Restoring Akt1 activity in outgrowth endothelial cells from South Asian men rescues vascular reparative potential.

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men.

A novel p53 mutant found in iatrogenic urothelial cancers is dysfunctional and can be rescued by a second-site global suppressor mutation.

Exposure to herbal remedies containing the carcinogen aristolochic acid (AA) has been widespread in some regions of the world. Rare A→T TP53 mutations were recently discovered in AA-associated urothelial cancers. The near absence of these mutations among all other sequenced human tumors suggests that they could be biologically silent.

PIK3CA mutation spectrum in urothelial carcinoma reflects cell context-dependent signaling and phenotypic outputs.

Although activating mutations of PIK3CA are frequent in urothelial carcinoma (UC), no information is available on their specific effects in urothelial cells or the basis for the observed mutation spectrum, which has a large excess of helical domain mutations. We investigated the phenotypic and signaling consequences of hotspot and UC-specific rare PIK3CA mutations in immortalized normal human urothelial cells (NHUC) and mouse fibroblasts (NIH3T3). Our results indicate that in NHUC, rare mutant forms and all three hotspot mutant forms of PIK3CA can activate the PI3K/AKT pathway.

EB1 is required for spindle symmetry in mammalian mitosis.

Most information about the roles of the adenomatous polyposis coli protein (APC) and its binding partner EB1 in mitotic cells has come from siRNA studies. These suggest functions in chromosomal segregation and spindle positioning whose loss might contribute to tumourigenesis in cancers initiated by APC mutation. However, siRNA-based approaches have drawbacks associated with the time taken to achieve significant expression knockdown and the pleiotropic effects of EB1 and APC gene knockdown.

Human ASPM participates in spindle organisation, spindle orientation and cytokinesis.

Background: Mutations in the Abnormal Spindle Microcephaly related gene (ASPM) are the commonest cause of autosomal recessive primary microcephaly (MCPH) a disorder characterised by a small brain and associated mental retardation. ASPM encodes a mitotic spindle pole associated protein. It is suggested that the MCPH phenotype arises from proliferation defects in neural progenitor cells (NPC).

The information and support needs of Faroese women hospitalised with an acute coronary syndrome.

Aim And Objectives: The aim of this study was to describe the information and support needs of Faroese women after their hospitalisation for acute coronary syndrome. The Faroe Islands are located between Iceland and Norway. There are no published studies examining recovery for women following an acute cardiac event.

How to become immortal: let MEFs count the ways.

Understanding the molecular mechanisms and biological consequences of genetic changes occurring during bypass of cellular senescence spans a broad area of medical research from the cancer field to regenerative medicine. Senescence escape and immortalisation have been intensively studied in murine embryonic fibroblasts as a model system, and are known to occur when the p53/ARF tumour suppressor pathway is disrupted. We showed recently that murine fibroblasts with a humanised p53 gene (Hupki cells, from a human p53 knock-in mouse model) first senesce, and then become immortalised in the same way as their homologues with normal murine p53.

Differential effects of Paclitaxel on dendritic cell function.

Background: The potential utility of dendritic cells (DC) as cancer vaccines has been established in early trials in human cancers. The concomitant administration of cytotoxic agents and DC vaccines has been previously avoided due to potential immune suppression by chemotherapeutics. Recent studies show that common chemotherapy agents positively influence adaptive and innate anti-tumour immune responses.

AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K.

The phosphatidylinositol-3-kinase (PI3 kinase)-AKT pathway is frequently activated in cancer. Recent reports have identified a transforming mutation of AKT1 in breast, colorectal, ovarian and lung cancers. We report here the occurrence of this mutation in bladder tumours.

Methylmercury exposure and adverse cardiovascular effects in Faroese whaling men.

Background: Methylmercury (MeHg), a worldwide contaminant found in fish and seafood, has been linked to an increased risk of cardiovascular mortality.

Objective: We examined 42 Faroese whaling men (30-70 years of age) to assess possible adverse effects within a wide range of MeHg exposures from consumption of pilot whale meat.

Methods: We assessed exposure levels from mercury analysis of toenails and whole blood (obtained at the time of clinical examination), and a hair sample collected 7 years previously.

Social and ethnic differences in attendance for antenatal care in England.

Objectives: Evidence about sociodemographic factors associated with late attendance for antenatal care in the UK is of poor quality. This study aimed to identify any social or ethnic differences in access to antenatal care, and to quantify the effect of any such differences using data collected in a survey of women's experiences of antenatal screening.

Study Design: Cross-sectional survey using a postal questionnaire.

Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms.

More than 50% of transitional cell carcinomas of the bladder show loss of heterozygosity of a region spanning the TSC1 locus at 9q34 and mutations of TSC1 have been identified in 14.5% of tumours. These comprise nonsense mutations, splicing mutations, small deletions and missense mutations.

MCAK associates with EB1.

