Publications

Campbell, M, Chabria, M, Figtree, GA, Polonchuk, L & Gentile, C 2018, 'Stem Cell-Derived Cardiac Spheroids as 3D In Vitro Models of the Human Heart Microenvironment' in Methods in Molecular Biology, Springer New York, Switzerland, pp. 51-59.
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Our laboratory has recently developed a novel three-dimensional in vitro model of the human heart, which we call the vascularized cardiac spheroid (VCS). These better recapitulate the human heart's cellular and extracellular microenvironment compared to the existing in vitro models. To achieve this, human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes, cardiac fibroblasts, and human coronary artery endothelial cells are co-cultured in hanging drop culture in ratios similar to those found in the human heart in vivo. The resulting three-dimensional cellular organization, extracellular matrix, and microvascular network formation throughout the VCS has been shown to mimic the one present in the human heart tissue. Therefore, VCSs offer a promising platform to study cardiac physiology, disease, and pharmacology, as well as bioengineering constructs to regenerate heart tissue.

Campbell, M, Surija, L, Peceros, K, Sharma, P, Figtree, G & Gentile, C 2018, 'Stem Cell Spheroids' in Reference Module in Biomedical Sciences, Elsevier, pp. 387-393.
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Stem cells are undifferentiated cells that reside in a dynamic, specialized microenvironment (or niche) and play a fundamental role in embryogenesis, tissue homeostasis and regeneration. Three-dimensional stem cell spheroid cultures have emerged as a promising alternative to culture, maintain and differentiate stem cells in vitro by better mimicing the in vivo stem cell niche. These spheroid cultures recapitulate cellular and extracellular features of the in vivo stem cell niche, including biochemical and biophysical cues, which regulate stem cell self-renewal and differentiation potential. This review will provide an overview of the essential features of the niche typical of different stem cell types, to better engineer in vitro culture systems for enhanced stem viability and better control over stem cell behavior and fate. Finally, this review will delve into the many exciting applications of stem cell spheroid culture, including in vitro models of human disease, high-throughput drug discovery and toxicity assays, as well stem-cell based regenerative therapies and 3D bioprinting of organs for transplantation.

Lawson, J & Hadgraft, R 2018, 'Building Global Awareness in Remote Locations' in McLaughlin, P & Kennedy, B (eds), The Global Canopy Stories of Discipline-Based Learning Interactions to Promote Global Mobility, The Writing Bureau, pp. 75-84.

McLaughlin, P, Baglin, J, Chester, A, Davis, P, Saha, S, Mills, A, Poronnik, P, Hinton, T, Lawson, J & Hadgraft, R 2018, 'The Global Canopy: Propagating Discipline-Based Global Mobility' in The Globalisation of Higher Education, Springer International Publishing, Germany, pp. 79-100.
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As Australian universities welcome significant numbers of inbound international students and increasingly encourage outbound domestic student mobility, the opportunities for global discipline connectedness, cross-cultural understandings, and fertile learning interactions abound. Yet these two “strands” of students rarely engage in deliberately organized discipline-based activities. They are passing “as ships in the night,” with opportunities for long-term relationships, improved discipline-based networks, and global mobility opportunities unrealized or operating coincidently at the margins of their curriculum. This chapter reports upon the outcomes of a range of approaches to discipline-based teaching and learning between these two cohorts at Australian universities, which illustrate how separate cohorts of inbound and outbound students can interrelate to build discipline-based competencies for navigating tomorrow’s world.

Nguyen, TV & Eisman, JA 2018, 'Pharmacogenetics and Pharmacogenomics of Osteoporosis: Personalized Medicine Outlook' in Genetics of Bone Biology and Skeletal Disease, Elsevier, pp. 139-157.
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© 2018 Elsevier Inc. All rights reserved. Osteoporosis and its consequence of fragility fracture are complex traits resulting from interactions of multiple genetic and environmental factors. Moreover, the response to antiosteoporotic therapies is highly variable among individuals, and this variability may also be partly determined by genetic factors. In the past decade, there has been substantial progress in the genetics and genomics of osteoporosis, but few advances in pharmacogenetics and pharmacogenomics of osteoporosis. Several genetic variants associated with bone mineral density and fracture risk have been identified by genome-wide association studies (GWAS). However, no genetic variants have been conclusively shown to be associated with response to antiosteoporotic therapies. Although the possibility of gene-based individualized assessment of fracture risk and personalized therapy in osteoporosis care is not yet realized, progress that has been made is reviewed.

