Publications by authors named "Au P"

110 Publications

Microstructure of Sodium Montmorillonite Gels with Long Aging Time Scale.

Langmuir 2018 08 13;34(33):9673-9682. Epub 2018 Aug 13.

Department of Chemical Engineering , Curtin University , Miri , Sarawak , Malaysia , 98009.

Purified sodium montmorillonite (SWy-2) gels of a few percent solids displayed pronounced time-dependent rheological or aging behavior with a long time scale. The aging behavior was characterized by an increasing yield stress with rest time. This increase continued even after a week of rest. An open sponge-like cellular microstructure of the aged gels was captured by cryo-SEM with samples prepared at high pressure. The size of the openings of the cellular structure is small, generally less than 1 μm formed by thin flexible platelet with curling edges. This structure was formed by strong attractive and repulsive forces. The rapid yield stress increase in the early stage of aging is due to rapid bond formation occurring between network platelets and free individual platelet, isolated aggregates, and platelet particles in network with free edges. Over time, all platelets are bonded in the network. During aging, the platelets in the structure would have to adjust continually in response to a net force acting on it by its neighbors. The high concentration of platelets responding to this force imbalance is the cause of the long aging time scale. The operation of the attractive and repulsive forces, and the shape and charge properties of the platelets are responsible for the cellular structure being built. At complete structural recovery, the structure should attain the state of lowest free energy. The repulsive force regulates the development of the microstructure. The aging data of the 3.3 wt % gel were fitted by different aging models.
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http://dx.doi.org/10.1021/acs.langmuir.8b00213DOI Listing
August 2018

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

Eur J Hum Genet 2018 09 14;26(9):1272-1281. Epub 2018 Jun 14.

Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.
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http://dx.doi.org/10.1038/s41431-018-0187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117294PMC
September 2018

Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies.

Case Rep Endocrinol 2018 18;2018:9412676. Epub 2018 Apr 18.

Department of Medicine, Division of Endocrinology and Metabolism and Department of Obstetrics and Gynaecology, University of Calgary, Calgary, AB, Canada.

Background: Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care.

Case: We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in were identified, supporting a diagnosis of classical WS.

Conclusions: The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve -cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for -cell preservation for individuals with type 1 and 2 diabetes.
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http://dx.doi.org/10.1155/2018/9412676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932515PMC
April 2018

First Report of a Novel Deletion Due to εγδβ-Thalassemia in a Chinese Family.

Hemoglobin 2017 May;41(3):175-179

a Department of Obstetrics & Gynaecology , The Chinese University of Hong Kong, Prince of Wales Hospital , Hong Kong , People's Republic of China.

A fetus of Chinese descent presented with ultrasound features of anemia at 20 weeks' gestation. Father had low a mean corpuscular volume (MCV) level. Multiplex gap-polymerase chain reaction (gap-PCR) excluded common α-thalassemia (α-thal) deletions and mutations and PCR sequencing of the α1- and α2-globin genes were negative. The fetus had a normal karyotype. Array comparative genomic hybridization (aCGH) showed a single copy loss of 189.87 kb in chromosome 11p15.4, involving the whole β-globin gene cluster, inherited from the father. Multiplex ligation-dependent probe amplification (MLPA) confirmed the deletion included the ε-globin gene, confirming the diagnosis of heterozygous (εγδβ)-thalassemia [(εγδβ)-thal], also inherited from the father. The fetus had a worsening anemic condition in utero and required a transfusion at 26 weeks' gestation, raising the hemoglobin (Hb) level from 5.3 to 12.6g/dL. A cesarean-section was subsequently performed at 32 weeks' gestation because of reduced fetal movements, and a 1650g baby girl with good Apgar scores was delivered. Hemoglobin at birth was 12.8g/dL, gradually dropping to 6.8 g/dL, requiring three neonatal transfusions. Her condition gradually stabilized after 2 months with Hb stable at 8.0 g/dL. Family screening by MLPA showed that the paternal grandmother carried the same deletion. The deletion in this case is distinct and is the reported first case. The deletion transmitted across three successive generations with great phenotypic variation. The final adult phenotype of (εγδβ)-thal is usually mild, therefore, with accurate prenatal diagnosis this condition is salvageable by in utero and early neonatal transfusions, preventing adverse pregnancy and neonatal outcomes.
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http://dx.doi.org/10.1080/03630269.2017.1366918DOI Listing
May 2017

Cover Image, Volume 173A, Number 10, October 2017.

