Bringing genetics into primary care: findings from a national evaluation of pilots in England.

Objectives: Developments in genetic knowledge and clinical applications are seen as rendering traditional modes of organizing genetics provision increasingly inappropriate. In common with a number of developed world countries the UK has sought to increase the role of primary care in delivering such services. However, efforts to reconfigure service delivery face multiple challenges associated with divergent policy objectives, organizational boundaries and professional cultures.

Clinical foundation for efficient treatment of obstructive sleep apnea.

Only a few decades ago, the entity known as obstructive sleep apnea (OSA) was unknown and untreated. Now, there is a rush to put literally millions of Americans on continuous positive airway pressure devices. Community practice standards are changing yearly under pressure from strong forces based on economic incentives for industry, government, and physicians, independent of the actual medical evidence supporting treatment and efficacy.

Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer.

Purpose: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non-HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC.

DASMI: exchanging, annotating and assessing molecular interaction data.

Motivation: Ever increasing amounts of biological interaction data are being accumulated worldwide, but they are currently not readily accessible to the biologist at a single site. New techniques are required for retrieving, sharing and presenting data spread over the Internet.

Results: We introduce the DASMI system for the dynamic exchange, annotation and assessment of molecular interaction data.

Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and one of the few malignancies with an increasing incidence in the USA. While the relationship between HCC and its inciting risk factors (e.g.

A phase I/II trial of trastuzumab plus erlotinib in metastatic HER2-positive breast cancer: a dual ErbB targeted approach.

Background: This phase I/II trial was conducted to determine the toxicities, recommended dose, pharmacokinetics, and response rate of erlotinib plus trastuzumab in metastatic HER2+ breast cancer.

Patients And Methods: In phase I, sequential groups of patients with unlimited previous treatment received erlotinib at dose levels of 50, 100, and 150 mg plus standard dose weekly trastuzumab. In phase II, only patients with no previous chemotherapy or trastuzumab in the metastatic setting were allowed.

Reconfiguring or reproducing intra-professional boundaries? Specialist expertise, generalist knowledge and the 'modernization' of the medical workforce.

Efforts to 'modernize' the clinical workforce of the English National Health Service have sought to reconfigure the responsibilities of professional groups in pursuit of more effective, joined-up service provision. Such efforts have met resistance from professions eager to protect their jurisdictions, deploying legitimacy claims familiar from the insights of the sociology of professions. Yet to date few studies of professional boundaries have grounded these insights in the specific context of policy challenges to the inter- and intra-professional division of labour, in relation to the medical profession and other health-related occupations.

Genomic and proteomic analyses reveal non-neofunctionalized vitellogenins in a basal clupeocephalan, the Atlantic herring, and point to the origin of maturational yolk proteolysis in marine teleosts.

Oocyte hydration is a unique event in oviparous marine teleosts that provides the single-celled egg with an essential pool of water for survival during early development in the saline oceanic environment. A conserved mechanism of maturational yolk proteolysis of a neofunctionalized vitellogenin (VtgAa) has been shown to underlie the hydration event in all teleosts that spawn pelagic eggs (pelagophils), and is argued to be a key adaptation for teleost radiation in the oceanic environment 55 Ma. We have recently shown that a small pool of free amino acids (FAAs) significantly contributes to the osmolarity of the ovulated egg in an ancestral marine teleost, the Atlantic herring that spawns benthic eggs (benthophil).

Reconstruction of the shallow vestibule edentulous mandible with simultaneous split thickness skin graft vestibuloplasty and mandibular endosseous implants for implant-supported overdentures.

Purpose: To evaluate the long-term outcome of simultaneous split thickness skin graft (STSG) vestibuloplasty and endosseous implant placement for implant-supported overdentures in patients with shallow mandibular vestibules.

Patients And Methods: This was a retrospective evaluation of 13 consecutive white male patients who underwent simultaneous mandibular vestibuloplasty with STSG combined with placement of 2 to 4 mandibular endosseous implants for construction of an implant-supported mandibular overdenture with a minimum of 2-year follow-up. Patients' charts were evaluated for implant survival and prosthetic success.

Evolution and differential expression of a vertebrate vitellogenin gene cluster.

