Publications by authors named "Andy Wu"

36 Publications

Treatment with a long-acting chimeric CSF1 molecule enhances fracture healing of healthy and osteoporotic bones.

Biomaterials 2021 08 3;275:120936. Epub 2021 Jun 3.

Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, 4102, Australia. Electronic address:

Macrophage-targeted therapies, including macrophage colony-stimulating factor 1 (CSF1), have been shown to have pro-repair impacts post-fracture. Preclinical/clinical applications of CSF1 have been expedited by development of chimeric CSF1-Fc which has extended circulating half-life. Here, we used mouse models to investigate the bone regenerative potential of CSF1-Fc in healthy and osteoporotic fracture. We also explored whether combination of CSF1-Fc with interleukin (IL)-4 provided additional fracture healing benefit in osteopenic bone. Micro-computed tomography, in situ histomorphometry, and bone mechanical parameters were used to assess systemic impacts of CSF1-Fc therapy in naive mice (male and female young, adult and geriatric). An intermittent CSF1-Fc regimen was optimized to mitigate undesirable impacts on bone resorption and hepatosplenomegaly, irrespective of age or gender. The intermittent CSF1-Fc regimen was tested in a mid-diaphyseal femoral fracture model in healthy bones with treatment initiated 1-day post-fracture. Weekly CSF1-Fc did not impact osteoclasts but increased osteal macrophages and improved fracture strength. Importantly, this treatment regimen also improved fracture union and strength in an ovariectomy-model of delayed fracture repair. Combining CSF1-Fc with IL-4 initiated 1-week post-fracture reduced the efficacy of CSF1-Fc. This study describes a novel strategy to specifically achieve bone regenerative actions of CSF1-Fc that has the potential to alleviate fragility fracture morbidity and mortality.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120936DOI Listing
August 2021

Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model.

J Bone Miner Res 2021 Jul 19. Epub 2021 Jul 19.

Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.

Osteal macrophages (osteomacs) support osteoblast function and promote bone anabolism, but their contribution to osteoporosis has not been explored. Although mouse ovariectomy (OVX) models have been repeatedly used, variation in strain, experimental design and assessment modalities have contributed to no single model being confirmed as comprehensively replicating the full gamut of osteoporosis pathological manifestations. We validated an OVX model in adult C3H/HeJ mice and demonstrated that it presents with human postmenopausal osteoporosis features with reduced bone volume in axial and appendicular bone and bone loss in both trabecular and cortical bone including increased cortical porosity. Bone loss was associated with increased osteoclasts on trabecular and endocortical bone and decreased osteoblasts on trabecular bone. Importantly, this OVX model was characterized by delayed fracture healing. Using this validated model, we demonstrated that osteomacs are increased post-OVX on both trabecular and endocortical bone. Dual F4/80 (pan-macrophage marker) and tartrate-resistant acid phosphatase (TRAP) staining revealed osteomacs frequently located near TRAP osteoclasts and contained TRAP intracellular vesicles. Using an in vivo inducible macrophage depletion model that does not simultaneously deplete osteoclasts, we observed that osteomac loss was associated with elevated extracellular TRAP in bone marrow interstitium and increased serum TRAP. Using in vitro high-resolution confocal imaging of mixed osteoclast-macrophage cultures on bone substrate, we observed macrophages juxtaposed to osteoclast basolateral functional secretory domains scavenging degraded bone byproducts. These data demonstrate a role for osteomacs in supporting osteoclastic bone resorption through phagocytosis and sequestration of resorption byproducts. Overall, our data expose a novel role for osteomacs in supporting osteoclast function and provide the first evidence of their involvement in osteoporosis pathogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4413DOI Listing
July 2021

Evaluation of structured data from electronic health records to identify clinical classification criteria attributes for systemic lupus erythematosus.

Lupus Sci Med 2021 04;8(1)

Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Objective: Our objective was to develop algorithms to identify lupus clinical classification criteria attributes using structured data found in the electronic health record (EHR) and determine whether they could be used to describe a cohort of people with lupus and discriminate them from a defined healthy control cohort.

Methods: We created gold standard lupus and healthy patient cohorts that were fully adjudicated for the American College of Rheumatology (ACR), Systemic Lupus International Collaborating Clinics (SLICC) and European League Against Rheumatism/ACR (EULAR/ACR) classification criteria and had matched EHR data. We implemented rule-based algorithms using structured data within the EHR system for each attribute of the three classification criteria. Individual criteria attribute and classification criteria algorithms as a whole were assessed over our combined cohorts and the overall performance of the algorithms was measured through sensitivity and specificity.

Results: Individual classification criteria attributes had a wide range of sensitivities, 7% (oral ulcers) to 97% (haematological disorders) and specificities, 56% (haematological disorders) to 98% (photosensitivity), but all could be identified in EHR data. In general, algorithms based on laboratory results performed better than those primarily based on diagnosis codes. All three classification criteria systems effectively distinguished members of our case and control cohorts, but the SLICC criteria-based algorithm had the highest overall performance (76% sensitivity, 99% specificity).

Conclusions: It is possible to characterise disease manifestations in people with lupus using classification criteria-based algorithms that assess structured EHR data. These algorithms may reduce chart review burden and are a foundation for identifying subpopulations of patients with lupus based on disease presentation to support precision medicine applications.
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http://dx.doi.org/10.1136/lupus-2021-000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076919PMC
April 2021

Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice.

J Hematol Oncol 2021 01 6;14(1). Epub 2021 Jan 6.

Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia.

Background: Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation.

Methods: We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay.

Results: CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48CD150 HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48CD150 HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment.

Conclusion: These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.
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http://dx.doi.org/10.1186/s13045-020-00997-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786999PMC
January 2021

A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy.

Cell Mol Gastroenterol Hepatol 2021 1;11(1):33-53. Epub 2020 Jun 1.

Inflammatory Bowel Diseases Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; School of Clinical Medicine, Faculty of Medicine, University of Queensland. Electronic address:

Background & Aims: Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.

Methods: Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7). TG or vehicle was administered intrarectally, and the effect on tumor burden and β-catenin activity was assessed. The mechanisms of action of TG were investigated in vitro and in vivo.

Results: TG ameliorated DSS colitis in wild-type but not Atg7 mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both wild-type and Atg7 mice. This was associated with decreased β-catenin activation/nuclear translocation demonstrating that TG's inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines, and the dependency on Rac1 GTPase was demonstrated by siRNA knockdown and overexpression of constitutively active Rac1.

Conclusions: Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.
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http://dx.doi.org/10.1016/j.jcmgh.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593585PMC
June 2020

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma.

Cancers (Basel) 2020 Apr 3;12(4). Epub 2020 Apr 3.

Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses-of more than 10-fold lower than previously reported for other cancers-significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.
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http://dx.doi.org/10.3390/cancers12040869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226162PMC
April 2020

Development and validation of an analytical method for the analysis of Sterigmatocystin in roasted coffee beans and black pepper using liquid chromatography-tandem mass spectrometry.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 Feb 6;37(2):355-362. Epub 2019 Dec 6.

Food Research Laboratory, Centre for Food Safety, Food and Environmental Hygiene Department, 4/F Public Health Laboratory Centre, Hong Kong, People's Republic of China.

Sterigmatocystin (STC) is a toxic and potentially carcinogenic fungal toxin found in a variety of food commodities. This study describes the development of an analytical method to determine STC in roasted coffee beans and black pepper using ultra performance liquid chromatography (UPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS). C-STC was used as internal standard. STC was extracted with a mixture of acetonitrile/water, diluted with a buffer, followed by purification with a solid-phase extraction and an immunoaffinity column prior to the UPLC-MS/MS analysis. Two multiple reaction monitoring (MRM) transitions were employed, one for quantification and one for confirmation of STC. The UPLC-MS/MS analytical method was validated with respect to selectivity, linearity, sensitivity, accuracy, precision, recovery, and stability. Calibration curves were linear over a concentration range 25-2,500 pg mL with correlation coefficients () > 0.998. The method limit of quantification for STC in roasted coffee beans and black pepper was 0.10 μg kg. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. This method was suitable to determine STC levels because of its selectivity, precision, and accuracy. The method was successfully applied to roasted coffee beans and black pepper samples.
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http://dx.doi.org/10.1080/19440049.2019.1693635DOI Listing
February 2020

CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin.

Oncogene 2020 01 30;39(1):219-233. Epub 2019 Aug 30.

Mater Research Institute-University of Queensland, Woolloongabba, Qld, 4102, Australia.

Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of β-catenin and E-cadherin.
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http://dx.doi.org/10.1038/s41388-019-0983-3DOI Listing
January 2020

MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity.

Oncogene 2019 11 19;38(48):7294-7310. Epub 2019 Aug 19.

Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103 dendritic cells and CD8 T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.
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http://dx.doi.org/10.1038/s41388-019-0951-yDOI Listing
November 2019

Deformation behavior of porous PHBV scaffold in compression: A finite element analysis study.

J Mech Behav Biomed Mater 2019 08 17;96:1-8. Epub 2019 Apr 17.

School of Mechanical and Mining Engineering, The University of Queensland, QLD, 4072, Australia.

Macroscopic mechanical properties of porous PHBV bone TE scaffolds have been well studied. However, their mechanical behavior at microscopic level has yet to be explored. In this study, the micro-mechanical behavior of a PHBV bone scaffold under compression was investigated using a numerical method that combines micro-computed tomography (μ-CT) and finite element analysis (FEA). It was found that the use of a linear-elastic model resulted in an overestimation of the stiffness of the scaffold, whereas a more realistic estimation of the scaffold's deformation behavior was obtained by utilizing a bilinear material model. The onset of plastic deformation occurred in the very early stage of loading resulting in significantly reduced stiffness of the scaffold. The non-uniform and arbitrary microstructure of the scaffold led to a heterogeneous stress distribution within the porous construct, which was subjected to a mixture of compressive and tensile stresses. Nevertheless, the resultant stress contours showed that the scaffold experienced primarily elastic deformation when it was loaded up to 0.003 strain, while localized plastic deformation occurred at sharp corners and necked regions of the micro-struts. The scaffold expanded slightly in the horizontal direction as it was compressed and the change in geometries of pores within the scaffold was insignificant. The proposed method provides a valuable tool to study the localized mechanical behavior of bone scaffolds in micrometer scale with arbitrary porous architecture. This approach could prove highly useful for guiding the fabrication of scaffolds that have anatomy specific mechanical properties and porous architecture.
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http://dx.doi.org/10.1016/j.jmbbm.2019.04.030DOI Listing
August 2019

Comparing medical, dental, and nursing students' preparedness to address lesbian, gay, bisexual, transgender, and queer health.

PLoS One 2018 20;13(9):e0204104. Epub 2018 Sep 20.

School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America.

Background: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) populations face multiple health disparities including barriers to healthcare. Few studies have examined healthcare trainees' perceptions of their preparedness to care for LGBTQ populations and none have compared perceptions of training across medicine, dental medicine, and nursing. We aimed to understand variations across disciplines in LGBTQ health by assessing medical, dental, and nursing students' perceptions of preparedness across three domains: comfort levels, attitudes, and formal training.

Methods: We developed a 12-item survey with an interprofessional panel of LGBTQ students from the schools of medicine, dental medicine, and nursing at a top-tier private university in the United States. Any student enrolled full time in any of the three schools were eligible to respond. We performed descriptive statistical analyses and examined patterns in responses using Kruskal-Wallis tests and an ordered logistic regression model.

Results: 1,010 students from the Schools of Medicine, Dental Medicine, and Nursing responded to the survey for an overall response rate of 43%. While 70-74% of all student respondents felt comfortable treating LGBTQ patients, fewer than 50% agreed that their formal training had prepared them to do so. Overall, 71-81% of students reported interest in receiving formal LGBTQ health education, though dental students were significantly less likely than medical students to report this interest (OR 0.53, p<0.01). Respondents who identified as LGBQ were significantly less likely than heterosexual students to agree that training was effective (OR 0.55, p<0.01) and that their instructors were competent in LGBTQ health (OR 0.56, p<0.01).

Conclusion: Despite high comfort levels and positive attitudes towards LGBTQ health, most student respondents did not report adequate formal preparation. There were some significant differences between disciplines, but significant gaps in training exist across disciplines. Health professional schools should develop formal content on LGBTQ health and utilize this content as an opportunity for interprofessional training.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147466PMC
March 2019

A case study evaluating the portability of an executable computable phenotype algorithm across multiple institutions and electronic health record environments.

J Am Med Inform Assoc 2018 11;25(11):1540-1546

Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.
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http://dx.doi.org/10.1093/jamia/ocy101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213083PMC
November 2018

DNA barcoding Brooklyn (New York): A first assessment of biodiversity in Marine Park by citizen scientists.

PLoS One 2018 18;13(7):e0199015. Epub 2018 Jul 18.

High School for Construction Trades, Engineering and Architecture, New York City Department of Education, Queens, New York, United States of America.

DNA barcoding is both an important research and science education tool. The technique allows for quick and accurate species identification using only minimal amounts of tissue samples taken from any organism at any developmental phase. DNA barcoding has many practical applications including furthering the study of taxonomy and monitoring biodiversity. In addition to these uses, DNA barcoding is a powerful tool to empower, engage, and educate students in the scientific method while conducting productive and creative research. The study presented here provides the first assessment of Marine Park (Brooklyn, New York, USA) biodiversity using DNA barcoding. New York City citizen scientists (high school students and their teachers) were trained to identify species using DNA barcoding during a two-week long institute. By performing NCBI GenBank BLAST searches, students taxonomically identified 187 samples (1 fungus, 70 animals and 116 plants) and also published 12 novel DNA barcodes on GenBank. Students also identified 7 ant species and demonstrated the potential of DNA barcoding for identification of this especially diverse group when coupled with traditional taxonomy using morphology. Here we outline how DNA barcoding allows citizen scientists to make preliminary taxonomic identifications and contribute to modern biodiversity research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051577PMC
December 2018

Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment.

Blood 2018 08 26;132(7):735-749. Epub 2018 Jun 26.

Mater Research Institute-The University of Queensland, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia.

Distinct subsets of resident tissue macrophages are important in hematopoietic stem cell niche homeostasis and erythropoiesis. We used a myeloid reporter gene (-eGFP) to dissect the persistence of bone marrow and splenic macrophage subsets following lethal irradiation and autologous hematopoietic stem cell transplantation in a mouse model. Multiple recipient bone marrow and splenic macrophage subsets survived after autologous hematopoietic stem cell transplantation with organ-specific persistence kinetics. Short-term persistence (5 weeks) of recipient resident macrophages in spleen paralleled the duration of extramedullary hematopoiesis. In bone marrow, radiation-resistant recipient CD169 resident macrophages and erythroid-island macrophages self-repopulated long-term after transplantation via autonomous cell division. Posttransplant peak expansion of recipient CD169 resident macrophage number in bone marrow aligned with the persistent engraftment of phenotypic long-term reconstituting hematopoietic stem cells within bone marrow. Selective depletion of recipient CD169 macrophages significantly compromised the engraftment of phenotypic long-term reconstituting hematopoietic stem cells and consequently impaired hematopoietic reconstitution. Recipient bone marrow resident macrophages are essential for optimal hematopoietic stem cell transplantation outcomes and could be an important consideration in the development of pretransplant conditioning therapies and/or chemoresistance approaches.
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http://dx.doi.org/10.1182/blood-2018-01-829663DOI Listing
August 2018

CD169 macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair.