Am J Med Genet A 2017 Oct;173(10)

Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.

The cover image, by Rani A. Bashir et al., is based on the Original Article Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders, DOI: 10.1002/ajmg.a.38355.
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http://dx.doi.org/10.1002/ajmg.a.38481DOI Listing
October 2017

The PD COMM trial: a protocol for the process evaluation of a randomised trial assessing the effectiveness of two types of SLT for people with Parkinson's disease.

Trials 2017 08 29;18(1):397. Epub 2017 Aug 29.

Faculty of Life Science and Medicine, King's College London, London, UK.

Background: The PD COMM trial is a phase III multi-centre randomised controlled trial whose aim is to evaluate the effectiveness and cost-effectiveness of two approaches to speech and language therapy (SLT) compared with no SLT intervention (control) for people with Parkinson's disease who have self-reported or carer-reported problems with their speech or voice. Our protocol describes the process evaluation embedded within the outcome evaluation whose aim is to evaluate what happened at the time of the PD COMM intervention implementation and to provide findings that will assist in the interpretation of the PD COMM trial results. Furthermore, the aim of the PD COMM process evaluation is to investigate intervention complexity within a theoretical model of how the trialled interventions might work best and why.

Methods/design: Drawing from the Normalization Process Theory and frameworks for implementation fidelity, a mixed method design will be used to address process evaluation research questions. Therapists' and participants' perceptions and experiences will be investigated via in-depth interviews. Critical incident reports, baseline survey data from therapists, treatment record forms and home practice diaries also will be collected at relevant time points throughout the running of the PD COMM trial. Process evaluation data will be analysed independently of the outcome evaluation before the two sets of data are then combined.

Discussion: To date, there are a limited number of published process evaluation protocols, and few are linked to trials investigating rehabilitation therapies. Providing a strong theoretical framework underpinning design choices and being tailored to meet the complex characteristics of the trialled interventions, our process evaluation has the potential to provide valuable insight into which components of the interventions being delivered in PD COMM worked best (and what did not), how they worked well and why.

Trial Registration: ISRCTN Registry, ISRCTN12421382 . Registered on 18 April 2016.
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http://dx.doi.org/10.1186/s13063-017-2130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576370PMC
August 2017

Analysis of Argonaute 4-Associated Long Non-Coding RNA in Arabidopsis thaliana Sheds Novel Insights into Gene Regulation through RNA-Directed DNA Methylation.

Genes (Basel) 2017 Aug 7;8(8). Epub 2017 Aug 7.

Commonwealth Scientific and Industrial Research Organisation Agriculture, Canberra, Australian Capital Territory 2601, Australia.

RNA-directed DNA methylation (RdDM) is a plant-specific de novo DNA methylation mechanism that requires long noncoding RNA (lncRNA) as scaffold to define target genomic loci. While the role of RdDM in maintaining genome stability is well established, how it regulates protein-coding genes remains poorly understood and few RdDM target genes have been identified. In this study, we obtained sequences of RdDM-associated lncRNAs using nuclear RNA immunoprecipitation against ARGONAUTE 4 (AGO4), a key component of RdDM that binds specifically with the lncRNA. Comparison of these lncRNAs with gene expression data of RdDM mutants identified novel RdDM target genes. Surprisingly, a large proportion of these target genes were repressed in RdDM mutants suggesting that they are normally activated by RdDM. These RdDM-activated genes are more enriched for gene body lncRNA than the RdDM-repressed genes. Histone modification and RNA analyses of several RdDM-activated stress response genes detected increased levels of active histone mark and short RNA transcript in the lncRNA-overlapping gene body regions in the mutant despite the repressed expression of these genes. These results suggest that RdDM, or AGO4, may play a role in maintaining or activating stress response gene expression by directing gene body chromatin modification preventing cryptic transcription.
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http://dx.doi.org/10.3390/genes8080198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575662PMC
August 2017

Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders.

Am J Med Genet A 2017 Oct 11;173(10):2596-2604. Epub 2017 Jul 11.

Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.