Background: The multiplicity or loss of the vitellogenin (vtg) gene family in vertebrates has been argued to have broad implications for the mode of reproduction (placental or non-placental), cleavage pattern (meroblastic or holoblastic) and character of the egg (pelagic or benthic). Earlier proposals for the existence of three forms of vertebrate vtgs present conflicting models for their origin and subsequent duplication.

Results: By integrating phylogenetics of novel vtg transcripts from old and modern teleosts with syntenic analyses of all available genomic variants of non-metatherian vertebrates we identify the gene orthologies between the Sarcopterygii (tetrapod branch) and Actinopterygii (fish branch).

HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer.

Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy.

Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel +/- lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine +/- lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory.

Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors.

Motivation: Phospholipid scramblases (PLSCRs) constitute a family of cytoplasmic membrane-associated proteins that were identified based upon their capacity to mediate a Ca(2+)-dependent bidirectional movement of phospholipids across membrane bilayers, thereby collapsing the normally asymmetric distribution of such lipids in cell membranes. The exact function and mechanism(s) of these proteins nevertheless remains obscure: data from several laboratories now suggest that in addition to their putative role in mediating transbilayer flip/flop of membrane lipids, the PLSCRs may also function to regulate diverse processes including signaling, apoptosis, cell proliferation and transcription. A major impediment to deducing the molecular details underlying the seemingly disparate biology of these proteins is the current absence of any representative molecular structures to provide guidance to the experimental investigation of their function.

Modifier effects between regulatory and protein-coding variation.

Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants.

Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer.

Purpose: Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC.

Patients And Methods: Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo.

Rfam: updates to the RNA families database.

Rfam is a collection of RNA sequence families, represented by multiple sequence alignments and covariance models (CMs). The primary aim of Rfam is to annotate new members of known RNA families on nucleotide sequences, particularly complete genomes, using sensitive BLAST filters in combination with CMs. A minority of families with a very broad taxonomic range (e.

InterPro: the integrative protein signature database.

The InterPro database (http://www.ebi.ac.

The genome of the simian and human malaria parasite Plasmodium knowlesi.

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4).

Identifying protein domains with the Pfam database.

Pfam is a database of protein domain families, with each family represented by multiple sequence alignments and profile hidden Markov models (HMMs). In addition, each family has associated annotation, literature references, and links to other databases. The entries in Pfam are available via the World Wide Web and in flatfile format.

Defining the in Vivo Role for cytochrome b5 in cytochrome P450 function through the conditional hepatic deletion of microsomal cytochrome b5.

In vitro, cytochrome b5 modulates the rate of cytochrome P450-dependent mono-oxygenation reactions. However, the role of this enzyme in determining drug pharmacokinetics in vivo and the consequential effects on drug absorption distribution, metabolism, excretion, and toxicity are unclear. In order to resolve this issue, we have carried out the conditional deletion of microsomal cytochrome b5 in the liver to create the hepatic microsomal cytochrome b5 null mouse.

PEGylation of somatropin (recombinant human growth hormone): impact on its clearance in humans.

1. PHA-794428 is a PEGylated version of somatropin (human growth hormone). The pharmacokinetics of PHA-794428 have been studied in humans following single subcutaneous administration (dose range 10-500 microg kg(-1)).

Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway.

The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes.

Leishmania donovani peroxin 14 undergoes a marked conformational change following association with peroxin 5.

The import of PTS1 proteins into the glycosome or peroxisome requires binding of a PTS1-laden PEX5 receptor to the membrane-associated protein PEX14 to facilitate translocation of PTS1 proteins into the lumen of these organelles. Quaternary structure analysis of protozoan parasite Leishmania donovani PEX14 (LdPEX14) revealed that this protein forms a homomeric complex with a size > 670 kDa. Moreover, deletion mapping indicated that disruption of LdPEX14 oligomerization correlated with the elimination of the hydrophobic region and coiled-coil motif present in LdPEX14.

Integrating biological data--the Distributed Annotation System.

Background: The Distributed Annotation System (DAS) is a widely adopted protocol for dynamically integrating a wide range of biological data from geographically diverse sources. DAS continues to expand its applicability and evolve in response to new challenges facing integrative bioinformatics.

Results: Here we describe the various infrastructure components of DAS and present a new extended version of the DAS specification.