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Darlinghurst, Australia

Bridge P.,University of Sydney | Pocock N.A.,St. Vincents Hospital | Pocock N.A.,The Garvan Institute | Nguyen T.,The Garvan Institute | And 4 more authors.
Journal of Clinical Densitometry | Year: 2011

Dual-energy X-ray absorptiometry (DXA) has been used extensively for bone mineral density and body composition assessments. Surprisingly, the role of DXA in monitoring changes in children's body composition, using direct imaging methods such as magnetic resonance imaging (MRI) as reference, is still yet to be validated. We aimed at validating the use of DXA in monitoring change in the thigh lean soft tissue mass (LSTM) and fat mass (FM) when compared with thigh skeletal muscle mass (SM) and FM, measured using MRI as the reference standard, from childhood to midadolescence. At baseline, 22 healthy children (16 boys and 6 girls) aged 8-11 yr were included, and then recalled at pubertal stage Tanner2-Tanner4. LSTM-DXA and FM-DXA of the mid-third femur and SM-MRI and FM-MRI of the same region were measured on the same day. The same protocol was repeated 26-48. mo later. At baseline, DXA overestimated LSTM-DXA on average by 222. g (95% confidence interval [CI]: 33-410. g) with a concordance C-LSTM. = 0.576. FM-MRI and FM-DXA were not significantly different (95% CI. = 213 to 199. g, the C-FM. = 0.907). At follow-up, change in LSTM-DXA and FM-DXA were not significantly different to change in SM-MRI and FM-MRI, respectively (95% CI of the difference was -278 to 208. g for LSTM, and -148 to 236. g for FM). The coefficient of concordance between the 2 techniques was 0.88 for both LSTM and FM. This study validates the use of DXA in monitoring changes in LSTM and FM in children, confirming its significant potential in clinical and research roles in pediatric body composition. © 2011.

Cossetti C.,University of Cambridge | Cossetti C.,Wellcome Trust Medical Research Council Stem Cell Institute | Iraci N.,University of Cambridge | Iraci N.,Wellcome Trust Medical Research Council Stem Cell Institute | And 26 more authors.
Molecular Cell | Year: 2014

The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. Wedescribed induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system. © 2014 Elsevier Inc.

Kruszka P.,Human Genome Research Institutes | Addissie Y.A.,Human Genome Research Institutes | Yarnell C.M.P.,Human Genome Research Institutes | Hadley D.W.,Human Genome Research Institutes | And 14 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P=0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss. © 2016 Wiley Periodicals, Inc.

Laterriere M.G.,The Garvan Institute | Pinho A.V.,The Garvan Institute | Pinho A.V.,University of New South Wales | Eling N.,The Garvan Institute | And 3 more authors.
Current Cancer Drug Targets | Year: 2015

Sirtuin 1 is a protein deacetylase that regulates a large number of proteins often functionally implicated in tumor development and progression. Its pleiotropic function has turned SIRT1 into an attractive chemotherapeutic target, underscored by very promising preclinical results with SIRT1 inhibitors in the treatment of chronic myeloid leukemia. Here, we revisit the studies on SIRT1 as an emerging target for therapy in pancreatic cancer, a tumor with dismal outcomes for which currently few therapeutic options are available. We highlight those potential SIRT1 target genes that are commonly affected in pancreatic cancer according to recent genomic analyses. © 2015 Bentham Science Publishers.

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