We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.
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http://dx.doi.org/10.1002/ajmg.a.38355DOI Listing
October 2017

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.

Am J Hum Genet 2017 Jul;101(1):139-148

Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
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http://dx.doi.org/10.1016/j.ajhg.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501873PMC
July 2017

Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.

Eur J Med Genet 2017 Jul 1;60(7):359-364. Epub 2017 Apr 1.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada. Electronic address:

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.
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http://dx.doi.org/10.1016/j.ejmg.2017.03.013DOI Listing
July 2017

An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.

Hemoglobin 2016 Nov;40(6):431-434

a Department of Obstetrics and Gynaecology , Queen Elizabeth Hospital , Hong Kong SAR , People's Republic of China.

Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.
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http://dx.doi.org/10.1080/03630269.2016.1267017DOI Listing
November 2016

Review of the recurrent 8q13.2q13.3 branchio-oto-renal related microdeletion, and report of an additional case with associated distal arthrogryposis.

Am J Med Genet A 2016 11 19;170(11):2984-2987. Epub 2016 Aug 19.

Department of Medical Genetics, University of Calgary, Alberta, Canada.

Recurrent 2.65 Mb deletions of 8q13.2q13.3 encompassing EYA1 have been recently described in the literature as a cause of branchio-oto-renal syndrome (BOR). Other clinical features of this recurrent microdeletion syndrome are still being delineated. We describe an additional patient with BOR due to microdeletion of 8q13.2q13.3. In addition to BOR related features, our patient presented with distal arthrogryposis that was detected prenatally, a phenotype that has not previously been described in patients with this deletion. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37695DOI Listing
November 2016

Refining Ovarian Cancer Test accuracy Scores (ROCkeTS): protocol for a prospective longitudinal test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

BMJ Open 2016 08 9;6(8):e010333. Epub 2016 Aug 9.

Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK Diagnostic Test Accuracy Group, University of Birmingham, Birmingham, UK.

Introduction: Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III).

Methods And Analysis: ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios.
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http://dx.doi.org/10.1136/bmjopen-2015-010333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985790PMC
August 2016

The Accuracy of 6 Inexpensive Pulse Oximeters Not Cleared by the Food and Drug Administration: The Possible Global Public Health Implications.

Anesth Analg 2016 08;123(2):338-45

From the *Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California; and †Physio Monitor LLC., San Ramon, California.

Background: Universal access to pulse oximetry worldwide is often limited by cost and has substantial public health consequences. Low-cost pulse oximeters have become increasingly available with limited regulatory agency oversight. The accuracy of these devices often has not been validated, raising questions about performance.

Methods: The accuracy of 6 low-cost finger pulse oximeters during stable arterial oxygen saturations (SaO2) between 70% and 100% was evaluated in 22 healthy subjects. Oximeters tested were the Contec CMS50DL, Beijing Choice C20, Beijing Choice MD300C23, Starhealth SH-A3, Jumper FPD-500A, and Atlantean SB100 II. Inspired oxygen, nitrogen, and carbon dioxide partial pressures were monitored and adjusted via a partial rebreathing circuit to achieve 10 to 12 stable target SaO2 plateaus between 70% and 100% and PaCO2 values of 35 to 45 mm Hg. Comparisons of pulse oximeter readings (SpO2) with arterial SaO2 (by Radiometer ABL90 and OSM3) were used to calculate bias (SpO2 - SaO2) mean, precision (SD of the bias), and root mean square error (ARMS).

Results: Pulse oximeter readings corresponding to 536 blood samples were analyzed. Four of the 6 oximeters tested showed large errors (up to -6.30% mean bias, precision 4.30%, 7.53 ARMS) in estimating saturation when SaO2 was reduced <80%, and half of the oximeters demonstrated large errors when estimating saturations between 80% and 90%. Two of the pulse oximeters tested (Contec CMS50DL and Beijing Choice C20) demonstrated ARMS of <3% at SaO2 between 70% and 100%, thereby meeting International Organization for Standardization (ISO) criteria for accuracy.

Conclusions: Many low-cost pulse oximeters sold to consumers demonstrate highly inaccurate readings. Unexpectedly, the accuracy of some low-cost pulse oximeters tested here performed similarly to more expensive, ISO-cleared units when measuring hypoxia in healthy subjects. None of those tested here met World Federation of Societies of Anaesthesiologists standards, and the ideal testing conditions do not necessarily translate these findings to the clinical setting. Nonetheless, further development of accurate, low-cost oximeters for use in clinical practice is feasible and, if pursued, could improve access to safe care, especially in low-income countries.
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http://dx.doi.org/10.1213/ANE.0000000000001300DOI Listing
August 2016

Mouse embryonic fibroblasts exhibit extensive developmental and phenotypic diversity.

Proc Natl Acad Sci U S A 2016 Jan 22;113(1):122-7. Epub 2015 Dec 22.

Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Department of Genetics, Harvard Medical School, Boston, MA 02115;

Analysis of embryonic fibroblasts from GFP reporter mice indicates that the fibroblast cell type harbors a large collection of developmentally and phenotypically heterogeneous subtypes. Some of these cells exhibit multipotency, whereas others do not. Multiparameter flow cytometry analysis shows that a large number of distinct populations of fibroblast-like cells can be found in cultures initiated from different embryonic organs, and cells sorted according to their surface phenotype typically retain their characteristics on continued propagation in culture. Similarly, surface phenotypes of individual cloned fibroblast-like cells exhibit significant variation. The fibroblast cell class appears to contain a very large number of denumerable subtypes.
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http://dx.doi.org/10.1073/pnas.1522401112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711836PMC
January 2016

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

Am J Hum Genet 2015 Dec;97(6):922-32

Gene by Gene Ltd., Houston, TX 77008, USA.

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2015.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678794PMC
December 2015

Expression analysis of Cdx2 and Pou5f1 in a marsupial, the stripe-faced dunnart, during early development.

Mol Reprod Dev 2016 Feb 23;83(2):108-23. Epub 2016 Jan 23.

School of Biosciences, University of Melbourne, Parkville, Victoria, Australia.

The first lineage allocation during mouse development forms the trophectoderm and inner cell mass, in which Cdx2 and Pou5f1 display reciprocal expression. Yet Cdx2 is not required for trophectoderm specification in other mammals, such as the human, cow, pig, or in two marsupials, the tammar and opossum. The role of Cdx2 and Pou5f1 in the first lineage allocation of Sminthopsis macroura, the stripe-faced dunnart, is unknown. In this study, expression of Cdx2 and Pou5f1 during oogenesis, development from cleavage to blastocyst stages, and in the allocation of the first three lineages was analyzed for this dunnart. Cdx2 mRNA was present in late antral-stage oocytes, but not present again until Day 5.5. Pou5f1 mRNA was present from primary follicles to zygotes, and then expression resumed starting at the early unilaminar blastocyst stage. All cleavage stages and the pluriblast and trophoblast cells co-expressed CDX2 and POU5F1 proteins, which persisted until early stages of hypoblast formation. Hypoblast cells also show co-localisation of POU5F1 and CDX2 once they were allocated, and this persisted during their division and migration. Our studies suggest that CDX2, and possibly POU5F1, are maternal proteins, and that the first lineage to differentiate is the trophoblast, which differentiates to trophectoderm after shell loss one day before implantation. In the stripe-faced dunnart, cleavage cells, as well as trophoblast and pluriblast cells, are polarized, suggesting the continued presence of CDX2 in both lineages until late blastocyst stages may play a role in the formation and maintenance of polarity.
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http://dx.doi.org/10.1002/mrd.22597DOI Listing
February 2016

Gene therapy for cancer: regulatory considerations for approval.

Cancer Gene Ther 2015 Dec 20;22(12):554-63. Epub 2015 Nov 20.

Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration, Silver Spring, MD, USA.

The rapidly changing field of gene therapy promises a number of innovative treatments for cancer patients. Advances in genetic modification of cancer and immune cells and the use of oncolytic viruses and bacteria have led to numerous clinical trials for cancer therapy, with several progressing to late-stage product development. At the time of this writing, no gene therapy product has been approved by the United States Food and Drug Administration (FDA). Some of the key scientific and regulatory issues include understanding of gene transfer vector biology, safety of vectors in vitro and in animal models, optimum gene transfer, long-term persistence or integration in the host, shedding of a virus and ability to maintain transgene expression in vivo for a desired period of time. Because of the biological complexity of these products, the FDA encourages a flexible, data-driven approach for preclinical safety testing programs. The clinical trial design should be based on the unique features of gene therapy products, and should ensure the safety of enrolled subjects. This article focuses on regulatory considerations for gene therapy product development and also discusses guidance documents that have been published by the FDA.
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http://dx.doi.org/10.1038/cgt.2015.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722245PMC
December 2015

A Fetus with Hb Bart's Disease Due to Maternal Uniparental Disomy for Chromosome 16.

