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1.  The prevalence and correlation of carotid artery calcification on panoramic radiographs and peripheral arterial disease in a population from the Republic of Korea: the Dong-gu study 
Dentomaxillofacial Radiology  2013;42(3):29725099.
Objectives:
The aim of this study was to determine the prevalence of carotid artery calcification (CAC) detected on panoramic radiographs and peripheral arterial disease (PAD), and to evaluate the difference in the prevalence of PAD between patients with CAC and patients without CAC detectable by panoramic radiograph.
Methods:
The surveyed population consisted of 4078 subjects aged 50 years and older (1410 males and 2668 females) who underwent medical and dental examination in Gwangju city, South Korea. Two oral and maxillofacial radiologists interpreted the panoramic radiographs for the presence of carotid artery calcification. A trained research technician measured the ankle–brachial index (ABI). An ABI <0.9 in either leg was considered evidence of PAD.
Results:
The prevalence of CAC on panoramic radiographs was 6.2% and that of PAD was 2.6%. Subjects with CAC had a significantly higher prevalence of PAD than those without CAC (5.5% vs 2.4%, respectively). The presence of CAC on panoramic radiographs was associated with PAD (odds ratio 1.84; 95% confidence interval 1.01–3.36) after adjusting for potential confounders.
Conclusion:
CACs detected on panoramic radiographs were positively associated with PAD in middle-aged and older Korean adults.
doi:10.1259/dmfr/29725099
PMCID: PMC3667535  PMID: 22752323
carotid artery; panoramic radiography; peripheral arterial disease; ankle–brachial index
2.  The effect of photobiomodulation on root resorption during orthodontic treatment 
Photobiomodulation is used to accelerate tooth movement during orthodontic treatments. The changes in root morphology in a group of orthodontic patients who received photobiomodulation were evaluated using the cone beam computed tomography technique. The device used is called OrthoPulse, which produces low levels of light with a near infrared wavelength of 850 nm and an intensity of 60 mW/cm2 continuous wave. Twenty orthodontic patients were recruited for these experiments, all with class 1 malocclusion and with Little’s Irregularity Index (>2 mm) in either of the arches. Root resorption was detected by measuring changes in tooth length using cone beam computed tomography. These changes were measured before the orthodontic treatment and use of low-level laser therapy and after finishing the alignment level. Little’s Irregularity Index for all the patients was calculated in both the maxilla and mandible and patients were divided into three groups for further analysis, which were then compared to the root resorption measurements. Our results showed that photobiomodulation did not cause root resorption greater than the normal range that is commonly detected in orthodontic treatments. Furthermore, no correlation between Little’s Irregularity Index and root resorption was detected.
doi:10.2147/CCIDE.S49489
PMCID: PMC3896253  PMID: 24470774
photobiomodulation; root resorption; accelerate tooth movement; orthodontics; cone beam computed tomography
3.  Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aβ1–42-infused mouse model of Alzheimer's disease 
Cell Death & Disease  2013;4(12):e958-.
Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of central nervous system (CNS) and are currently being tested in clinical trials for neurological disorders, but preventive mechanisms of placenta-derived MSCs (PD-MSCs) for Alzheimer's disease are poorly understood. Herein, we investigated the inhibitory effect of PD-MSCs on neuronal cell death and memory impairment in Aβ1–42-infused mice. After intracerebroventrical (ICV) infusion of Aβ1–42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. Our results showed that the transplantation of PD-MSCs into Aβ1–42-infused mice significantly improved cognitive impairment, and behavioral changes attenuated the expression of APP, BACE1, and Aβ, as well as the activity of β-secretase and γ-secretase. In addition, the activation of glia cells and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by the transplantation of PD-MSCs. Furthermore, we also found that PD-MSCs downregulated the release of inflammatory cytokines as well as prevented neuronal cell death and promoted neuronal cell differentiation from neuronal progenitor cells in Aβ1–42-infused mice. These data indicate that PD-MSC mediates neuroprotection by regulating neuronal death, neurogenesis, glia cell activation in hippocampus, and altering cytokine expression, suggesting a close link between the therapeutic effects of MSCs and the damaged CNS in Alzheimer's disease.
doi:10.1038/cddis.2013.490
PMCID: PMC3877561  PMID: 24336078
PD-MSC; Alzheimer's disease; amyloid-β; cytokines; neurogenesis
4.  HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia 
Oncotarget  2013;4(11):1933-1947.
Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro. Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia.
PMCID: PMC3875760  PMID: 24177192
HoxA9; Bcl-2; Leukemia; apoptosis
5.  MRI to differentiate benign from malignant soft-tissue tumours of the extremities: a simplified systematic imaging approach using depth, size and heterogeneity of signal intensity 
The British Journal of Radiology  2012;85(1018):e831-e836.
Objective
Differentiating between malignant and benign lesions on the basis of MR images depends on the experience of the radiologist. For non-experts, we aimed to develop a simplified systematic MRI approach that uses depth, size and heterogeneity on T2 weighted MR images (T2WI) to differentiate between malignant and benign lesions, and evaluated its diagnostic accuracy.
Methods
MR images of 266 patients with histologically proven soft-tissue tumours of the extremities (102 malignant, 164 benign) were analysed according to depth (superficial or deep), size (<50, ≥50 mm) and signal intensity (homogeneous or heterogeneous) on T2WI, to determine the ability of each to predict benign and malignant tumours. These three parameters were categorised into systematic combinations of different orders of application, and each combination was assessed for its ability to differentiate between benign and malignant lesions.
Results
Univariate analysis showed that depth, size and heterogeneity on T2WI differed significantly between benign and malignant masses (p<0.0001 each). Multiple logistic regression analysis, however, showed that depth was not helpful in distinguishing benign from malignant lesions. The systematic combination of signal intensity, size and depth, in that order, was superior to other combinations, resulting in higher diagnostic values for malignancy, with a sensitivity of 64%, a specificity of 85%, a positive predictive value of 32%, a negative predictive value of 59% and an accuracy of 77%.
Conclusion
A simplified systematic imaging approach, in the order signal intensity, size and depth, would be a reference to distinguish between benign and malignant soft-tissue tumours for non-experts.
doi:10.1259/bjr/27487871
PMCID: PMC3474004  PMID: 22553293
6.  Contrast-enhanced MR cholangiography: comparison of Gd-EOB-DTPA and Mn-DPDP in healthy volunteers 
The British Journal of Radiology  2012;85(1017):1250-1254.
Objective
The purpose of this study was to compare the biliary enhancement dynamics of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid (Gd-EOB-DTPA) and mangafodipir trisodium (Mn-DPDP) for contrast-enhanced MR cholangiography (MRC) in healthy subjects.
Methods
15 healthy volunteers underwent MRI at 1.5 T with volumetric interpolated breath-hold examination sequence. Each volunteer was scanned once for each contrast agent. The signal-to-noise ratio (SNR) of the liver parenchyma and common hepatic duct (CHD) and the contrast-to-noise ratio (CNR) of CHD to liver parenchyma were evaluated and compared before and at several time points (5, 15, 30, 45, 60, 90, and 120 min) after injection of each agent.
Results
SNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP in liver parenchyma after 5 min and in CHD after 15 min (p<0.05). CNR of CHD to liver parenchyma using Gd-EOB-DTPA showed an initial decrease at 5 min post-injection followed by a steep increase to a peak at 15 min post-injection. CNR using Mn-DPDP showed a steady increase to a peak at 15 min post-injection without an initial decrease. At 15 min, the value of CNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP (p<0.05).