The microtubule (MT)-associated protein EB1 localizes to and promotes growth at MT plus ends. The MT depolymerizing kinesin MCAK has also been reported to track growing MT plus ends. Here, we confirm that human MCAK colocalizes with EB1 at growing MT ends when expressed as a GFP fusion protein in transfected cells.

Speculations on the future of taught masters courses in gerontology: lessons from a comparison of England, Scotland, Finland, and Spain.

Postgraduate education in gerontology is now widespread within European universities, but, even so, such developments remain very uneven. This paper outlines the variety of provision by describing Master's programmes in a sample of countries: England, Scotland, Finland, and Spain. These programmes illustrate some of the common problems: lack of funding for students, limited availability of academic staff, and reliance on a small core of dedicated teachers.

Adenomatous polyposis coli localization is both cell type and cell context dependent.

The adenomatous polyposis coli (APC) tumor suppressor protein is mutated in most colorectal carcinomas. In addition to its role in WNT signaling it is proposed to be involved in both cell migration and mitosis. Although a variety of studies have shown an APC localization along lateral membranes of adjacent epithelial cells the existence of a cortical APC localization in mammalian cells remains controversial.

Examination of actin and microtubule dependent APC localisations in living mammalian cells.

Background: The trafficking of the adenomatous polyposis coli (APC) tumour suppressor protein in mammalian cells is a perennially controversial topic. Immunostaining evidence for an actin-associated APC localisation at intercellular junctions has been previously presented, though live imaging of mammalian junctional APC has not been documented.

Results: Using live imaging of transfected COS-7 cells we observed intercellular junction-associated pools of GFP-APC in addition to previously documented microtubule-associated GFP-APC and a variety of minor localisations.

Phenotypic changes associated with DYNACTIN-2 (DCTN2) over expression characterise SJSA-1 osteosarcoma cells.

DYNACTIN-2 (DCTN2) localises to chromosome 12q13-q15, a region prone to stable amplification in several cancers. Transient DCTN2 overexpression has a significant impact on cellular phenotype primarily due to disruption of the DYNEIN-dynactin motor. Changes reported include alterations of microtubule-directed movement of molecular (e.

Trapping of normal EB1 ligands in aggresomes formed by an EB1 deletion mutant.

Background: EB1 is a microtubule tip-associated protein that interacts with the APC tumour suppressor protein and the p150glued subunit of dynactin. We previously reported that an EB1 deletion mutant that retains both of these interactions but does not directly associate with microtubules (EB1-DeltaN2-GFP) spontaneously formed perinuclear aggregates when expressed in COS-7 cells.

Results: In the present study live imaging indicated that EB1-DeltaN2-GFP aggregates underwent dynamic microtubule-dependent changes in morphology and appeared to be internally cohesive.

Expression of BUB1 protein in gastric cancer correlates with the histological subtype, but not with DNA ploidy or microsatellite instability.

During mitosis, the spindle checkpoint delays the onset of anaphase until all chromosomes have attached properly to the mitotic spindle, preventing chromosome missegregation. BUB (budding uninhibited by benzimidazole) 1 is one of the key components of this checkpoint. BUB1 mutations are rare in cancer tissues and no mutations have been identified in gastric cancer.

Accomplishing care at home for people with dementia: using observational methodology.

The authors consider the problems and possibilities presented by using unstructured observation in the home setting. The findings of the original study are described elsewhere (Briggs, Askham, Norman, & Redfern 1998; National Health Service [NHS] Executive 1998). In this article, the authors discuss process issues (e.

Evidence that an interaction between EB1 and p150(Glued) is required for the formation and maintenance of a radial microtubule array anchored at the centrosome.

EB1 is a microtubule tip-associated protein that interacts with the APC tumor suppressor protein and components of the dynein/dynactin complex. We have found that the C-terminal 50 and 84 amino acids (aa) of EB1 were sufficient to mediate the interactions with APC and dynactin, respectively. EB1 formed mutually exclusive complexes with APC and dynactin, and a direct interaction between EB1 and p150(Glued) was identified.

ASPM is a major determinant of cerebral cortical size.

One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. Humans with autosomal recessive primary microcephaly (MCPH) show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex.

cDNA cloning and molecular characterization of mink SMAD4.

The Smad family of proteins have been implicated as major components of the TGF beta signalling pathway and are important mediators of its pleiotrophic effects. Here we describe the cloning and characterization of the mink (Mustela vison) ortholog of Smad4. Mink Smad4 has a high level of conservation to its human counterpart showing 96% homology at the DNA level and 99% at the amino acid level.

EB1 identifies sites of microtubule polymerisation during neurite development.

EB1 is a microtubule associated protein which interacts with the APC tumour suppressor protein and components of the cytoplasmic dynein/dynactin complex. EB1 is also a specific marker of growing microtubule tips. Here we demonstrate that EB1 protein levels are increased during axon but not dendrite formation in differentiated N2A neuroblastoma cells, and that EB1 localises to microtubule tips throughout extending neurites in these cells.