Hemoglobin 2016 16;40(1):66-9. Epub 2015 Nov 16.

a Department of Obstetrics & Gynaecology , Queen Mary Hospital , Hong Kong SAR , People's Republic of China.

We here report an unusual case of Hb Bart's (γ4) disease. Thalassemia screening of a couple showed that the wife was an α(0)-thalassemia (α(0)-thal) carrier and her husband's mean corpuscular volume (MCV) was normal. Chorionic villus sampling (CVS) was performed at 13 weeks' gestation for positive Down syndrome screening and chromosomal study of the cultured CVS showed a normal karyotype. Ultrasound examination at 22 weeks' gestation showed fetal cardiomegaly and raised middle cerebral artery peak systolic velocity. Cordocentesis confirmed fetal anemia and showed Hb Bart's disease. Multiplex gap-polymerase chain reaction (gap-PCR) for α-thal deletions on DNA extracted from the CVS showed the presence of a homozygous α(0)-thal - -(SEA) (Southeast Asian) deletion. The husband was found to be a carrier of the α(+)-thal -α(3.7) (rightward) deletion. Non paternity was excluded by fluorescent PCR using short tandem repeat (STR) markers on chromosomes 13, 18 and 21. A de novo terminal deletion of chromosome 16 was excluded by array comparative genomic hybridization (aCGH). Detection of uniparental disomy (UPD), using STR markers on chromosome 16 showed maternal uniparental isodisomy from 16pter to 16p13.2, and uniparental heterodisomy from 16p13.13 to 16qter.
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http://dx.doi.org/10.3109/03630269.2015.1096283DOI Listing
October 2016

Preferential retrotransposition in aging yeast mother cells is correlated with increased genome instability.

DNA Repair (Amst) 2015 Oct 7;34:18-27. Epub 2015 Aug 7.

Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United States. Electronic address:

Retrotransposon expression or mobility is increased with age in multiple species and could promote genome instability or altered gene expression during aging. However, it is unclear whether activation of retrotransposons during aging is an indirect result of global changes in chromatin and gene regulation or a result of retrotransposon-specific mechanisms. Retromobility of a marked chromosomal Ty1 retrotransposon in Saccharomyces cerevisiae was elevated in mother cells relative to their daughter cells, as determined by magnetic cell sorting of mothers and daughters. Retromobility frequencies in aging mother cells were significantly higher than those predicted by cell age and the rate of mobility in young populations, beginning when mother cells were only several generations old. New Ty1 insertions in aging mothers were more strongly correlated with gross chromosome rearrangements than in young cells and were more often at non-preferred target sites. Mother cells were more likely to have high concentrations and bright foci of Ty1 Gag-GFP than their daughter cells. Levels of extrachromosomal Ty1 cDNA were also significantly higher in aged mother cell populations than their daughter cell populations. These observations are consistent with a retrotransposon-specific mechanism that causes retrotransposition to occur preferentially in yeast mother cells as they begin to age, as opposed to activation by phenotypic changes associated with very old age. These findings will likely be relevant for understanding retrotransposons and aging in many organisms, based on similarities in regulation and consequences of retrotransposition in diverse species.
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http://dx.doi.org/10.1016/j.dnarep.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592464PMC
October 2015

GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.

Hum Mutat 2015 Oct 6;36(10):1009-1014. Epub 2015 Aug 6.

Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.
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http://dx.doi.org/10.1002/humu.22837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589226PMC
October 2015

An Investigation of the Feasibility and Utility of a Low-dose Cone-beam Computed Tomography Scan Protocol for Head and Neck Cancer Patients.

J Med Imaging Radiat Sci 2015 Jun 31;46(2):141-147. Epub 2015 Jan 31.