Conclusion
For both contrast agents, CNR reached a peak at 15 min after contrast injection. At this time point, CNR of Gd-EOB-DTPA was significantly higher than that of Mn-DPDP. Therefore, Gd-EOB-DTPA may provide better contrast-enhanced MRC than Mn-DPDP at 15 min after contrast administration.
doi:10.1259/bjr/22238911
PMCID: PMC3487056  PMID: 22553292
7.  Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis 
British Journal of Cancer  2012;106(11):1833-1841.
Background:
Colorectal cancer (CRC) is a leading cause of death in the United States. Increased level of interleukin-8 (IL-8) and CXCR2 on tumours and in the tumour microenvironment has been associated with CRC growth, progression and recurrence in patients. Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis.
Methods:
A novel immunodeficient, skin-specific IL-8-expressing transgenic model was generated to evaluate colon cancer growth and metastasis. Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth.
Results:
Elevated levels of IL-8 in the serum and tumour microenvironment profoundly enhanced the growth of human and mouse colon cancer cells with increased peri-tumoural angiogenesis, and also promoted the extravasation of the cancer cells into the lung and liver. The tumour growth was inhibited in CXCR2 KO mice with significantly reduced tumour angiogenesis and increased tumour necrosis.
Conclusion:
Increased expression of IL-8 in the tumour microenvironment enhanced colon cancer growth and metastasis. Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth. Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.
doi:10.1038/bjc.2012.177
PMCID: PMC3364111  PMID: 22617157
colorectal cancer; CXCR2; IL-8; tumour microenvironment
8.  The anatomical evaluation of the dental arches using cone beam computed tomography - an investigation of the availability of bone for placement of mini-screws 
Head & Face Medicine  2013;9:13.
Objective
To assess the amount of maxillary and mandibular inter-radicular bone mass and determine the most reliable mini-screw placement sites.
Materials and methods
Retrospective Cone Beam Computed Tomography (CBCT) images of 40 Angle Class I subjects (20 females, 20 males, aged 16 to 32) were obtained. Measurements on the buccal (BI), medial (MI) and lingual (LI) sides of the inter-radicular spaces were taken at 0, 1, 2, 3, 4, 5 mm from the cemento-enamel junction (CEJ) in an apical direction.
Results
The male and female BI scores ranged from 2.99±0.73 mm to 6.18±1.03 mm and 2.69±0.84 mm to 6.21±1.22 mm respectively. The male and female MI scores ranged from 1.36±0.38 mm to 4.50±0.99 and 1.53±0.66 to 4.77±1.99 mm respectively. LI scores ranged from 2.37±0.70 to 6.47±1.0 mm and 2.45±0.56 mm and 6.66±1.33 mm respectively. In both maxillary and mandibular arch, the inter-radicular space increased in the apical direction except for the buccal and medial inter-radicular spaces between the maxillary first and second molars.
Conclusion
The medial inter-radicular spaces are the decisive parameter for mini-screw placement. In the maxillary arch, regions between central and lateral incisors, lateral incisor and canine, first and second molars are not viable for mini-screw insertion. The residual inter-radicular regions are proper for implantation at 3 mm above the CEJ. In the mandible, the regions between incisors and canines are too narrow for mini-screw insertion and the reliable sites for mini-screws are regions between premolars, molars or first molar and second premolar at 2 mm below the CEJ.
doi:10.1186/1746-160X-9-13
PMCID: PMC3662167  PMID: 23601073
9.  Olig2/Plp-positive progenitor cells give rise to Bergmann glia in the cerebellum 
Cell Death & Disease  2013;4(3):e546-.