Tay, AKP, Khoo, BL & Warkiani, ME 2018, 'Microfluidics for Fast and Frugal Diagnosis of Malaria, Sepsis, and HIV/AIDS' in Frugal Innovation in Bioengineering for the Detection of Infectious Diseases, Springer International Publishing, Switzerland, pp. 57-75.
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© Springer International Publishing AG 2018. Rapid diagnosis of infectious diseases is necessary for timely treatment and to control spread of diseases. Conventional laboratory approaches are often labor-intensive and associated with time delays that are unacceptable in medical practice. Recent advances in micro-/nanotechnologies have facilitated the development of low-cost microfluidic devices with high sensitivity and throughput that can help reduce healthcare costs and pave the way toward personalized therapy. This chapter covers recent advances in point-of-care (POC) technologies with an emphasis on demonstrated and commercially available systems for diagnosis and treatment of malaria, sepsis, and human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS). The current challenges to practical implementation of these technologies are discussed together with some future perspectives.

Tran, B, Center, JR & Nguyen, TV 2018, 'Translational Genetics of Osteoporosis' in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Wiley, pp. 385-392.
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© 2019 American Society for Bone and Mineral Research. This chapter focuses on the clinical aspects and management of osteoporosis in postmenopausal women, men, young women, and various forms of secondary osteoporosis. Dual energy X-ray absorptiometry is an important tool for clinical research, including clinical trials of bisphosphonates and other drugs. There is strong consensus, based on solid clinical trial evidence, that postmenopausal women, and probably older men, who have experienced fragility fractures of the spine and hip are definite candidates for pharmacological therapy, irrespective of other risk factors. Patients with nonhip, nonspine fractures are also at higher risk for fracture and deserve, at least, to be evaluated for other risk factors and as potential candidates for therapy. Finite element analysis of routine CT scans of the hip and spine provides accurate in vivo measurement of skeletal strength. The anticipated availability of abaloparatide and romosozumab will be the first new treatments for osteoporosis.

Abbasnejad, B, Thorby, W, Razmjou, A, Jin, D, Asadnia, M & Ebrahimi Warkiani, M 2018, 'MEMS piezoresistive flow sensors for sleep apnea therapy', Sensors and Actuators A: Physical, vol. 279, pp. 577-585.
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© 2018 Elsevier B.V. A MEMS liquid crystal polymer (LCP), used in the membrane-based pressure sensor, has been found highly useful as a flow sensor. Here we conducted a set of elaborate experiments using an air flow generator to investigate the potential of our LCP flow sensor for sleep apnea therapy. Critical properties of the LCP flow sensor, including flow range, resolution (sensitivity), accuracy, and response time, have been systematically characterized. As a result, LCP flow sensor achieves a limit of detection of 8 LPM to measure flow rate, better than the commercial flow sensor (>10 LPM). Our LCP flow sensor shows a favourable response in a large flow range (8–160 LPM) with a sensitivity of detecting a linear voltage response of 0.004 V per 1 LPM flow rate. With minimum detectable flow, high sensitivity and resolution, we further demonstrated our LCP flow sensor for detecting human respiration. Moreover, using a two- dimensional simulation in COMSOL Multiphysics, we demonstrated the deformation of LCP membrane in response to different flow velocities which leads to resistance change in sensor's strain gauge.

