Search tips
Search criteria


Important Notice

PubMed Central Canada to be taken offline in February 2018

On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

Read more

Results 1-25 (22913)

Clipboard (0)

Select a Filter Below

more »
more »
Year of Publication
more »
1.  Distinct Requirements for Cranial Ectoderm and Mesenchyme-Derived Wnts in Specification and Differentiation of Osteoblast and Dermal Progenitors 
PLoS Genetics  2014;10(2):e1004152.
The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.
Author Summary
Craniofacial abnormalities are relatively common congenital birth defects, and the Wnt signaling pathway and its effectors have key roles in craniofacial development. Wntless/Gpr177 is required for the efficient secretion of all Wnt ligands and maps to a region that contains SNPs strongly associated with reduced bone mass, and heterozygous deletion is associated with facial dysmorphology. Here we test the role of specific sources of secreted Wnt proteins during early stages of craniofacial development and obtained dramatic craniofacial anomalies. We found that the overlying cranial surface ectoderm Wnts generate an instructive cue of Wnt signaling for skull bone and skin cell fate selection and transcription of additional Wnts in the underlying mesenchyme. Once initiated, mesenchymal Wnts may maintain Wnt signal transduction and function in an autocrine manner during differentiation of skull bones and skin. These results highlight how Wnt ligands from two specific tissue sources are integrated for normal craniofacial patterning and can contribute to complex craniofacial abnormalities.
PMCID: PMC3930509  PMID: 24586192
2.  Functional MnO nanoclusters for efficient siRNA delivery† 
A non-viral gene delivery nanovehicle based on Alkyl-PEI2k capped MnO nanoclusters was synthesized via a simple, facile method and used for efficient siRNA delivery and magnetic resonance imaging.
PMCID: PMC4620662  PMID: 21991584
3.  Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo 
NeuroImage  2014;102(0 2):809-816.
Dystrophin, the main component of the dystrophin–glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood–brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38± 0.30 × 10−4mm2/s) and 10-month-old (6.93 ± 0.53 × 10−4 mm2/s) mdx mice as compared to WT (8.49±0.24×10−4, 8.24±0.25× 10−4mm2/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.
PMCID: PMC4320943  PMID: 25213753
dystrophin; perfusion; diffusion; cryoimaging
4.  Gadolinium MRI Contrast Agents Based on Triazine Dendrimers: Relaxivity and In Vivo Pharmacokinetics 
Bioconjugate chemistry  2012;23(11):2291-2299.
Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)24, G5-(Gd-DOTA)96, G3-(Gd-DTPA)24, and G5-(Gd-DTPA)96, were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metallated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metallated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)24 and G5-(Gd-DOTA)96, demonstrated exceptionally high r1 relaxivity values at off peak magnetic fields. Additionally, G5-(Gd-DOTA)96 showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3-(Gd-DOTA)24 and G3-(Gd-DTPA)24 were rapidly excreted into the urine, G5-(Gd-DOTA)96 and G5-(Gd-DTPA)96 did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers provides a single-molecular level characterization of the structures and suggests that a majority of the metallated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure.
PMCID: PMC3586605  PMID: 23035964
magnetic resonance imaging; triazine dendrimer; relaxivity; pharmacokinetics; gadolinium
5.  Dendrimer-Based MRI Contrast Agents: The Effects of PEGylation on Relaxivity and Pharmacokinetics 
Polyethylene glycol (PEG)-surface modification can make nano-materials highly hydrophilic, reducing sequestration in the reticuloendothelial system. In this study, polyamidoamine (PAMAM) dendrimers bearing gadolinium chelates were PEGylated with different PEG-chain lengths and the effects on paramagnetic and pharmacokinetic properties were evaluated. Specifically, gadolinium chelate-bearing PAMAM dendrimers (G4 and G5) were conjugated with two different PEG chains (2k and 5k). Long PEG chains (5k) on the smaller (G4) dendrimer resulted in reduced relaxivity compared to unPEGylated dendrimer whereas short PEG (2k) and larger (G5) dendrimer produced comparable relaxivities to unPEGylated G4 dendrimer. The relaxivity of all PEGylated or lysine conjugated dendrimers increased at higher temperature, while that of intact G4 Gd-PAMAM-dendrimer decreased. All PEGylated dendrimers had minimal liver and kidney uptake and remained in circulation for at least 1 hour. Thus, surface-PEGylated Gd-PAMAM-Dendrimers showed decreased plasma clearance and prolonged retention in the blood pool. Shorter PEG, higher generation conjugates led higher relaxivity.