Department of Medical Physics, Odette Cancer Centre, Toronto, Ontario, Canada.

Introduction: Routine use of cone-beam computed tomography (CBCT) scan protocols as part of the image guidance process (image-guided radiation therapy) has become an integral part of the practice of radiation therapists (RTs). Concerns regarding imaging dose as well as increased in-room time for patients led to reluctance among site group members to adopt CBCT for all radical head and neck cancer (HNC) patients at our institution. This investigation set out to assess the feasibility and utility of a revised CBCT scan protocol with the aim of supporting daily CBCT for HNC patients receiving radiation therapy.

Methods: The project was performed in three phases. Phase 1 involved the experimental adjustment of CBCT scan protocol parameters in clinical use for HNC patients at our institution. An Elekta Synergy linear accelerator with kilovoltage CBCT capability and a RANDO head phantom were used for scan acquisition procedures. Image registration using bony anatomy was performed on two image sets generated using the current clinical scan protocol (HNS20) and an experimental modified scan protocol (MHNS20). Image registration results were compared by two investigators. Measurements of scan doses using a metal-oxide-semiconductor field-effect transistor and a Unidose meter were performed. Catphan phantom images were acquired using HNS20 and MHNS20 protocols. In phase 2, ten volunteer RTs performed image registration and matching processes on two image sets performed using HNS20 and MHNS20 protocols. RTs were unaware of the scan protocols used for image acquisition. A threshold of 3 mm was set (the current maximum couch shift allowance in the clinical HNC IGRT protocol) to compare the image registration data from HNS20 and MHNS20. In phase 3, after research ethics board approval, 10 HNC patients consented to the study. Two pretreatment CBCT scans were performed: scan 1 was acquired using MHNS20 protocol, and scan 2 was acquired using the HNS20 protocol. A threshold of 2 mm was set to compare the differences in couch shift data resulting from the image registration of the two image sets. Comparison of HNS20 and MHNS20 based on image registration results was performed.

Results: In phase 1, radiation doses measured by the investigators on the left optical lens using a metal-oxide-semiconductor field-effect transistor and a Unidose meter indicated that the MHNS20 protocol would result in a lower dose to the left optical lens. In phase 2, shifts of the treatment table to achieve the planned isocentre, which were recorded after the image matching process, were within 3 mm in 80% of the RT procedures. In the y-axis (superior/inferior direction), 100% of the procedures were within 3 mm. In the z-axis (anterior/posterior) and x-axis (lateral), 90% of the procedures were within 3 mm. Qualitative data from a questionnaire completed by RTs after the image matching indicated that 50% of the RTs had no preference between the images sets in terms of visibility of structures. Forty percent of RTs had no preference regarding speed of matching or preference for registration between the image sets. When a preference was indicated, the HNS20 scan protocol was chosen by the RTs. In phase 3, couch shift data recorded after each CBCT scan were compared. All results in all three planes for 10 patients included in the study were within the 2-mm threshold.

Conclusions: The feasibility and clinical utility of a potential lower-dose CBCT scan protocol has been investigated. The modified protocol (MHNS20) produced image data acceptable within current practice using bony anatomy for registration purposes. The MHNS20 protocol also delivered lower doses to the left optical lens and therefore potentially to other pertinent structures. The actual delivered doses to patients during IGRT procedures using the MHNS20 may be different than those measured during this investigation.
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http://dx.doi.org/10.1016/j.jmir.2014.10.005DOI Listing
June 2015

Satellite RNAs interfere with the function of viral RNA silencing suppressors.

Front Plant Sci 2015 24;6:281. Epub 2015 Apr 24.

Commonwealth Scientific and Industrial Research Organisation Plant Industry Canberra, ACT, Australia.