Aboulkheyr Es, H, Montazeri, L, Aref, AR, Vosough, M & Baharvand, H 2018, 'Personalized Cancer Medicine: An Organoid Approach', Trends in Biotechnology, vol. 36, no. 4, pp. 358-371.
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Personalized cancer therapy applies specific treatments to each patient. Using personalized tumor models with similar characteristics to the original tumors may result in more accurate predictions of drug responses in patients. Tumor organoid models have several advantages over pre-existing models, including conserving the molecular and cellular composition of the original tumor. These advantages highlight the tremendous potential of tumor organoids in personalized cancer therapy, particularly preclinical drug screening and predicting patient responses to selected treatment regimens. Here, we highlight the advantages, challenges, and translational potential of tumor organoids in personalized cancer therapy and focus on gene–drug associations, drug response prediction, and treatment selection. Finally, we discuss how microfluidic technology can contribute to immunotherapy drug screening in tumor organoids.

Al Muderis, MM, Lu, WY, Li, JJ, Kaufman, K, Orendurff, M, Highsmith, MJ, Lunseth, PA & Kahle, JT 2018, 'Clinically Relevant Outcome Measures Following Limb Osseointegration; Systematic Review of the Literature', Journal of Orthopaedic Trauma, vol. 32, no. 2, pp. e64-e75.
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Objectives: The current standard of care for an amputee is a socket-based prostheses. An osseointegrated implant (OI) is an alternative for prosthetic attachment. Osseointegration addresses reported problems related to wearing a socket interface, such as skin issues, discomfort, diminished function, quality of life, prosthetic use, and abandonment. The purpose of this report is to systematically review current literature regarding OI to identify and categorize the reported clinically relevant outcome measures, rate the quality of available evidence, and synthesize the findings. Data sources: A multidisciplinary team used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methods. Search methodology was based on identifying clinically relevant articles. Three databases were searched: PubMed, CINAHL, and Web of Science. Study Selection: Clinical studies with aggregated data reporting at least 1 clinically relevant outcome measure were included. Data Extraction: The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criterion was used for critical appraisal and recommendations. Conclusions: This review identified 21 clinically relevant observational studies. Outcome measures were categorized into the following 9 categories: vibratory stimulation, complications, biomechanics, economics, patient-reported outcome measures, electromyography, x-ray, physical functional performance, and energy consumption. This systemat...

Alajlouni, D, Bliuc, D, Tran, T, Pocock, N, Nguyen, TV, Eisman, JA & Center, JR 2018, 'Nonstandard Lumbar Region in Predicting Fracture Risk', Journal of Clinical Densitometry, vol. 21, no. 2, pp. 220-226.
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© 2017 The International Society for Clinical Densitometry Femoral neck (FN) bone mineral density (BMD) is the most commonly used skeletal site to estimate fracture risk. The role of lumbar spine (LS) BMD in fracture risk prediction is less clear due to osteophytes that spuriously increase LS BMD, particularly at lower levels. The aim of this study was to compare fracture predictive ability of upper L1–L2 BMD with standard L2–L4 BMD and assess whether the addition of either LS site could improve fracture prediction over FN BMD. This study comprised a prospective cohort of 3016 women and men over 60 yr from the Dubbo Osteoporosis Epidemiology Study followed up for occurrence of minimal trauma fractures from 1989 to 2014. Dual-energy X-ray absorptiometry was used to measure BMD at L1–L2, L2–L4, and FN at baseline. Fracture risks were estimated using Cox proportional hazards models separately for each site. Predictive performances were compared using receiver operating characteristic curve analyses. There were 565 women and 179 men with a minimal trauma fracture during a mean of 11 ± 7 yr. L1–L2 BMD T-score was significantly lower than L2–L4 T-score in both genders (p < 0.0001). L1–L2 and L2–L4 BMD models had a similar fracture predictive ability. LS BMD was better than FN BMD in predicting vertebral fracture risk in women [area under the curve 0.73 (95% confidence interval, 0.68–0.79) vs 0.68 (95% confidence interval, 0.62–0.74), but FN was superior for hip fractures prediction in both women and men. The addition of L1–L2 or L2–L4 to FN BMD in women increased overall and vertebral predictive power compared with FN BMD alone by 1% and 4%, respectively (p < 0.05). In an elderly population, L1–L2 is as good as but not better than L2–L4 site in predicting fracture risk. The addition of LS BMD to FN BMD provided a modest additional benefit in overall fracture risk. Further studies in individuals with spinal degenerative disease are needed.