Biomaterials 2019 03 22;196:51-66. Epub 2017 Oct 22.

Bones and Immunology Laboratory, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, 4102, Australia; The University of Queensland, Faculty of Medicine, Herston, Queensland, 4092, Australia. Electronic address:

Osteal macrophages (osteomacs) contribute to bone homeostasis and regeneration. To further distinguish their functions from osteoclasts, which share many markers and growth factor requirements, we developed a rapid, enzyme-free osteomac enrichment protocol that permitted characterization of minimally manipulated osteomacs by flow cytometry. Osteomacs differ from osteoclasts in expression of Siglec1 (CD169). This distinction was confirmed using the CD169-diphtheria toxin (DT) receptor (DTR) knock-in model. DT treatment of naïve CD169-DTR mice resulted in selective and striking loss of osteomacs, whilst osteoclasts and trabecular bone area were unaffected. Consistent with a previously-reported trophic interaction, osteomac loss was accompanied by a concomitant and proportionately striking reduction in osteoblasts. The impact of CD169 macrophage depletion was assessed in two models of bone injury that heal via either intramembranous (tibial injury) or endochondral (internally-plated femoral fracture model) ossification. In both models, CD169 macrophage, including osteomac depletion compromised bone repair. Importantly, DT treatment in CD169-DTR mice did not affect osteoclast frequency in either model. In the femoral fracture model, the magnitude of callus formation correlated with the number of F4/80 macrophages that persisted within the callus. Overall these observations provide compelling support that CD169 osteomacs, independent of osteoclasts, provide vital pro-anabolic support to osteoblasts during both bone homeostasis and repair.
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http://dx.doi.org/10.1016/j.biomaterials.2017.10.033DOI Listing
March 2019

Determination of butyltins, phenyltins and octyltins in foods with preservation of their moieties: A critical review on analytical methods.

J Chromatogr A 2017 Jul 8;1505:18-34. Epub 2017 May 8.

Food Research Laboratory, Centre for Food Safety, Food and Environmental Hygiene Department, 4/F Public Health Laboratory Centre, 382 Nam Cheong Street, Hong Kong.

Tributyltin and triphenyltin have been extensively applied in anti-fouling paints since the 1960s. Hence, organotin compounds (OTCs), especially butyltins and phenyltins, in seafood has been of concern for decades. Even though the "International Convention on the Control of Harmful Anti-Fouling Systems on Ships, 2001" entered into force internationally in 2008 and prohibited the use of OTCs in anti-fouling paints used on ships, the analysis of OTCs in seafood was not commonly included in routine monitoring programmes. Besides, species of triphenyltin, including triphenyltin hydroxide and acetate, have been used as pesticides and may accumulate in food. Moreover, the European Food Safety Agency established a group tolerable daily intake for tributyltin, dibutyltin, triphenyltin and dioctyltin in 2004 as they exert their immunotoxic effects by similar mode of action and potency. Therefore, suitable methods are needed to analyze butyl-, phenyl- and octyl-tins simultaneously in food without affecting their moieties. This review aims to provide background information in this area.
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http://dx.doi.org/10.1016/j.chroma.2017.05.014DOI Listing
July 2017

CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer.

J Pathol 2016 06 27;239(2):218-30. Epub 2016 Apr 27.

Faculty of Medicine and Biomedical Sciences, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Australia.

Skeletal metastases present a major clinical challenge for prostate cancer patient care, inflicting distinctive mixed osteoblastic and osteolytic lesions that cause morbidity and refractory skeletal complications. Macrophages are abundant in bone and bone marrow and can influence both osteoblast and osteoclast function in physiology and pathology. Herein, we examined the role of macrophages in prostate cancer bone lesions, particularly the osteoblastic response. First, macrophage and lymphocyte distributions were qualitatively assessed in patient's prostate cancer skeletal lesions by immunohistochemistry. Second, macrophage functional contributions to prostate tumour growth in bone were explored using an immune-competent mouse model combined with two independent approaches to achieve in vivo macrophage depletion: liposome encapsulated clodronate that depletes phagocytic cells (including macrophages and osteoclasts); and targeted depletion of CD169(+) macrophages using a suicide gene knock-in model. Immunohistochemistry and histomorphometric analysis were performed to quantitatively assess cancer-induced bone changes. In human bone metastasis specimens, CD68(+) macrophages were consistently located within the tumour mass. Osteal macrophages (osteomacs) were associated with pathological woven bone within the metastatic lesions. In contrast, lymphocytes were inconsistently present in prostate cancer skeletal lesions and when detected, had varied distributions. In the immune-competent mouse model, CD169(+) macrophage ablation significantly inhibited prostate cancer-induced woven bone formation, suggesting that CD169(+) macrophages within pathological woven bone are integral to tumour-induced bone formation. In contrast, pan-phagocytic cell, but not targeted CD169(+) macrophage depletion resulted in increased tumour mass, indicating that CD169(-) macrophage subset(s) and/or osteoclasts influenced tumour growth. In summary, these observations indicate a prominent role for macrophages in prostate cancer bone metastasis that may be therapeutically targetable to reduce the negative skeletal impacts of this malignancy, including tumour-induced bone modelling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4718DOI Listing
June 2016

Enhancing osteogenic differentiation of MC3T3-E1 cells by immobilizing inorganic polyphosphate onto hyaluronic acid hydrogel.

Biomacromolecules 2015 Jan 5;16(1):166-73. Epub 2014 Dec 5.

Department of Mechanical Engineering, ‡Department of Chemical System Engineering, §Center for Disease Biology and Integrative Medicine, and ∥Department of Bioengineering, The University of Tokyo , 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

In tissue engineering, precise control of cues in the microenvironment is essential to stimulate cells to undergo bioactivities such as proliferation, differentiation, and matrix production. However, current approaches are inefficient in providing nondepleting cues. In this study, we have developed a novel bioactive hydrogel (HAX-PolyP) capable of enhancing tissue growth by conjugating inorganic polyphosphate chains onto hyaluronic acid macromers. The immobilized polyphosphates provided constant osteoconductive stimulation to the embedded murine osteoblast precursor cells, resulting in up-regulation of osteogenic marker genes and enhanced levels of ALP activity. The osteoconductive activity was significantly higher when compared to those stimulated with free-floating polyphosphates. Even at very low concentrations, immobilization of polyphosphates onto the scaffold allowed sufficient signaling leading to more effective osteoconduction. These results demonstrate the potential of our novel material as an injectable bioactive scaffold, which can be clinically useful for developing bone grafts and bone regeneration applications.
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http://dx.doi.org/10.1021/bm501356cDOI Listing
January 2015

Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification.

Am J Pathol 2014 Dec 5;184(12):3192-204. Epub 2014 Oct 5.

Bone and Immunology Laboratory, Mater Research Institute-UQ, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia; UQ-Centre for Clinical Research, Faculty of Health Sciences, The University of Queensland, Herston, Queensland, Australia. Electronic address:

The distribution, phenotype, and requirement of macrophages for fracture-associated inflammation and/or early anabolic progression during endochondral callus formation were investigated. A murine femoral fracture model [internally fixed using a flexible plate (MouseFix)] was used to facilitate reproducible fracture reduction. IHC demonstrated that inflammatory macrophages (F4/80(+)Mac-2(+)) were localized with initiating chondrification centers and persisted within granulation tissue at the expanding soft callus front. They were also associated with key events during soft-to-hard callus transition. Resident macrophages (F4/80(+)Mac-2(neg)), including osteal macrophages, predominated in the maturing hard callus. Macrophage Fas-induced apoptosis transgenic mice were used to induce macrophage depletion in vivo in the femoral fracture model. Callus formation was completely abolished when macrophage depletion was initiated at the time of surgery and was significantly reduced when depletion was delayed to coincide with initiation of early anabolic phase. Treatment initiating 5 days after fracture with the pro-macrophage cytokine colony stimulating factor-1 significantly enhanced soft callus formation. The data support that inflammatory macrophages were required for initiation of fracture repair, whereas both inflammatory and resident macrophages promoted anabolic mechanisms during endochondral callus formation. Overall, macrophages make substantive and prolonged contributions to fracture healing and can be targeted as a therapeutic approach for enhancing repair mechanisms. Thus, macrophages represent a viable target for the development of pro-anabolic fracture treatments with a potentially broad therapeutic window.
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http://dx.doi.org/10.1016/j.ajpath.2014.08.017DOI Listing
December 2014

Osteocyte expression of caspase-3, COX-2, IL-6 and sclerostin are spatially and temporally associated following stress fracture initiation.

Bonekey Rep 2014 3;3:571. Epub 2014 Sep 3.

School of Medical Science and Griffith Health Institute, Griffith University, Gold Coast Campus , Gold Coast, Queensland, Australia.

Stress fractures (SFxs) are debilitating injuries and exact mechanisms that initiate their repair incompletely understood. We hypothesised that osteocyte apoptosis and expression of cytokines and proteins such as sclerostin, VEGF, TGF-β, COX-2 and IL-6 were early signalling events to facilitate the formation of periosteal woven bone and recruitment of osteoclast precursors to the site of remodelling. A SFx was created in the right ulna of mature female wistar rats using cyclic end loading. Rats were killed 1, 4 and 7 days after loading (n=5 per group). Standard histological staining was used to examine SFx morphology and immunohistochemistry to detect the localisation of these proteins and in situ hybridisation to detect mRNA along the SFx line or gene expression to quantify the target genes. Unloaded ulnae served as controls. The labelling index of caspase-3, COX-2 and IL-6 was significantly elevated in the region of SFxs at all time points compared with controls (P<0.001). In addition, the labelling index of sclerostin protein was significantly reduced in osteocytes adjacent to the SFx region when compared with controls at all three time points (P<0.001). Both VEGF and TGF-β expressions were only localised in the woven bone. These data reinforce the involvement of osteocyte apoptosis in the healing of fatigue damage in bone, and demonstrate that local regulation of sclerostin, COX-2 and IL-6 are important signalling events associated with new bone formation and SFx remodelling.
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http://dx.doi.org/10.1038/bonekey.2014.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162464PMC
September 2014

Inpatient rehabilitation outcomes of patients with apraxia after stroke.

Top Stroke Rehabil 2014 May-Jun;21(3):211-9

Department of Occupational Therapy Education, University of Kansas Medical Center, Kansas City, Kansas Departments of Ophthalmology and Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.

Background: Stroke-induced paresis commands much attention during rehabilitation; other stroke-related consequences receive less consideration. Apraxia is a stroke disorder that may have important implications for rehabilitation and recovery.

Objective: To investigate association of apraxia with stroke rehabilitation outcomes during inpatient rehabilitation.

Methods: This cohort study compared patients with and without apraxia after a first left hemispheric stroke. All study patients received standard of care. Clinical measures were the Functional Independence Measure (FIM) and the upper extremity section of the Fugl-Meyer Assessment (FMA) administered upon admission and at discharge. Length of stay was also documented. Florida Apraxia Battery subtests were used to classify patients with apraxia.

Results: Fifteen patients were included in this study, 10 of whom had apraxia. Data analysis revealed that patients with apraxia exhibited improvement from admission to discharge in clinical measures; however, admission FIM score was significantly lower compared to patients without apraxia. There was no statistically significant difference between groups on FMA score, length of stay, or amount of change on clinical measures.

Conclusions: This study of acute patients found those with apraxia to be significantly less independent upon admission to inpatient rehabilitation compared to patients without apraxia. Although both groups improved a similar amount during rehabilitation, patients with apraxia discharged at a level of independence comparable to patients without apraxia upon admission. Such disparity in independence is of concern, and apraxia as a factor in stroke rehabilitation and recovery deserves further attention.
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http://dx.doi.org/10.1310/tsr2103-211DOI Listing
July 2014

Reducing the radiation sterilization dose improves mechanical and biological quality while retaining sterility assurance levels of bone allografts.

Bone 2013 Nov 2;57(1):194-200. Epub 2013 Aug 2.

Griffith Health Institute and School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia; Queensland Bone Bank, Organ and Tissue Donation Service, Queensland Health, Brisbane, QLD, Australia.

Background: Bone allografts carry a risk of infection, so terminal sterilization by gamma irradiation at 25kGy is recommended; but is deleterious to bone quality. Contemporary bone banking significantly reduces initial allograft bioburden, questioning the need to sterilize at 25kGy.

Methods: We inoculated allograft bone with Staphylococcus epidermidis and Bacillus pumilus, then exposed them to gamma irradiation at 0, 5, 10, 15, 20 and 25kGy. Mechanical and biological properties of allografts were also assessed. Our aim was to determine an optimal dose that achieves sterility assurance while minimizing deleterious effects on allograft tissue.

Results: 20-25kGy eliminated both organisms at concentrations from 10(1) to 10(3)CFU, while 10-15kGy sterilized bone samples to a bioburden concentration of 10(2)CFU. Irradiation did not generate pro-inflammatory bone surfaces, as evidenced by macrophage activation, nor did it affect attachment or proliferation of osteoblasts. At doses ≥10kGy, the toughness of cortical bone was reduced (P<0.05), and attachment and fusion of osteoclasts onto irradiated bone declined at 20 and 25kGy (P<0.05). There was no change in collagen cross-links, but a significant dose-response increase in denatured collagen (P<0.05).

Conclusions: Our mechanical and cell biological data converge on 15kGy as a threshold for radiation sterilization of bone allografts. Between 5 and 15kGy, bone banks can undertake validation that provides allografts with an acceptable sterility assurance level, improving their strength and biocompatibility significantly.

Clinical Relevance: The application of radiation sterilization doses between 5 and 15kGy will improve bone allograft mechanical performance and promote integration, while retaining sterility assurance levels. Improved quality of allograft bone will promote superior clinical outcomes.
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http://dx.doi.org/10.1016/j.bone.2013.07.036DOI Listing
November 2013

Absence of B cells does not compromise intramembranous bone formation during healing in a tibial injury model.

Am J Pathol 2013 May 13;182(5):1501-8. Epub 2013 Mar 13.

University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia.

Previous studies have generated conflicting results regarding the contribution of B cells to bone formation during physiology and repair. Here, we have investigated the role of B cells in osteoblast-mediated intramembranous anabolic bone modeling. Immunohistochemistry for CD45 receptor expression indicated that B cells had no propensity or aversion for endosteal regions or sites of bone modeling and/or remodeling in wild-type mice. In the endocortical diaphyseal region, quantitative immunohistology demonstrated that young wild-type and B-cell deficient mice had similar amounts of osteocalcin(+) osteoblast bone modeling surface. The degree of osteoblast-associated osteomac canopy was also comparable in these mice inferring that bone modeling cellular units were preserved in the absence of B cells. In a tibial injury model, only rare CD45 receptor positive B cells were located within areas of high anabolic activity, including minimal association with osterix(+) osteoblast-lineage committed mesenchymal cells in wild-type mice. Quantitative immunohistology demonstrated that collagen type I matrix deposition and macrophage and osteoclast distribution within the injury site were not compromised by the absence of B cells. Overall, osteoblast distribution during normal growth and bone healing via intramembranous ossification proceeded normally in the absence of B cells. These observations support that in vivo, these lymphoid cells have minimal influence, or at most, make redundant contributions to osteoblast function during anabolic bone modeling via intramembranous mechanisms.
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http://dx.doi.org/10.1016/j.ajpath.2013.01.046DOI Listing
May 2013

Unraveling macrophage contributions to bone repair.

Bonekey Rep 2013 26;2:373. Epub 2013 Jun 26.

Mater Research, Translational Research Institute , Woolloongabba, Queensland, Australia ; UQ-Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland , Herston, Queensland, Australia.

Macrophages have reemerged to prominence with widened understanding of their pleiotropic contributions to many biologies and pathologies. This includes clear advances in revealing their importance in wound healing. Here we have focused on the current state of knowledge with respect to bone repair, which has received relatively little scientific attention compared with its soft-tissue counterparts. Our detailed characterization of resident tissue macrophages residing in bone-lining tissues (osteomacs), including their pro-anabolic function, exposed a more prominent role for these cells in bone biology than previously anticipated. Recent studies have confirmed the importance of macrophages in early inflammatory processes that establish the healing cascade after bone fracture. Emerging data support that macrophage influence extends into both anabolic and catabolic phases of repair, suggesting that these cells have prolonged and diverse functions during fracture healing. More research is needed to clarify macrophage phase-specific contributions, temporospatial subpopulation variance and macrophage specific-molecular mediators. There is also clear motivation for determining whether macrophage alterations underlie compromised fracture healing. Overall, there is strong justification to pursue strategies targeting macrophages and/or their products for improving normal bone healing and overcoming failed repair.
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http://dx.doi.org/10.1038/bonekey.2013.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098570PMC
July 2014

Changes in apparent diffusion coefficient and T2 relaxation during radiotherapy for prostate cancer.

J Magn Reson Imaging 2013 Apr 23;37(4):909-16. Epub 2012 Oct 23.

Radiation Medicine Program, Princess Margaret Hospital, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

Purpose: To evaluate regional and temporal changes in apparent diffusion coefficient (ADC) and T2 relaxation during radiation therapy (RT) in patients with low and intermediate risk localized prostate cancer.

Materials And Methods: Seventeen patients enrolled on a prospective clinical trial where MRI was acquired every 2 weeks throughout eight weeks of image-guided prostate IMRT (78 Gy/39 fractions). ADC and T2 quantification used entire prostate, central gland, benign peripheral zone, and tumor-dense regions-of-interest, and mean values were evaluated for common response trends.

Results: Overall, the RT responses were greater than volunteer measurement repeatability, and week 6 appeared to be an optimum time-point for early detection. RT effects on the entire prostate were best detected using ADC (5-7% by week 2, P < 0.0125), effects on peripheral zone were best detected using T2 (19% reduction at week 6; P = 0.004) and effects on tumors were best detected using ADC (14% elevation at week 6; P = 0.004).

Conclusion: ADC and T2 may be candidate biomarkers of early response to RT warranting further investigation against clinical outcomes.
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http://dx.doi.org/10.1002/jmri.23885DOI Listing
April 2013

Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna.

J Orthop Res 2013 Feb 30;31(2):235-42. Epub 2012 Jul 30.

School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia.

Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected.
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http://dx.doi.org/10.1002/jor.22203DOI Listing
February 2013

Quantitative evaluation of transform domains for compressive sampling-based recovery of sparsely sampled volumetric OCT images.

IEEE Trans Biomed Eng 2013 Feb 15;60(2):470-8. Epub 2012 May 15.

School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada.

Recently, compressive sampling has received significant attention as an emerging technique for rapid volumetric imaging. We have previously investigated volumetric optical coherence tomography (OCT) image acquisition using compressive sampling techniques and showed that it was possible to recover image volumes from a subset of sampled images. Our previous findings used the multidimensional wavelet transform as the domain of sparsification for recovering OCT image volumes. In this report, we analyzed and compared the potential and efficiency of three other image transforms to reconstruct the same volumetric OCT image. Two quantitative measures, the mean square error and the structural similarity index, were applied to compare the quality of the reconstructed volumetric images. We observed that fast Fourier transformation and wavelet both are capable of reconstructing OCT image volumes for the orthogonal sparse sampling masks used in this report, but with different merits.
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http://dx.doi.org/10.1109/TBME.2012.2199489DOI Listing
February 2013

Physical properties of root cementum: Part 18. The extent of root resorption after the application of light and heavy controlled rotational orthodontic forces for 4 weeks: a microcomputed tomography study.

Am J Orthod Dentofacial Orthop 2011 May;139(5):e495-503

Discipline of Orthodontics, Faculty of Dentistry, University of Sydney, Australia.

Introduction: The aim of this prospective randomized clinical trial was to quantitatively measure and compare the locations, dimensions, and volume of root resorption craters in human premolars after the application of controlled light and heavy rotational orthodontic forces over a 28-day (4-week) period.

Methods: Fifteen patients requiring bilateral extraction of maxillary first premolars as part of their orthodontic treatment were recruited for this study. Each patient received a heavy (225 g) rotational force on 1 premolar and a light (25 g) rotational force on the contralateral premolar. Orthodontic rotational forces were applied over 28 days with buccal and palatal cantilever springs; 0.016-inch beta-titanium molybdenum alloys were used to apply the light force and 0.018-inch stainless steel was used for the heavy force. After the 28-day experimental period, the upper first premolars were extracted under stringent protocols to prevent root surface damage. The samples were then scanned using a microcomputed tomography (micro-CT) scan x-ray system (SkyScan 1072, Skyscan, Aartselaar, Belgium), and analyzed using convex hull algorithm (CHULL2D; University of Sydney, Sydney, Australia) software to obtain direct volumetric measurements.

Results: The mean volume of resorption craters was 0.42 in the light force group and 0.51 in the heavy force group (P = 0.013). When separated at the root level, the difference in volume of root resorption craters between the 2 groups was significantly different only at the midlevel (P = 0.001). Root resorption craters were consistently detected at the boundaries between the buccal and distal surfaces and the mesial and lingual surfaces. The result supports our hypothesis that positive areas develop significantly more root resorption craters at all 3 levels, as compared with minimal areas (paired t test <0.001).

Conclusions: Heavy rotational forces caused more root resorption than light rotational forces and compression areas (buccal-distal and lingual-mesial surfaces in this study) showed significantly higher root resorption than other areas at all levels of the root.
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http://dx.doi.org/10.1016/j.ajodo.2010.01.036DOI Listing
May 2011

Improved function after combined physical and mental practice after stroke: a case of hemiparesis and apraxia.

Am J Occup Ther 2011 Mar-Apr;65(2):161-8

Department of Occupational Therapy Education, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2003, Kansas City, KS, USA.

This study describes change in functional performance and self-perception after participation in combined training with physical practice followed by mental practice. The patient was a 44-yr-old white man who experienced a single left ischemic stroke 7 mo before enrollment in the study. He engaged in physical and mental practice of two functional tasks: (1) reaching for and grasping a cup and (2) turning pages in a book with the more-affected arm. Practice took place 3 times per week during 60-min sessions for 6 consecutive wk. Primary outcome measures were the Arm Motor Ability Test (AMAT) and the Canadian Occupational Performance Measure (COPM). An abbreviated version of the Florida Apraxia Battery gesture-to-verbal command test approximated severity of ideomotor apraxia. After intervention, the patient demonstrated increased functional performance (AMAT) and self-perception of performance (COPM) despite persistent ideomotor apraxia. The results of this single-case report indicate functional benefit from traditional rehabilitation techniques despite comorbid, persisting ideomotor apraxia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354684PMC
http://dx.doi.org/10.5014/ajot.2011.000786DOI Listing
May 2011

Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model.

J Bone Miner Res 2011 Jul;26(7):1517-32

The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.

Bone-lining tissues contain a population of resident macrophages termed osteomacs that interact with osteoblasts in vivo and control mineralization in vitro. The role of osteomacs in bone repair was investigated using a mouse tibial bone injury model that heals primarily through intramembranous ossification and progresses through all major phases of stabilized fracture repair. Immunohistochemical studies revealed that at least two macrophage populations, F4/80(+) Mac-2(-/low) TRACP(-) osteomacs and F4/80(+) Mac-2(hi) TRACP(-) inflammatory macrophages, were present within the bone injury site and persisted throughout the healing time course. In vivo depletion of osteomacs/macrophages (either using the Mafia transgenic mouse model or clodronate liposome delivery) or osteoclasts (recombinant osteoprotegerin treatment) established that osteomacs were required for deposition of collagen type 1(+) (CT1(+)) matrix and bone mineralization in the tibial injury model, as assessed by quantitative immunohistology and micro-computed tomography. Conversely, administration of the macrophage growth factor colony-stimulating factor 1 (CSF-1) increased the number of osteomacs/macrophages at the injury site significantly with a concurrent increase in new CT1(+) matrix deposition and enhanced mineralization. This study establishes osteomacs as participants in intramembranous bone healing and as targets for primary anabolic bone therapies.
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http://dx.doi.org/10.1002/jbmr.354DOI Listing
July 2011
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