Viral satellite RNAs (satRNAs) are small subviral RNAs and depend on the helper virus for replication and spread. satRNAs can attenuate helper virus-induced symptoms, the mechanism of which remains unclear. Here, we show that two virus-encoded suppressors of RNA silencing (VSRs), Cucumber mosaic virus (CMV) 2b and Tombusvirus P19, suppress hairpin RNA (hpRNA)-induced silencing of a β-glucuronidase (GUS) gene in Nicotiana benthamiana. This suppression can be overcome by CMV Y-satellite RNA (Y-Sat) via the Y-Sat-derived small interfering RNAs (siRNAs), which bind to the VSRs and displace the bound hpGUS-derived siRNAs. We also show that microRNA target gene expression in N. tabacum was elevated by CMV infection, presumably due to function of the 2b VSR, but this upregulation of microRNA target genes was reversed in the presence of Y-Sat. These results suggest that satRNA infection minimizes the effect of VSRs on host siRNA and microRNA-directed silencing. Our results suggest that the high abundance of satRNA-derived siRNAs contributes to symptom attenuation by binding helper virus-encoded VSRs, minimizing the capacity of the VSRs to bind host siRNA and miRNA and interfere with their function.
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http://dx.doi.org/10.3389/fpls.2015.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408847PMC
May 2015

Characterization of a novel mutation in F8 gene causing severe haemophilia A by deletion mapping with STS markers.

Haemophilia 2015 Mar 27;21(2):e136-9. Epub 2015 Jan 27.

Department of Obstetrics & Gynaecology, Queen Mary Hospital, Hong Kong, Hong Kong.

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http://dx.doi.org/10.1111/hae.12607DOI Listing
March 2015

DNA demethylases target promoter transposable elements to positively regulate stress responsive genes in Arabidopsis.

Genome Biol 2014 Sep 17;15(9):458. Epub 2014 Sep 17.

Background: DNA demethylases regulate DNA methylation levels in eukaryotes. Arabidopsis encodes four DNA demethylases, DEMETER (DME), REPRESSOR OF SILENCING 1 (ROS1), DEMETER-LIKE 2 (DML2), and DML3. While DME is involved in maternal specific gene expression during seed development, the biological function of the remaining DNA demethylases remains unclear.

Results: We show that ROS1, DML2, and DML3 play a role in fungal disease resistance in Arabidopsis. A triple DNA demethylase mutant, rdd (ros1 dml2 dml3), shows increased susceptibility to the fungal pathogen Fusarium oxysporum. We identify 348 genes differentially expressed in rdd relative to wild type, and a significant proportion of these genes are downregulated in rdd and have functions in stress response, suggesting that DNA demethylases maintain or positively regulate the expression of stress response genes required for F. oxysporum resistance. The rdd-downregulated stress response genes are enriched for short transposable element sequences in their promoters. Many of these transposable elements and their surrounding sequences show localized DNA methylation changes in rdd, and a general reduction in CHH methylation, suggesting that RNA-directed DNA methylation (RdDM), responsible for CHH methylation, may participate in DNA demethylase-mediated regulation of stress response genes. Many of the rdd-downregulated stress response genes are downregulated in the RdDM mutants nrpd1 and nrpe1, and the RdDM mutants nrpe1 and ago4 show enhanced susceptibility to F. oxysporum infection.

Conclusions: Our results suggest that a primary function of DNA demethylases in plants is to regulate the expression of stress response genes by targeting promoter transposable element sequences.
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http://dx.doi.org/10.1186/s13059-014-0458-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189188PMC
September 2014

An FDA perspective on preclinical development of cell-based regenerative medicine products.

Nat Biotechnol 2014 Aug;32(8):721-3

FDA, Center for Biologics Evaluation and Research, Office of Cellular Tissue and Gene Therapies, Silver Spring, Maryland, USA.

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http://dx.doi.org/10.1038/nbt.2971DOI Listing
August 2014

Characterizing RNA-protein interaction using cross-linking and metabolite supplemented nuclear RNA-immunoprecipitation.

Mol Biol Rep 2014 May 4;41(5):2971-7. Epub 2014 Feb 4.

Black Mountain Laboratories, Commonwealth Scientific and Industrial Research Organisation Plant Industry, GPO 1600, Canberra, ACT, 2601, Australia.