PMCID: PMC3159711  PMID: 21515406
MRI; dendrimer; polyethylene glycol (PEG); relaxivity; pharmacokinetics
6.  New nano-sized biocompatible MR contrast agents based on lysine-dendri-graft macromolecules 
Bioconjugate chemistry  2010;21(5):955-960.
Paramagnetic nano-materials for use as magnetic resonance imaging (MRI) contrast agents have higher relaxivity than conventional low molecular weight MRI agents. However, the biocompatibility and pharmacokinetics of such nano-materials will strongly affect the likelihood of clinical approval. We synthesized MRI contrast agents based on biocompatible lysine-dendri-grafts: Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3. The relaxivity of Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3 increased with sample temperature, while the relaxivity of Gd-BzDTPA-PAMAMG4 decreased with increasing sample temperature. The increase in relaxivity with increasing temperature may be attributed to inaccessibility of water to the internal Gd chelates with lysine-dendri-grafts, which does not occur with PAMAM dendrimers. Gd-BzDTPA-lysineG3 had a long intravascular half life but were largely excreted by the kidneys. Therefore, Gd-BzDTPA-lysineG3 enhanced the blood vessels for longer periods than Gd-BzDTPA-PAMAMG4, but was still excreted through the kidney. Because of their biocompatibility, desirable magneto-physical characteristics and favorable pharmacokinetics, which are derived from different interior structures rather than the physical size, lysine-dendri-graft MR contrast agents may be feasible for clinical use.
PMCID: PMC2884170  PMID: 20235572
Soft nanomaterial; MRI contrast agent; Relaxivity; Lysine-dendri graft; Polyamidoamine dendrimer
8.  Twist1 contributes to cranial bone initiation and dermal condensation by maintaining Wnt signaling responsiveness 
Specification of cranial bone and dermal fibroblast progenitors in the supraorbital arch mesenchyme is Wnt/β-catenin signaling-dependent. The mechanism underlying how these cells interpret instructive signaling cues and differentiate into these two lineages is unclear. Twist1 is a target of the Wnt/β-catenin signaling pathway and is expressed in cranial bone and dermal lineages.
Here, we show that onset of Twist1 expression in the mouse cranial mesenchyme is dependent on ectodermal Wnts and mesenchymal β-catenin activity. Conditional deletion of Twist1 in the supraorbital arch mesenchyme leads to cranial bone agenesis and hypoplastic dermis, as well as craniofacial malformation of eyes and palate. Twist1 is preferentially required for cranial bone lineage commitment by maintaining Wnt responsiveness. In the conditional absence of Twist1, the cranial dermis fails to condense and expand apically leading to extensive cranial dermal hypoplasia with few and undifferentiated hair follicles.
Thus, Twist1, a target of canonical Wnt/β-catenin signaling, also functions to maintain Wnt responsiveness and is a key effector for cranial bone fate selection and dermal condensation.
PMCID: PMC4715624  PMID: 26677825
skull bone; skin; craniofacial development
9.  Dentate Gyrus Development Requires ERK Activity to Maintain Progenitor Population and MAPK Pathway Feedback Regulation 
The Journal of Neuroscience  2015;35(17):6836-6848.