NG2 (nerve/glial antigen2)-expressing cells represent the largest population of postnatal progenitors in the central nervous system and have been classified as oligodendroglial progenitor cells, but the fate and function of these cells remain incompletely characterized. Previous studies have focused on characterizing these progenitors in the postnatal and adult subventricular zone and on analyzing the cellular and physiological properties of these cells in white and gray matter regions in the forebrain. In the present study, we examine the types of neural progeny generated by NG2 progenitors in the cerebellum by employing genetic fate mapping techniques using inducible Cre–Lox systems in vivo with two different mouse lines, the Plp-Cre-ERT2/Rosa26-EYFP and Olig2-Cre-ERT2/Rosa26-EYFP double-transgenic mice. Our data indicate that Olig2/Plp-positive NG2 cells display multipotential properties, primarily give rise to oligodendroglia but, surprisingly, also generate Bergmann glia, which are specialized glial cells in the cerebellum. The NG2+ cells also give rise to astrocytes, but not neurons. In addition, we show that glutamate signaling is involved in distinct NG2+ cell-fate/differentiation pathways and plays a role in the normal development of Bergmann glia. We also show an increase of cerebellar oligodendroglial lineage cells in response to hypoxic–ischemic injury, but the ability of NG2+ cells to give rise to Bergmann glia and astrocytes remains unchanged. Overall, our study reveals a novel Bergmann glia fate of Olig2/Plp-positive NG2 progenitors, demonstrates the differentiation of these progenitors into various functional glial cell types, and provides significant insights into the fate and function of Olig2/Plp-positive progenitor cells in health and disease.
doi:10.1038/cddis.2013.74
PMCID: PMC3615735  PMID: 23492777
Olig2 progenitor cell; cerebellum; Bergmann glia
10.  The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiation 
Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes the growth, survival, differentiation and activation of normal myeloid cells and is essential for fully functional macrophage differentiation in vivo. To better understand the mechanisms by which growth factors control the balance between proliferation and self-renewal versus growth-suppression and differentiation we have used the bi-potent FDB1 myeloid cell line, which proliferates in IL-3 and differentiates to granulocytes and macrophages in response to GM-CSF. This provides a manipulable model in which to dissect the switch between growth and differentiation. We show that, in the context of signaling from an activating mutant of the GM-CSF receptor β subunit, a single intracellular tyrosine residue (Y577) mediates the granulocyte fate decision. Loss of granulocyte differentiation in a Y577F second-site mutant is accompanied by enhanced macrophage differentiation, accumulation of β-catenin together with activation of Tcf4 and other Wnt target genes. These include the known macrophage lineage inducer, Egr1. We show that forced expression of Tcf4 or a stabilised β-catenin mutant is sufficient to promote macrophage differentiation in response to GM-CSF and that GM-CSF can regulate β-catenin stability, most likely via GSK3β. Consistent with this pathway being active in primary cells we show that inhibition of GSK3β activity promotes the formation of macrophage colonies at the expense of granulocyte colonies in response to GM-CSF. This study therefore identifies a novel pathway through which growth factor receptor signalling can interact with transcriptional regulators to influence lineage choice during myeloid differentiation.
doi:10.1016/j.diff.2011.08.003
PMCID: PMC3394929  PMID: 22099176
Myeloid; transcription-factor; β-catenin; Tcf4; signal-transduction
11.  Functionally distinct monomers and trimers produced by a viral oncoprotein 
Oncogene  2007;27(10):1412-1420.
While the process of homo-oligomer formation and disassembly into subunits represents a common strategy to regulate protein activity, reports of proteins in which the subunit and homo-oligomer perform independent functions are scarce. Tumorigenesis induced by the adenovirus E4-ORF1 oncoprotein depends on its binding to a select group of cellular PDZ proteins, including MUPP1, MAGI-1, ZO-2 and Dlg1. We report here that in cells E4-ORF1 exists as both a monomer and trimer and that monomers specifically bind and sequester MUPP1, MAGI-1 and ZO-2 within insoluble complexes whereas trimers specifically bind Dlg1 and promote its translocation to the plasma membrane. This work exposes a novel strategy wherein the oligomerization state of a protein not only determines the capacity to bind separate related targets but also couples the interactions to different functional consequences.
doi:10.1038/sj.onc.1210784
PMCID: PMC3471668  PMID: 17828302
adenovirus; E4-ORF1; monomer; PDZ; trimer
12.  Apical root resorption caused by orthodontic forces: A brief review and a long-term observation 
European Journal of Dentistry  2012;6(4):445-453.