RNA-immunoprecipitation (RNA-IP) is a method used to isolate and identify RNA molecules specifically associated with an RNA-binding protein. Non-coding RNAs are emerging as key regulators of many biological and developmental pathways and RNA-IP has become an important tool in studying their function(s). While RNA-IP is successfully used to determine protein-RNA interaction, specific details regarding the level of this association and the metabolic requirement of this interaction which can influence the success of RNA-IP remain unclear. Here, we investigate the conditions required for efficient nuclear RNA-IP using Arabidopsis AGO4 (Argonaute 4) and siRNA binding as the study model. We showed that formaldehyde cross-linking, but not UV cross-linking, allowed for efficient pull-down of 24-nt siRNAs, suggesting that AGO4-siRNA interaction involves other protein(s). We also showed that, while formaldehyde cross-linking could also be performed on purified nuclei, ATP supplementation to the nuclei isolation buffer was needed to efficiently pull down 24-nt siRNAs. This result indicates that ATP is required for efficient siRNA loading onto AGO4. As most of the known RNA-mediated regulatory processes occur in the nucleus, our findings on cross-linking conditions and metabolite requirement for successful AGO4 nuclear RNA-IP provide a valuable insight and future consideration when studying the function of protein-RNA interactions in plants.
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http://dx.doi.org/10.1007/s11033-014-3154-1DOI Listing
May 2014

De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review.

Am J Med Genet A 2014 Mar 19;164A(3):676-84. Epub 2013 Dec 19.

Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Alberta, Canada.

Shprintzen-Goldberg syndrome (OMIM #182212) is a connective tissue disorder characterized by craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome. SKI is a known regulator of TGFβ signaling. Therefore, like Marfan syndrome and Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome is likely caused by deregulated TGFβ signals, explaining the considerable phenotypic overlap between these three disorders. We describe two additional patients with exon 1 SKI mutations and review the clinical features and literature of Shprintzen-Goldberg syndrome.
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http://dx.doi.org/10.1002/ajmg.a.36340DOI Listing
March 2014

Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures.

Am J Med Genet A 2014 Feb 19;164A(2):441-8. Epub 2013 Dec 19.

Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.

A clinically recognizable syndrome associated with 1q41q42 microdeletion has recently been described in the literature (OMIM 612530). Patients with microdeletions in this region of chromosome 1 typically have developmental delay, characteristic dysmorphic features, and a predisposition to seizures. Malformations such as congenital diaphragmatic hernia and cleft lip have also been described. There has been considerable interest in mapping the smallest region of overlap for this syndrome in order to identify the critical pathogenic genes. The smallest region of overlap has recently been refined to a region encompassing four genes. Using array comparative genome hybridization (array CGH), we have identified a female with a 590-kB deletion within chromosome1q41q42. This patient's deletion further refines the previously defined region of overlap to a single gene, FBXO28. We propose that FBXO28 is a possible candidate causative gene contributing to the intellectual disability and seizure phenotype observed in 1q41q42 microdeletion syndrome.
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http://dx.doi.org/10.1002/ajmg.a.36320DOI Listing
February 2014

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells.

Proc Natl Acad Sci U S A 2013 Jul 16;110(31):12774-9. Epub 2013 Jul 16.

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.

Efficient generation of competent vasculogenic cells is a critical challenge of human induced pluripotent stem (hiPS) cell-based regenerative medicine. Biologically relevant systems to assess functionality of the engineered vessels in vivo are equally important for such development. Here, we report a unique approach for the derivation of endothelial precursor cells from hiPS cells using a triple combination of selection markers--CD34, neuropilin 1, and human kinase insert domain-containing receptor--and an efficient 2D culture system for hiPS cell-derived endothelial precursor cell expansion. With these methods, we successfully generated endothelial cells (ECs) from hiPS cells obtained from healthy donors and formed stable functional blood vessels in vivo, lasting for 280 d in mice. In addition, we developed an approach to generate mesenchymal precursor cells (MPCs) from hiPS cells in parallel. Moreover, we successfully generated functional blood vessels in vivo using these ECs and MPCs derived from the same hiPS cell line. These data provide proof of the principle that autologous hiPS cell-derived vascular precursors can be used for in vivo applications, once safety and immunological issues of hiPS-based cellular therapy have been resolved. Additionally, the durability of hiPS-derived blood vessels in vivo demonstrates a potential translation of this approach in long-term vascularization for tissue engineering and treatment of vascular diseases. Of note, we have also successfully generated ECs and MPCs from type 1 diabetic patient-derived hiPS cell lines and use them to generate blood vessels in vivo, which is an important milestone toward clinical translation of this approach.
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http://dx.doi.org/10.1073/pnas.1310675110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732948PMC
July 2013