Bajan, S, Johnston, M & Hutvagner, G 2018, 'Destabilisation of Argonaute 2 generates a truncated protein: halfAgo2', Matters.
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The Argonaute 2 (Ago2) protein is an essential effector protein in miRNA-mediated mechanisms that regulate gene expression. Ago2 directly binds to the miRNA, forming the RISC. RISC function is critical to controlling key biological processes and when dysregulated can result in disease pathogenesis. Understanding Ago2 protein stability and turnover will further our understanding in how RISC function is regulated. In human cells, we discovered a previously unidentified ~55 kDa protein that is a truncated form of Ago2, that is formed from proteolytic cleavage of the full length Ago2 protein. Further experiments are needed to determine (i) the detailed mechanism that forms halfAgo2 (ii) the cellular or environmental triggers or stresses that initiate halfAgo2 production and (iii) if halfAgo2 has a potentially new role in gene regulation.

Barnet, MB, Blinman, P, Cooper, W, Boyer, MJ, Kao, S & Goodnow, CC 2018, 'Understanding Immune Tolerance of Cancer: Re‐Purposing Insights from Fetal Allografts and Microbes', BioEssays, vol. 40, no. 8.
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Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non‐self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm.

Barnet, MB, Zielinski, RR, Warby, A, Lewis, CR & Kao, S 2018, 'Pseudoprogression Associated with Clinical Deterioration and Worsening Quality of Life in Malignant Pleural Mesothelioma', Journal of Thoracic Oncology, vol. 13, no. 1, pp. e1-e2.
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Bazaz, SR, Mehrizi, AA, Ghorbani, S, Vasilescu, S, Asadnia, M & Warkiani, ME 2018, 'A hybrid micromixer with planar mixing units', RSC Advances, vol. 8, no. 58, pp. 33103-33120.
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Taguchi-optimized “hybrid micromixer” has been proposed which can be utilized in a wide range of chemical and biological applications.

Beck, D, Thoms, JAI, Palu, C, Herold, T, Shah, A, Olivier, J, Boelen, L, Huang, Y, Chacon, D, Brown, A, Babic, M, Hahn, C, Perugini, M, Zhou, X, Huntly, BJ, Schwarzer, A, Klusmann, J-H, Berdel, WE, Wörmann, B, Büchner, T, Hiddemann, W, Bohlander, SK, To, LB, Scott, HS, Lewis, ID, D'Andrea, RJ, Wong, JWH & Pimanda, JE 2018, 'A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients', Leukemia, vol. 32, no. 2, pp. 263-272.
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© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.

Cao, Z, Adnan, NNM, Wang, G, Rawal, A, Shi, B, Liu, R, Liang, K, Zhao, L, Gooding, JJ, Boyer, C & Gu, Z 2018, 'Enhanced colloidal stability and protein resistance of layered double hydroxide nanoparticles with phosphonic acid-terminated PEG coating for drug delivery', Journal of Colloid and Interface Science, vol. 521, pp. 242-251.
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Chen, C, Wang, F, Wen, S, Su, QP, Wu, MCL, Liu, Y, Wang, B, Li, D, Shan, X, Kianinia, M, Aharonovich, I, Toth, M, Jackson, SP, Xi, P & Jin, D 2018, 'Multi-photon near-infrared emission saturation nanoscopy using upconversion nanoparticles', Nature Communications, vol. 9, no. 1.
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AbstractMultiphoton fluorescence microscopy (MPM), using near infrared excitation light, provides increased penetration depth, decreased detection background, and reduced phototoxicity. Using stimulated emission depletion (STED) approach, MPM can bypass the diffraction limitation, but it requires both spatial alignment and temporal synchronization of high power (femtosecond) lasers, which is limited by the inefficiency of the probes. Here, we report that upconversion nanoparticles (UCNPs) can unlock a new mode of near-infrared emission saturation (NIRES) nanoscopy for deep tissue super-resolution imaging with excitation intensity several orders of magnitude lower than that required by conventional MPM dyes. Using a doughnut beam excitation from a 980 nm diode laser and detecting at 800 nm, we achieve a resolution of sub 50 nm, 1/20th of the excitation wavelength, in imaging of single UCNP through 93 μm thick liver tissue. This method offers a simple solution for deep tissue super resolution imaging and single molecule tracking.