External apical root resorption (ARR) is a common iatrogenic consequence of orthodontic treatment. One of the aims of this article is to present a brief overview of the literature, including; diagnosis and etiology, with emphasis on orthodontic forces to facilitate an understand of the prevention or management of ARR in orthodontic patients. We also present a long-term follow-up observation of severe ARR, including the last obtained cone beam computed tomography (CBCT) records, to demonstrate the effect of orthodontic forces on ARR.
PMCID: PMC3474562  PMID: 23077427
Root resorption; orthodontic treatment; orthodontic forces; follow- up case
13.  Outcome Study of Computer-Aided Surgical Simulation in the Treatment of Patients with Craniomaxillofacial Deformities 
Purpose
The purpose of this study is to determine whether the surgical outcomes achieved with computer-aided surgical simulation (CASS) are better than those achieved with traditional methods.
Material and Methods
Twelve consecutive patients with craniomaxillofacial deformities (CMF) deformities were enrolled. Following our CASS clinical protocol, a 3D computer composite skull model for each patient was generated and reoriented to the neutral head posture. These models underwent 2 virtual surgeries: one was based on CASS (experimental group) and the other was based on traditional methods a year later (control group). Once both virtual surgeries were completed, 2 experienced oral-maxillofacial surgeons at 2 different settings evaluated both surgical outcomes. They were blinded to the planning method used on the virtual models, and each other’s evaluation results. The primary outcome was overall CMF skeletal harmony. The secondary outcomes were individual maxillary, mandibular and chin harmonies. Finally, statistical analyses were performed.
Results
Overall CMF skeletal harmony achieved with CASS was statistically significantly better than that achieved with traditional methods. In addition, the maxillary and mandibular surgical outcomes achieved with CASS method were also significantly better. Furthermore, although not included in the statistical model, the chin symmetry achieved by CASS tended to be better. Finally, a regression model was established between the mandibular symmetry and the overall CMF skeletal harmony.
Conclusion
The surgical outcomes achieved with CASS are significantly better than those achieved with traditional planning methods. In addition, CASS enables the surgeon to better correct maxillary yaw deformity, better place proximal/distal segment, and better restore mandibular symmetry. Finally, the critical step in achieving better overall CMF skeletal harmony is to restore mandibular symmetry.
doi:10.1016/j.joms.2011.02.018
PMCID: PMC3119456  PMID: 21684451
14.  Does hyrax expansion therapy affect maxillary sinus volume? A cone-beam computed tomography report 
Imaging Science in Dentistry  2012;42(2):83-88.
Purpose
The aim of this study was to investigate the initial effects of maxillary expansion therapy with Hyrax appliance and to evaluate the related changes in maxillary sinus volume.
Materials and Methods
Thirty patients (20 females, 10 males; 13.8 years) requiring maxillary expansion therapy, as part of their comprehensive orthodontic treatment, were examined. Each patient had cone-beam computed tomography (CBCT) images taken before (T1) and after (T2) maxillary expansion therapy with a banded Hyrax appliance. Multiplanar slices were used to measure linear dimensions and palatal vault angle. Volumetric analysis was used to measure maxillary sinus volumes. Student t tests were used to compare the pre- and post-treatment measurements. Additionally, differences between two age groups were compared with Mann-Whitney U test. The level of significance was set at p=0.05.
Results
Comparison of pre-treatment to post-treatment variables revealed significant changes in the transverse dimension related to both maxillary skeletal and dental structures and palatal vault angle, resulting in a widened palatal vault (p<0.05). Hard palate showed no significant movement in the vertical and anteroposterior planes. Nasal cavity width increased on a mean value of 0.93mm(SD=0.23, p<0.05). Maxillary sinus volume remained virtually stable. No significant age differences were observed in the sample.