The ERK/MAPK pathway is an important developmental signaling pathway. Mutations in upstream elements of this pathway result in neuro-cardio-facial cutaneous (NCFC) syndromes, which are typified by impaired neurocognitive abilities that are reliant upon hippocampal function. The role of ERK signaling during hippocampal development has not been examined and may provide critical insight into the cause of hippocampal dysfunction in NCFC syndromes. In this study, we have generated ERK1 and conditional ERK2 compound knock-out mice to determine the role of ERK signaling during development of the hippocampal dentate gyrus. We found that loss of both ERK1 and ERK2 resulted in 60% fewer granule cells and near complete absence of neural progenitor pools in the postnatal dentate gyrus. Loss of ERK1/2 impaired maintenance of neural progenitors as they migrate from the dentate ventricular zone to the dentate gyrus proper, resulting in premature depletion of neural progenitor cells beginning at E16.5, which prevented generation of granule cells later in development. Finally, loss of ERK2 alone does not impair development of the dentate gyrus as animals expressing only ERK1 developed a normal hippocampus. These findings establish that ERK signaling regulates maintenance of progenitor cells required for development of the dentate gyrus.
PMCID: PMC4412899  PMID: 25926459
dentate gyrus; ERK; MAPK pathway; NCFC; neurogenesis
11.  Rapid Spectrophotometric Technique for Quantifying Iron in Cells Labeled with Superparamagnetic Iron Oxide Nanoparticles: Potential Translation to the Clinic 
Labeling cells with superparamagnetic iron oxide (SPIO) nanoparticles provides the ability to track cells by Magnetic Resonance Imaging. Quantifying intracellular iron concentration in SPIO labeled cells would allow for the comparison of agents and techniques used to magnetically label cells. Here we describe a rapid spectrophotometric technique (ST) to quantify iron content of SPIO labeled cells, circumventing the previous requirement of an overnight acid digestion. Following lysis with 10% SDS of magnetically labeled cells, quantification of SPIO doped or labeled cells was performed using commonly available spectrophotometric instrument(s) by comparing absorptions at 370 and 750 nm with correction for turbidity of cellular products to determine iron content of each sample. Standard curves demonstrated high linear correlation (R2 = 0.998) between absorbance spectra of iron oxide nanoparticles and concentration in known SPIO doped cells. Comparisons of the ST to ICP-MS or NMR relaxometric (R2) determinations of intracellular iron contents in SPIO containing samples resulted in significant linear correlation between the techniques (R2 vs. ST, R2>0.992, p<0.0001, ST vs. ICP-MS, R2>0.995, p<0.0001) with the limit of detection of ST for iron = 0.66μg/ml. We have developed a rapid straightforward protocol that does not require overnight acid digestion for quantifying iron oxide content in magnetically labeled cells using readily available analytic instrumentation that should greatly expedite advances in comparing SPIO agents and protocols for labeling cells.
PMCID: PMC3490434  PMID: 23109392
Relaxometry; Iron Content; Cell Labeling; Stem Cells; Superparamagnetic Iron Oxide Nanoparticles; Ferumoxides; Ferumoxytol; ICP-MS; Spectrophotometry; Prussian Blue; MRI
12.  Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI† 
Nanoscale  2011;3(12):4943-4945.
We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.
PMCID: PMC3617494  PMID: 22064945
13.  Cancer of the Larynx—Results of Surgical and Radiological Treatment in One Institution 
California Medicine  1966;105(1):8-10.
Of 67 consecutive patients with cancer of the larynx seen at the San Francisco General Hospital from 1948-1960 inclusive, 25 were treated primarily by radical radiotherapy and 31 by radical surgical operation. Of the 25 treated by radiotherapy (with surgery for failure in three instances) 13 apparently had arrest of disease and nine of these remained cured five or more years. Four died of intercurrent disease.
Of the 31 treated primarily by radical operation (with subsequent radiation for surgical failure in 11 patients), 13 had potential arrest of disease and seven of the 13 remained cured for five or more years. Six died of intercurrent disease before the lapse of five years, three of them within four weeks of radical operation.
Radical radiotherapy of laryngeal cancer produced results superior to those of radical surgery in patients seen and treated during the period under review in this hospital.
PMCID: PMC1516264  PMID: 5947002
California Medicine  1965;103(1):78.
PMCID: PMC1516100
20.  The Diagnosis of Cancer—Radiology 
California Medicine  1964;100(6):397-401.
PMCID: PMC1515627  PMID: 14154284
California Medicine  1964;100(2):143-144.
PMCID: PMC1515120
California Medicine  1963;99(6):428-429.
PMCID: PMC1515333

Results 1-25 (22913)