Chen, W, Deng, W, Xu, X, Zhao, X, Vo, JN, Anwer, AG, Williams, TC, Cui, H & Goldys, EM 2018, 'Photoresponsive endosomal escape enhances gene delivery using liposome–polycation–DNA (LPD) nanovectors', Journal of Materials Chemistry B, vol. 6, no. 32, pp. 5269-5281.
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Light-triggered endolysosomal escape enhances gene delivery by photoresponsive LPD nanoparticles.

Chen, W, Simpson, JM, March, LM, Blyth, FM, Bliuc, D, Tran, T, Nguyen, TV, Eisman, JA & Center, JR 2018, 'Comorbidities Only Account for a Small Proportion of Excess Mortality After Fracture: A Record Linkage Study of Individual Fracture Types', Journal of Bone and Mineral Research, vol. 33, no. 5, pp. 795-802.
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ABSTRACT   Nonhip, nonvertebral (NHNV) fractures constitute the majority of osteoporotic fractures, but few studies have examined the association between these fractures, comorbidity, and mortality. Our objective was to examine the relationship between individual nonhip, nonvertebral fractures, comorbidities, and mortality. The prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 to 2013. Associations between fracture and mortality were examined using multivariate, time-dependent Cox models, adjusted for age, prior fracture, body mass index, smoking, and comorbidities (cardiovascular disease, diabetes, stroke, thrombosis, and cancer), and survival function curves. Population attributable fraction was calculated for each level of risk exposure. During 1,490,651 person-years, women and men experienced 7571 and 4571 fractures and 7064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men were associated with increased multivariable-adjusted mortality hazard ratios ranging from 1.3 to 3.4. Comorbidity independently added to mortality such that a woman with a humeral fracture and 1 comorbidity had a similarly reduced 5-year survival as that of a woman with a hip fracture and no comorbidities. Population mortality attributable to any fracture without comorbidity was 9.2% in women and 5.3% in men. All proximal nonhip, nonvertebral fractures in women and men were associated with increased mortality risk. Coexistent comorbidities independently further increased mortality. Population attributable risk for mortality for fractures was similar to cardiovascul...

Chen, Y, Su, QP, Sun, Y & Yu, L 2018, 'Visualizing Autophagic Lysosome Reformation in Cells Using In Vitro Reconstitution Systems', Current Protocols in Cell Biology, vol. 78, no. 1, pp. 11.24.1-11.24.15.
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AbstractAutophagy is a lysosome‐based degradation pathway. Autophagic lysosome reformation (ALR) is a lysosomal membrane recycling process that marks the terminal step of autophagy. During ALR, LAMP1‐positive tubules, named reformation tubules, are extruded from autolysosomes, and nascent lysosomes are generated from these tubules. By combining proteomic analysis of purified autolysosomes and RNA interference screening of identified candidates, we systematically elucidated the ALR pathway at the molecular level. Based on the key components clathrin, PtdIns(4,5)P2, and the motor protein KIF5B, among others, we reconstituted this process in vitro. This unit describes a detailed method for visualizing ALR in cells during the autophagy process. This unit also present a protocol for reconstituting the ALR tubular protrusion and elongation process in vitro and three methods for preparing materials for in vitro reconstitution: (1) autolysosome purification from cultured cells, (2) liposome preparation, and (3) KIF5B purification and quality testing. © 2018 by John Wiley & Sons, Inc.

Chiu, SK, Saw, J, Huang, Y, Sonderegger, SE, Wong, NC, Powell, DR, Beck, D, Pimanda, JE, Tremblay, CS & Curtis, DJ 2018, 'A novel role for Lyl1 in primitive erythropoiesis', Development, vol. 145, no. 19.
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Stem Cell Leukemia (Scl or Tal1) and Lymphoblastic Leukemia 1 (Lyl1) are highly related members of the basic helix-loop-helix (bHLH) family of transcription factors that are co- expressed in the erythroid lineage. Previous studies suggest that Scl is essential for primitive erythropoiesis. However, analysis of single-cell RNA-sequencing data of early embryos showed that primitive erythroid cells express both Scl and Lyl1. Therefore, to determine whether Lyl1 can function in primitive erythropoiesis, we crossed conditional Scl knockout mice with mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Embryos with 20% expression of Scl from E9.5 survived to adulthood. However, mice with reduced expression of Scl and absence of Lyl1 (double knockout; DKO) died at E10.5 due to progressive loss of erythropoiesis. Gene expression profiling of DKO yolk sacs revealed loss of Gata1 and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses showed that LYL1 exclusively bound a small subset of SCL targets including GATA1. Together, these data show for the first time that Lyl1 can maintain primitive erythropoiesis.

Chuah, C, Wang, J, Tavakoli, J & Tang, Y 2018, 'Novel Bacterial Cellulose-Poly (Acrylic Acid) Hybrid Hydrogels with Controllable Antimicrobial Ability as Dressings for Chronic Wounds', Polymers, vol. 10, no. 12, pp. 1323-1323.
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This investigation examines the combination of poly (acrylic acid) (PAA) and bacterial cellulose (BC) nanofibers to synthesize hydrogel hybrid composites used for wound dressing application. Amoxicillin (AM) was also grafted onto the composites for drug release. Fourier transform infrared analysis and scanning electron microscopy conducted revealed the structure and porosity of the composite being developed, as well as the successful fabrication of BC-PAA composites. The results of mechanical testing and hygroscopicity revealed that the composite shows higher stability than hydrogels which are currently used worldwide, albeit with a slight reduction in swelling capabilities. However, the composite was revealed to be responsive to a rise in pH values with an increase in composite swelling and drug release. These results together with their morphological characteristics suggest that BC-PAA hydrogel hybrid composite is a promising candidate for wound dressing application.

Clarke, C, Liu, D, Wang, F, Liu, Y, Chen, C, Ton-That, C, Xu, X & Jin, D 2018, 'Large-scale dewetting assembly of gold nanoparticles for plasmonic enhanced upconversion nanoparticles', Nanoscale, vol. 10, no. 14, pp. 6270-6276.
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The integrated methods of core shell upconversion nanoparticle synthesis, thermal annealing and gold dewetting produce gold-decorated upconversion nanoparticles with enhanced emission.

Clement, S, Chen, W, Deng, W & Goldys, EM 2018, 'X-ray radiation-induced and targeted photodynamic therapy with folic acid-conjugated biodegradable nanoconstructs', International Journal of Nanomedicine, vol. Volume 13, pp. 3553-3570.
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Cooper, WA, Barnet, MB, Kao, SC & Scolyer, RA 2018, 'Biomarkers that predict response to immunotherapy-no magic bullet', Cancer Forum, vol. 42, no. 1.
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Immunotherapeutic agents have shown impressive clinical efficacy in a broad range of tumour types, particularly in non-small cell lung cancer and melanoma. An effective predictive biomarker is needed to provide patients with the most effective available treatments, avoid unnecessary toxicity and improve cost effectiveness. While it has been an area of very active research in recent years, the ideal biomarker for predicting response to immune check point inhibitor therapy has not yet been universally agreed upon. Approaches to date have focussed on assessment of tumour related factors such as immunohistochemical expression of programmed death ligand-1 (PD-L1), mutational load and DNA mismatch repair gene or protein status. Alternatively, assessment of the immune microenvironment by techniques such as gene expression profiling or measurement of tumour infiltrating lymphocytes can also be informative. Identifying and validating effective biomarkers is particularly challenging for immunotherapy because the dynamic and multifactorial nature of the interaction between tumours and host immunity. In this review, we discuss the relative advantages and disadvantages of different biomarker approaches in the quest to identify a clinically effective predictive biomarker that can improve the overall utility for immune checkpoint inhibitors.