Conclusion
Hyrax expansion therapy did not have a significant impact on maxillary sinus volume.
doi:10.5624/isd.2012.42.2.83
PMCID: PMC3389054  PMID: 22783476
Palatal Expansion Technique; Maxillary Sinus; Cone-Beam Computed Tomography
15.  Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia 
Nature genetics  2011;43(10):1012-1017.
We report the discovery of the GATA2 gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS/AML in three families, and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS/AML family. The mutations reside within the second zinc finger of GATA2 which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutants on transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counselling, selection of related bone marrow transplant donors, and development of therapies.
doi:10.1038/ng.913
PMCID: PMC3184204  PMID: 21892162
16.  A New Method to Orient Three-Dimensional Computed Tomography Models to the Natural Head Position: A Clinical Feasibility Study 
Purpose
The purpose of this study was to evaluate the clinical feasibility of a new method to orient three-dimensional (3D) computed tomography (CT) models to the natural head position (NHP). This method utilizes a small and inexpensive digital orientation device to record NHP in 3D. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer two questions: 1) whether the weight of the new device can negatively influence the NHP; and 2) wether the new method is as accurate as the gold standard.
Materials and Methods
Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient’s NHP is recorded 3 times. The 1st NHP was recorded using a laser scanning method without the presence of the digital orientation device. The 2nd NHP was recorded using the digital orientation device. Simultaneously, the 3rd NHP wa also recorded using the laser scanning method. Each recorded NHP measurement was then transferred to the patient’s 3D CT facial model, resulting in 3 different orientations for each patient. They include: the orientation generated using the laser scanning method without the presence of the digital orientation sensor and facebow (Orientation 1); the orientation generated using the laser scanning method with the presence of the digital orientation sensor and facebow (Orientation 2); and the orientation generated using the digital orientation device (Orientation 3). The comparisons are then made between Orientations 1 and 2, and Orientations 2 and 3, respectively. Statistical analyses are performed.
Results
The results show that in each pair, the delta between the 2 measurements is not statistically significantly different from 0 degrees. In addition, in the 1st pair, Bland and Altman’s lower and upper limits of the delta between the 2 measurements are within 1.5° in pitch and sub-degree in roll and yaw. In the 2nd pair, the limits of the delta in all three dimensions are within 0.5°.
Conclusion
Our technique can accurately record NHP in three dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.
doi:10.1016/j.joms.2010.10.034
PMCID: PMC3053123  PMID: 21353923
Natural head position; self-balanced; three-dimensional; recording; transferring; computed tomography; computer modeling
17.  p53-Dependent Transcriptional Responses to Interleukin-3 Signaling 
PLoS ONE  2012;7(2):e31428.
p53 is critical in the normal response to a variety of cellular stresses including DNA damage and loss of p53 function is a common feature of many cancers. In hematological malignancies, p53 deletion is less common than in solid malignancies but is associated with poor prognosis and resistance to chemotherapy. Compared to their wild-type (WT) counterparts, hematopoietic progenitor cells lacking p53 have a greater propensity to survive cytokine loss, in part, due to the failure to transcribe Puma, a proapoptotic Bcl-2 family member. Using expression arrays, we have further characterized the differences that distinguish p53−/− cells from WT myeloid cells in the presence of Interleukin-3 (IL-3) to determine if such differences contribute to the increased clonogenicity and survival responses observed in p53−/− cells. We show that p53−/− cells have a deregulated intracellular signaling environment and display a more rapid and sustained response to IL-3. This was accompanied by an increase in active ERK1/2 and a dependence on an intact MAP kinase signaling pathway. Contrastingly, we find that p53−/− cells are independent on AKT for their survival. Thus, loss of p53 in myeloid cells results in an altered transcriptional and kinase signaling environment that favors enhanced cytokine signaling.
doi:10.1371/journal.pone.0031428
PMCID: PMC3279357  PMID: 22348085
19.  Integration of CNS survival and differentiation by HIF2α 
Cell Death and Differentiation  2011;18(11):1757-1770.
Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.
doi:10.1038/cdd.2011.44
PMCID: PMC3190110  PMID: 21546908
HIF2α; surviving; neural progenitor cells; apoptosis
20.  A radiographic analysis of tooth morphology following the use of a novel cyclical force device in orthodontics 
Head & Face Medicine  2011;7:14.
Background
The purpose was to determine whether or not a novel device used in conjunction with orthodontic treatment produced root resorption shown on 3D images generated from a new cone beam computerized tomography.
Methods
Subjects were actively recruited and those who received braces for the first time were invited to participate. Patients were assigned to receive a functioning device and used the devices for 20 min daily for a six month study period. CBCT images were taken of the dentition at the start of treatment and at the end of the study period.
Results
14 subjects out of a possible 17 subjects completed using the device during the study period. The mean age of the subjects was 20.3 years. Measurements of all teeth present were made from the mesial buccal roots of the first molar on one side of the dental arch to the mesial buccal roots of the first molar on the opposing side of the same arch. These measurements were recorded as linear lengths in mm. A paired t-test was used to determine if significant differences occurred for root lengths at the end of treatment compared to the start of treatment for each of the individual tooth groups. No statistical differences were noted for root length changes above 0.5 mm and 1 mm.
Conclusions
No statistically significant findings were noted for root length change at the end of treatment compared to the start of treatment when using this novel robotic device. No significant differences were noted between roots of anterior and posterior teeth. No clinically significant changes between root lengths were noted above 0.5 mm.
doi:10.1186/1746-160X-7-14
PMCID: PMC3162905  PMID: 21827655
21.  Circulating osteocalcin level is associated with improved glucose tolerance, insulin secretion and sensitivity independent of the plasma adiponectin level 
Osteoporosis International  2011;23(4):1337-1342.
Summary
In agreement with the results of animal studies, the plasma osteocalcin level is positively associated with improved glucose tolerance and insulin secretion and sensitivity. In addition, the plasma osteocalcin level is inversely associated with the development of diabetes; however, the plasma adiponectin level may not be involved in osteocalcin-mediated energy metabolism in humans.
Introduction
Recent animal studies have suggested crosstalk between bone and energy metabolism through osteocalcin. The aims of this study were to determine whether or not osteocalcin is associated with the improved glucose tolerance and insulin secretion and sensitivity, and whether or not the association is dependent on the plasma adiponectin level in humans.
Methods
Four hundred twenty-five subjects, 19–82 years of age (mean age, 53 years), were enrolled. An oral glucose tolerance test (OGTT) and OGTT-based methods that were validated against the euglycemic clamp were determined. Total osteocalcin, leptin, and total adiponectin levels were measured.
Results
The plasma levels of total osteocalcin were significantly different between the normal glucose tolerance, pre-diabetes, and diabetes groups. The glucose levels and homeostasis model assessment insulin resistance values varied inversely with the osteocalcin tertiles, and OGTT-based insulin secretion (HOMA-B%, disposition index) and insulin sensitivity indices (Stumvoll’s and OGIS indices) were increased with the tertiles. Although the plasma adiponectin level was positively correlated with the osteocalcin level, no changes in the association were noted between the plasma osteocalcin level and the glucose tolerance or insulin secretion and sensitivity indices after adjustment for the plasma adiponectin level. Based on multiple logistic regression analysis, the plasma osteocalcin level was inversely associated with the development of type 2 diabetes mellitus independent of age, gender, body mass index, and fasting plasma glucose and plasma adiponectin levels.
