Prevalence of overt metastases in locally advanced breast cancer.

Aims: Locally advanced breast cancer (LABC) represents a wide spectrum of clinical presentations and poses significant clinical challenges for both patients and their physicians. Before starting neoadjuvant therapy, most patients undergo staging investigations, including a radioisotope bone scan, liver ultrasound and chest X-ray as per our provincial guidelines. The aim of this study was to document the prevalence of metastatic disease using standard baseline radiological staging in patients with LABC.

Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial.

Objective: To evaluate the impact of telling patients their estimated spirometric lung age as an incentive to quit smoking.

Design: Randomised controlled trial.

Setting: Five general practices in Hertfordshire, England.

The Chlamydomonas genome reveals the evolution of key animal and plant functions.

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the approximately 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella.

Screening for hereditary breast cancer.

Most women at risk for hereditary breast cancer opt for intensive breast screening rather than risk-reducing mastectomy. For this to be a rational choice, the vast majority of tumors must be detected either while still in situ or at a very early stage of invasion. Annual screening mammography has low sensitivity in this population, in part due to the greater breast density of younger women, resulting in cancers being detected at a suboptimal stage.

Gain-of-function R225W mutation in human AMPKgamma(3) causing increased glycogen and decreased triglyceride in skeletal muscle.

Background: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown.

Triple-negative breast cancer: clinical features and patterns of recurrence.

Purpose: To compare the clinical features, natural history, and outcomes for women with "triple-negative" breast cancer with women with other types of breast cancer.

Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative.

Peroxisome proliferator-activated receptor gamma 2 and acyl-CoA synthetase 5 polymorphisms influence diet response.

Peroxisome proliferator-activated receptor gamma (PPARgamma) and its response gene, Acyl CoA synthetase 5 (ACSL5), which has an important role in fatty acid metabolism, may affect weight loss in response to caloric restriction. Therefore, we aimed to determine whether these genes were involved in the interindividual response to dietary treatment. Genotypic/phenotypic comparisons were made between selected obese women from the quintiles losing the most (diet responsive, n = 74) and the quintiles losing the least (diet-resistant, n = 67) weight in the first 6 weeks of a 900-kcal formula diet.

Medical sequencing at the extremes of human body mass.

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96-Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways.

TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin.

After binding, central nervous system (CNS) myelin-derived axon growth inhibitory ligands, the Nogo-66 receptor (NgR), complexes with LINGO-1 and either the low-affinity neurotrophin receptor (p75(NTR)) or TROY to initiate growth cone collapse via a Rho-A inhibitory signaling pathway and/or Ca(2+)-dependent activation of epidermal growth factor receptor (EGFR) through an unknown signaling pathway. We have shown that axon growth through CNS myelin is disinhibited after neurotrophic factor administration by 1) initiating intramembranous proteolysis (RIP) of p75(NTR), leading to cleavage of the extracellular (p75(ECD)) and intracellular domains (p75(ICD)) by alpha- and gamma-secretase, respectively, thereby paralyzing inhibitory signaling; 2) shedding of soluble NgR(ECD), which acts as a competitive antagonist to NgR for binding of inhibitory ligands; and 3) antagonizing NgR/p75(NTR) clustering by competitive p75(ECD)/NgR interaction. Here, we report that TNF-alpha converting enzyme (TACE) (a disintegrin and metalloproteinase 17, ADAM17) induces disinhibition of FGF2-stimulated neurite outgrowth of dorsal root ganglion neurons (DRGN) cultured in the presence of a predetermined concentration of inhibitory CNS myelin-derived ligands.

Defects in the cytochrome b6/f complex prevent light-induced expression of nuclear genes involved in chlorophyll biosynthesis.

Mutants with defects in the cytochrome (cyt) b6/f complex were analyzed for their effect on the expression of a subgroup of nuclear genes encoding plastid-localized enzymes participating in chlorophyll biosynthesis. Their defects ranged from complete loss of the cytb6/f complex to point mutations affecting specifically the quinone-binding QO site. In these seven mutants, light induction of the tetrapyrrole biosynthetic genes was either abolished or strongly reduced.

Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro.

When associated with the Nogo receptor (NgR), the transmembrane receptor p75NTR signals growth cone collapse. Arrest of CNS axon growth in vivo is mediated by CNS myelin-derived inhibitory ligands through either an unknown pathway after NgR- and Ca2+-dependent activation of the epidermal growth factor receptor (EGFR), and/or sequential Rho-A/ROCK/LIM-kinase/cofilin phosphorylation leading to actin depolymerization. Paradoxically, rat retinal ganglion cell (RGC) axons regenerate through the CNS myelin-rich transected optic nerve after intravitreal sciatic nerve grafting without inhibitory ligand neutralization.

