during forebrain development. Wnt8b is expressed in a highly restricted pattern including the prospective hippocampus and hypothalamus.

The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development.

The precise regulation of programmed cell death is critical for the normal development of the nervous system. We show here that DYRK1A (minibrain), a protein kinase essential for normal growth, is a negative regulator of the intrinsic apoptotic pathway in the developing retina. We provide evidence that changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity of inner retina layers and result in severe functional alterations.

Analysis of early ventral telencephalic defects in mice lacking functional Gli3 protein.

The transcription factor Gli3 is expressed throughout developing telencephalon. Previous studies have focused on Gli3's role in dorsal telencephalon, which is greatly reduced in size in Gli3(Xt/Xt) mutants. We examined the effects of loss of Gli3 on early development of ventral telencephalon.

Newly identified patterns of Pax2 expression in the developing mouse forebrain.

Background: The availability of specific markers expressed in different regions of the developing nervous system provides a useful tool for the study of mouse mutants. One such marker, the transcription factor Pax2, is expressed at the midbrain-hindbrain boundary and in the cerebellum, spinal cord, retina, optic stalk, and optic chiasm. We recently described a group of diencephalic cells that express Pax2 as early as embryonic day (E) 10.

Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A).

Background: Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes.

Pax3 regulates Wnt1 expression via a conserved binding site in the 5' proximal promoter.

The development of the neural crest is orchestrated by a complex interplay between intercellular signalling molecules and transcription factors. Here, we demonstrate a direct interaction between two such factors, the paired-type transcription factor Pax3 and the secretory glycoprotein Wnt1. We found that the Wnt1 promoter can be regulated by Pax3 in a dose-dependent manner.

Abnormal positioning of diencephalic cell types in neocortical tissue in the dorsal telencephalon of mice lacking functional Gli3.

The transcription factor Gli3 (glioma-associated oncogene homolog) is essential for normal development of the mammalian forebrain. One extreme requirement for Gli3 is at the dorsomedial telencephalon, which does not form in Gli3(Xt/Xt) mutant mice lacking functional Gli3. In this study, we analyzed expression of Gli3 in the wild-type telencephalon and observed a (high)dorsal-to-(low)ventral gradient of Gli3 expression and predominance of the cleaved form of the Gli3 protein dorsally.

Loss of Gli3 enhances the viability of embryonic telencephalic cells in vitro.

The transcription factor Gli3 is important for brain and limb development. Mice homozygous for a mutation in Gli3 (Gli3Xt/Xt) have severe abnormalities of telencephalic development and previous studies have suggested that aberrant cell death may contribute to the Gli3Xt/Xt phenotype. We demonstrate that telencephalic cells from embryonic Gli3Xt/Xt embryos survive better and are more resistant to death induced by cytosine arabinoside, a nucleoside analogue that induces death in neuronal progenitors and neurons, than are control counterparts in vitro.

Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system.

Dyrk1A and its Drosophila orthologue, the protein minibrain (mnb), belong to a family of serine/threonine kinases involved in the development of the central nervous system (CNS). However, additional roles for Dyrk1A have to be proposed, as its expression is still prominent in the adult brain. To gain insight into Dyrk1A physiological roles we have studied the distribution of this kinase in the CNS of mice in adulthood.

Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice.

DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting.