Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects.

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors.

Interobserver Reliability of the Animal Welfare Indicators Welfare Assessment Protocol for Horses.

Objective tools for the assessment of animal welfare are needed. The present study analyzed the interobserver reliability of the Animal Welfare Indicators (AWIN) welfare assessment protocol for horses to further enhance knowledge concerning reliability. Therefore, two trained observers conducted 18 assessments on farm at the same time and on the same animals.

An Indication of Reliability of the Two-Level Approach of the AWIN Welfare Assessment Protocol for Horses.

To enhance feasibility, the Animal Welfare Indicators (AWIN) assessment protocol for horses consists of two levels: the first is a visual inspection of a sample of horses performed from a distance, the second a close-up inspection of all horses. The aim was to analyse whether information would be lost if only the first level were performed. In this study, 112 first and 112 second level assessments carried out on a subsequent day by one observer were compared by calculating the Spearman's Rank Correlation Coefficient (RS), Intraclass Correlation Coefficients (ICC), Smallest Detectable Changes (SDC) and Limits of Agreements (LoA).

Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness.

Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion.

Allelic heterogeneity of Crooked Tail Syndrome: result of balancing selection?

We report the identification of a second loss-of-function mutation (c.1906T>C) in the bovine MRC2 gene causing the Crooked Tail Syndrome in Belgian Blue Cattle. We demonstrate that the ensuing substitution of the highly conserved Cysteine 636 with Arginine causes illegitimate receptor oligomerization, which is predicted to impair function of the MRC2 encoded protein, Endo180.

The 'alternative' EMT switch.

Epithelial to mesenchymal transition (EMT) is an essential process in embryonic development and is aberrantly induced in many disease settings. Work carried out by Chonghui Cheng's laboratory addressed the involvement of alternative RNA splicing in EMT and its link to tumour progression. They describe a switch in CD44 expression from variant isoform(s) to the standard isoform and showed, for the first time, that this is required for normal epithelial cells to undergo EMT.

CD44v6 dependence of premetastatic niche preparation by exosomes.

The metastasizing capacity of the rat pancreatic adenocarcinoma BSp73ASML (ASML(wt)) is strikingly reduced by a knockdown of CD44v4-v7 (ASML(kd)). We used this model to analyze the role of the CD44 variant isoform (CD44v) in (pre)metastatic niche formation. Intrafootpad injections of ASML(wt)-, but not ASML(kd)-conditioned medium (CM), strongly promote settlement of ASML(kd) cells in lymph nodes and lung.

CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification.

Overexpression and alternative splicing of CD44 have been implicated in tumour progression. Here we describe the identification of a high level amplification of human 11p13, encompassing the CD44 gene, in primary breast cancers and cell lines and test whether CD44 acts as the driver of this amplicon. aCGH analysis revealed 11p13 amplification in 3% (3/100) of primary breast carcinomas and in two cell lines.

CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance.

CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v(kd)) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML(wt)) were established.

CD44 and EpCAM: cancer-initiating cell markers.

Embryonic stem cells are immortal, can self renew, and differentiate into all cells of the body. The adult organism maintains adult stem cells in regenerative organs that can differentiate into all cells of the respective organ. Virchow's hypothesis that cancer may arise from embryonic-like cells has received strong support, as it was demonstrated that tumors contain few cells, known as cancer stem or cancer-initiating cells (CIC), that account for primary and metastatic tumor growth.

A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression.

High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex.

The need for new SI-traceable magnesium isotopic reference materials.

Recent measurements revealed that commercial magnesium standard solutions showed isotopic abundance variations, which cannot clearly be distinguished from each other by calibrating against the only available isotopic reference material, SRM 980, or reference materials made from SRM 980 like IRMM-009. Therefore new SI-traceable magnesium isotopic reference materials are required.

CD44 variant isoforms associate with tetraspanins and EpCAM.