A PYY Q62P variant linked to human obesity.

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.

Lack of support for the association between GAD2 polymorphisms and severe human obesity.

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2).

Age-dependent changes in Fibroblast growth factor 2 (FGF-2) expression in mouse cerebellar neurons.

Fibroblast growth factor 2 (FGF-2) is a neurotrophic factor that regulates many neuronal functions and survival. We have characterised FGF-2 expression immunohistochemically in the cerebellum of young (4 months) and old (22 months) mice. About half of the population of the granule cells (GC), and all Purkinje cells (PC) expressed FGF-2 in all folia of the cerebellum at both ages.

Disinhibition of neurotrophin-induced dorsal root ganglion cell neurite outgrowth on CNS myelin by siRNA-mediated knockdown of NgR, p75NTR and Rho-A.

The presence of multiple axon growth inhibitors may partly explain why central nervous system axons are generally incapable of regenerating after injury. Using RNA interference (RNAi) in dorsal root ganglia neurons (DRGN), we demonstrate siRNA-mediated silencing of components of the inhibitory signalling cascade, including p75NTR, NgR and Rho-A mRNA, of 70%, 100% and 100% of the relevant protein, respectively, while changes in neither protein levels nor cellular immunoreactivity were detected using the relevant scrambled siRNA control sequences. Importantly, after 48 h in culture after siRNA-mediated knockdown of Rho-A, neurite outgrowth was enhanced by 30% compared to that after p75NTR and 50% after NgR silencing.

Functional genomics of eukaryotic photosynthesis using insertional mutagenesis of Chlamydomonas reinhardtii.

The unicellular green alga Chlamydomonas reinhardtii is a widely used model organism for studies of oxygenic photosynthesis in eukaryotes. Here we describe the development of a resource for functional genomics of photosynthesis using insertional mutagenesis of the Chlamydomonas nuclear genome. Chlamydomonas cells were transformed with either of two plasmids conferring zeocin resistance, and insertional mutants were selected in the dark on acetate-containing medium to recover light-sensitive and nonphotosynthetic mutants.

Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons.

After injury to the central nervous system, a glial/collagen scar forms at the lesion site, which is thought to act as a physicochemical barrier to regenerating axons. We have shown that scar formation in the transected optic nerve (ON) is attenuated when robust growth of axons is stimulated. Matrix metalloproteases (MMP), modulated by tissue inhibitors of MMP (TIMP), degrade a wide variety of extracellular matrix components (ECM) and may be activated by growing axons to remodel the ECM to allow regeneration through the inhibitory environment of the glial or collagen scar.

Adipogenic and antiapoptotic protein levels in human adipose stromal cells after weight loss.

Objective: Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. However, current strategies to achieve sustained weight loss are often unsuccessful. Fat reaccumulation might be favored by enhanced adipose cell differentiation or survival in the postreduced state.

Effect of weight reduction on respiratory function and airway reactivity in obese women.

Background: Population-based studies have documented an association between obesity and an increased prevalence of asthma in women.

Methods: We prospectively studied 58 obese women with a body mass index of > 30 kg/m(2), 24 of whom had asthma, who were enrolled in an intensive 6-month weight loss program to determine whether loss of body mass would be correlated with improvements in bronchial reactivity, lung function, and disease-specific health status.

Results: Patients lost an average of 20 kg over the 6-month period.

Quality of abstracts describing randomized trials in the proceedings of American Society of Clinical Oncology meetings: guidelines for improved reporting.

Purpose: To evaluate the quality of reporting in abstracts describing randomized controlled trials (RCTs) included in the Proceedings of American Society of Clinical Oncology (ASCO) meetings and to propose reporting guidelines for abstracts that are submitted to future meetings.

Methods: Guidelines for reporting of RCTs in abstracts were developed by extracting key elements from published guidelines for full reports of RCTs, and modified based on an expert survey. Abstracts presenting results of RCTs with sample size > or = 200 were identified from the ASCO Proceedings for the years 1989 to 1998.

Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.

Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss.

Development and evaluation of patient-centered software for a weight-management clinic.

Objective: To describe a weight-management clinic software system and to report on its preliminary evaluation.

Research Methods And Procedures: The software system standardizes the collection of relevant patient information from an initial medical assessment, weekly clinic visits, and laboratory testing protocol of a medically supervised proprietary meal-replacement program in a university-based referral clinic. It then generates monthly patient feedback reports with graphs of clinical and laboratory parameters to support a patient-centered approach to weight management.