Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis.

Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly low proliferation rate of malignant plasma cells, we hypothesize these to similarly express a novel class of inhibitory factors of potential prognostic relevance. Bone morphogenic proteins (BMPs) represent possible candidates as they inhibit proliferation, stimulate bone formation and have an effect on the survival of cancer patients. We assessed the expression of BMPs and their receptors by Affymetrix DNA microarrays (n=779) including CD138-purified primary myeloma cell samples (n=635) of previously untreated patients. BMP6 is the only BMP expressed by malignant and normal plasma cells. Its expression is significantly lower in proliferating myeloma cells, myeloma cell lines or plasmablasts. BMP6 significantly inhibits the proliferation of myeloma cell lines, survival of primary myeloma cells and in vitro angiogenesis. A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy independent of conventional prognostic factors (International Staging System (ISS) stage, beta(2) microglobulin).

A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept study.

Identification of new criteria for embryo quality is required to improve the clinical outcome of in vitro fertilization. The aim of this study was to determine the gene expression profile of cumulus cells (CC) surrounding the oocyte as biomarkers for embryo potential and to identify genes to be used as prognostic indicators of successful pregnancy. CC from single oocytes were analysed using DNA microarrays. Gene expression profiles of CC surrounding the oocyte associated with good embryonic quality and pregnancy outcome were computed. We observed that CC issued from oocytes that developed into embryos with a good morphology had differing gene expression profile according to the pregnancy outcome of the embryo. We demonstrated that the expression of BCL2L11, PCK1 and NFIB in CC is significantly correlated with embryo potential and successful pregnancy. These results were confirmed by quantitative RT-PCR. The gene expression profiling of human CC correlates with embryo potential and pregnancy outcome. BCL2L11, PCK1 and NFIB genes are proposed as biomarkers for predicting pregnancy. Our findings suggest a non-invasive approach, offering a new potential strategy for competent embryo selection. This approach should be validated in single-embryo transfer programmes.

Functional significance of a family of protein kinases encoded at the shaggy locus in Drosophila.

The characterization of the structurally complex gene shaggy is presented. This gene encodes multiple proteins with putative serine/threonine kinase activity thought to be involved in signal transduction mechanisms that take place during several patterning events throughout Drosophila development. The gene comprises two transcription units that give rise to 10 transcripts and five different proteins with a common kinase catalytic domain and overlapping patterns of expression during development. Mutational analysis of shaggy defines a single complementation group, lethality of which is associated with the loss of two major shaggy proteins. These studies allow the first definition of a true null allele. Two proteins may fulfill maternal requirements. Phenotypes of flies expressing individual shaggy proteins revealed that although there is some redundancy between the different forms they do not all carry out identical functions in vivo. However, under experimental conditions, a single form of the protein was able to carry out all known requirements. This protein probably also functions as part of a signal transduction cascade in the imaginal neuroepithelium, where cells have to choose between epidermal and neural fates.

Drosophila shaggy kinase and rat glycogen synthase kinase-3 have conserved activities and act downstream of Notch.

During neurogenesis in Drosophila, groups of equipotential, neurally competent cells choose between epidermal and neural fates. Notch, a phylogenetically conserved transmembrane protein, may act as a receptor in a lateral signalling pathway in which a single neural precursor is chosen from each group and the neural fate of the other cells is inhibited, causing them to differentiate into epidermis. Possible intracellular transduction events mediating signals from Notch are, however, unknown. shaggy is also required for the lateral signal and encodes serine/threonine protein kinases with homology to the glycogen synthase kinase-3 (GSK-3) enzymes that act in signal transduction pathways in vertebrates. We report here that, in transgenic flies, GSK-3 beta can substitute for shaggy, and we also present a study of epistatic relationships between shaggy and gain and loss of function alleles of Notch. The results indicate that shaggy/GSK-3 is part of a signalling pathway downstream of Notch.

Brief interventions for psychophysiological symptoms in hospitalized addicted patients.

The problem of psychosomatic complaints in newly sober substance abusers is longstanding. While somatic symptoms are common in withdrawal generally, some patients experience symptoms which prevail to the point of distracting from the treatment of the addiction. This paper illustrates brief, collaborative interventions conducted in a treatment hospital for three such patients who had significant, persistent, and common psychosomatic difficulties: migraine, insomnia, and hypertension. The importance and utility of holistic, multimodal treatment of the patient is emphasized.

Role of the oocyte nucleus in determination of the dorsoventral polarity of Drosophila as revealed by molecular analysis of the K10 gene.

In Drosophila, the establishment of dorsoventral polarity of the developing embryo depends on the expression of at least 11 maternally acting genes. Mutant females that lack any of these gene activities produce normally shaped eggs that develop into dorsalized embryos. The female sterile K10 mutation differs from these mutants, because in addition to the dorsalized development of the embryo, it causes a dorsalization of the egg shape. During oogenesis, the K10 gene is specifically expressed in the oocyte. Antibodies raised against a beta-galactosidase-K10 fusion protein were used to visualize the K10 product in ovaries by indirect immunofluorescence. The protein, which contains a putative DNA recognition helix, accumulates in the nucleus of the oocyte, where it is assumed to have a regulatory function. Our results thus indicate that the controlled expression of some of the genes of the oocyte nucleus is essential for the determination of the dorsoventral polarity of the oocyte and possibility of the developing embryo.