Conclusions
Circulating osteocalcin level is associated with improved glucose tolerance and insulin secretion and sensitivity independent of the plasma adiponectin level in humans.
doi:10.1007/s00198-011-1679-x
PMCID: PMC3304051  PMID: 21656264
Adiponectin; Insulin resistance; Insulin secretion; Osteocalcin
22.  Alteplase for the treatment of acute ischaemic stroke: NICE technology appraisal guidance 
Heart  2007;93(12):1616-1618.
This NICE technology appraisal guidance considers the clinical and cost effectiveness of the use of alteplase for acute ischaemic stroke
doi:10.1136/hrt.2007.132894
PMCID: PMC2095758  PMID: 18003692
23.  Correlation between array-comparative genomic hybridization-defined genomic gains and losses and survival: identification of 1p31-32 deletion as a prognostic factor in myeloma 
In this study, we correlated array-comparative genomic hybridization-defined abnormalities with survival in two different cohorts of patients treated with therapy based on high-dose melphalan with autologous stem-cell transplantation (64 from the Mayo Clinic and 67 from the University of Arkansas Medical School) and identified that several regions of genomic gains and losses were significantly associated with poorer survival. Three noncontiguous survival relevant regions covering 1p31-33 and two noncontiguous regions covering 20p12.3-12.1 were common between the two datasets. The prognostic relevance of these hotspots was validated in an independent cohort using fluorescent in situ hybridization, which showed that 1p31-32 loss is significantly associated with shorter survival (24.5 months versus 40 months, log-rank P-value=0.01), whereas 20p12 loss has a trend toward shorter survival (26.3 months versus 40 months, log-rank P-value=0.06). On multivariate analysis, 1p31-32 loss is an independent prognostic factor. On further analysis, the prognostic impact of 1p31-32 loss is due to shortening of post-relapse survival as there is no impact on complete response rates and progression-free survival.
doi:10.1038/leu.2010.21
PMCID: PMC2977975  PMID: 20220778
prognosis; array-comparative genomic hybridization; chromosome 1p
24.  UNDER GRADUATE RESEARCH 
Science (New York, N.Y.)  2008;322(5902):684-685.
The Genomics Education Partnership offers an inclusive model for undergraduate research experiences incorporated into the academic year science curriculum, with students pooling their work to contribute to international data bases.
doi:10.1126/science.1165351
PMCID: PMC2953277  PMID: 18974335
25.  Placental Vascular Pathology Findings and Pathways to Preterm Delivery 
American Journal of Epidemiology  2009;170(2):148-158.
The authors examined the associations between placental vascular findings and preterm delivery in 1,053 subcohort women (239 preterm, 814 term) from a Michigan pregnancy cohort study (1998–2004). Twenty-nine placental vascular variables from microscopic examinations were grouped into 5 constructs: 3 maternal constructs—obstructive lesions (MV-O), bleeding/vessel integrity (MV-I), and lack of physiologic conversion of maternal spiral arteries (MV-D)—and 2 fetal constructs—obstructive lesions (FV-O) and bleeding/vessel integrity (FV-I). Construct-specific scores were created by adding the number of positive findings and deriving a dichotomous variable to approximate the top quintile (“high”) and bottom 4 quintiles (“not high”) within each construct. In multivariate polytomous logistic regression models, medically indicated preterm delivery at <35 weeks was significantly associated with high scores for each of the vascular constructs; adjusted odds ratios ranged from 2.4 to 5.4. Spontaneous preterm delivery at 35–36 weeks was significantly associated with a high score on any 1 of 3 constructs: MV-I, MV-D, and FV-I. Spontaneous preterm delivery at <35 weeks was significantly associated with a high score on 2 or more of 3 constructs: MV-I, MV-D, and FV-I; adjusted odds ratios ranged from 4.1 to 7.4. These results support a role for various placental vascular lesions in medically indicated and spontaneous preterm delivery.
doi:10.1093/aje/kwp131
PMCID: PMC2727273  PMID: 19509320
blood vessels; placenta; premature birth

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