The metastasizing subline of the rat pancreatic adenocarcinoma BSp73 expresses a set of membrane molecules, the combination of which has not been detected on non-metastasizing tumor lines. Hence, it became of interest whether these molecules function independently or may associate and exert specialized functions as membrane complexes. Separation of CD44v4-v7 containing membrane complexes in mild detergent revealed an association with the alpha3 integrin, annexin I, EpCAM, and the tetraspanins D6.

Comparison of urinary monitoring, faecal monitoring and erythrocyte analysis of stable isotope labels to determine magnesium absorption in human subjects.

We have evaluated urinary monitoring and erythrocyte analysis to determine Mg absorption in human subjects as alternatives to the conventional technique of faecal monitoring by stable-isotope techniques. Ten healthy adults received 2.2 mmol (25)Mg in water, together with wheat bread, followed 15 min later by intravenous injection of 0.

Xenopus marginal coil (Xmc), a novel FGF inducible cytosolic coiled-coil protein regulating gastrulation movements.

Gastrulation in vertebrates is a highly dynamic process driven by convergent extension movements of internal mesodermal cells, under the regulatory activity of the Spemann-Mangold or gastrula organizer. In a large-scale screen for genes expressed in the organizer, we have isolated a novel gene, termed Xmc, an acronym for Xenopus marginal coil. Xmc encodes a protein containing two widely spaced evolutionarily non-conserved coiled coils.

Contribution of ICP-IDMS to the certification of antimony implanted in a silicon wafer--comparison with RBS and INAA results.

A thin-layer reference material for surface and near-surface analytical methods was produced and certified. The surface density of the implanted Sb layer was determined by Rutherford backscattering spectrometry (RBS), instrumental neutron activation analysis (INAA), and inductively coupled plasma isotope dilution mass spectrometry (ICP-IDMS) equipped with a multi-collector. The isotopic abundances of Sb (121Sb and 123Sb) were determined by multi-collector ICP-MS and INAA.

Comparative studies on the certification of reference materials by ICPMS and TIMS using isotope dilution procedures.

A comparison of different isotope dilution mass spectrometric (IDMS) procedures using inductively coupled plasma mass spectrometry (ICPMS) and thermal ionization mass spectrometry (TIMS) was carried out to examine the degree of equivalence between the used procedures in terms of requirements for reference material certification. The comparison was based on the measurement results and their uncertainties. The sample used in this study is a pure zinc metal to be certified by the Bureau Communie de Référence (BCR) for amount contents of different trace elements.

Xwig1, a novel putative endoplasmic reticulum protein expressed during epithelial morphogenesis and in response to embryonic wounding.

In a subtractive differential screening, we identified a novel gene with interesting characteristics, termed Xenopus wounding induced gene 1 (Xwig1). Xwig1 encodes a novel protein of 912 amino acids containing 13 putative transmembrane segments and an evolutionarily conserved carboxy-terminal domain. Protein localization studies revealed that Xwig1 is anchored in cytoplasmic structures, presumably the endoplasmic reticulum.

Xgravin-like (Xgl), a novel putative a-kinase anchoring protein (AKAP) expressed during embryonic development in Xenopus.

A-kinase anchoring proteins (AKAPs) are a heterogeneous family of scaffolding proteins that regulate the compartmentalization of signaling components, in particular that of the broad specificity kinase PKA. Here we describe the identification of a new member of this gene family, termed Xenopus gravin-like (Xgl), which encodes a highly acidic protein of 268 kDa that shares extensive homology with human Gravin and murine SSeCKS. Xgl is zygotically expressed in a highly dynamic fashion.

[The saccharin test in the pediatric broncho-pneumonologic outpatient clinic. A noninvasive screening method for the assessment of ciliary function of the respiratory tract in children].

The Saccharin test is a non-dangerous, inexpensive, suitable and repeatable method for assessing the mucociliary function of the respiratory epithelium. A small quantity of Saccharin (R) is deposited on the inferior nasal concha; the chemical agent will be transported by the respiratory epithelium (kinocilia) from the nasopharynx to the oropharynx and can be tasted here as "sweet". The time interval between the deposition of Saccharin and the "sweet" taste is the "nasal mucociliary transport time (nmctt)"; data in minutes.