Deng, W, Chen, W, Clement, S, Guller, A, Zhao, Z, Engel, A & Goldys, EM 2018, 'Controlled gene and drug release from a liposomal delivery platform triggered by X-ray radiation', Nature Communications, vol. 9, no. 1, p. 2713.
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AbstractLiposomes have been well established as an effective drug delivery system, due to simplicity of their preparation and unique characteristics. However conventional liposomes are unsuitable for the on-demand content release, which limits their therapeutic utility. Here we report X-ray-triggerable liposomes incorporating gold nanoparticles and photosensitizer verteporfin. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the efficiency of gene silencing in vitro and increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray-triggered liposomes. Importantly, our X-ray-mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation.

Deng, W, Goldys, EM & Zhao, Z 2018, 'Release of doxorubicin from liposomes by x-ray radiation', Nanomedicine: Nanotechnology, Biology and Medicine, vol. 14, no. 5, pp. 1753-1753.
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Depczynski, B, Young, T & White, C 2018, 'A high ankle-brachial index is associated with obesity and low serum 25-hydroxyvitamin D in patients with diabetes', Journal of Clinical & Translational Endocrinology, vol. 11, pp. 7-10.
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Dorneburg, C, Fischer, M, Barth, TFE, Mueller-Klieser, W, Hero, B, Gecht, J, Carter, DR, de Preter, K, Mayer, B, Christner, L, Speleman, F, Marshall, GM, Debatin, K-M & Beltinger, C 2018, 'LDHA in Neuroblastoma Is Associated with Poor Outcome and Its Depletion Decreases Neuroblastoma Growth Independent of Aerobic Glycolysis', Clinical Cancer Research, vol. 24, no. 22, pp. 5772-5783.
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Abstract Purpose: To investigate whether lactate dehydrogenase A (LDHA), an important component of the LDH tetramer crucial for aerobic glycolysis, is associated with patient outcome and constitutes a therapeutic target in neuroblastoma (NB). Experimental Design: Expression of LDHA mRNA and protein was determined in 709 and 110 NB patient samples, respectively, and correlated with survival and risk factors. LDHA and LDHB were depleted in human NB cell lines by CRISPR/Cas9 and shRNA, respectively, and aerobic glycolysis, clonogenicity, and tumorigenicity were determined. Expression of LDHA in relation to MYCN was measured in NB cell lines and in the TH-MYCN NB mouse model. Results: Expression of LDHA, both on the mRNA and the protein level, was significantly and independently associated with decreased patient survival. Predominant cytoplasmic localization of LDHA protein was associated with poor outcome. Amplification and expression of MYCN did not correlate with expression of LDHA in NB cell lines or TH-MYCN mice, respectively. Knockout of LDHA inhibited clonogenicity, tumorigenicity, and tumor growth without abolishing LDH activity or significantly decreasing aerobic glycolysis. Concomitant depletion of LDHA and the isoform LDHB ablated clonogenicity while not abrogating LDH activity or decreasing aerobic glycolysis. The isoform LDHC was not expressed. Conclusions: High expression of LDHA is independently associated with outcome of NB, and NB cells can be inhibited by depletion of LDHA or LDHB. This inhibition appears to be unrelated to LDH activity and aerobic glycolysis. Thus, investigations of inhibitory mechanisms beyond attenuation of aerobic glycolysis are warranted, both in NB and normal cells. Clin Cancer Res; 24(22); 5772–83. ©2018 AACR.

Du, X, Li, W, Shi, B, Su, L, Li, X, Huang, H, Wen, Y & Zhang, X 2018, 'Facile synthesis of mesoporous organosilica nanobowls with bridged silsesquioxane framework by one-pot growth and dissolution mechanism', Journal of Colloid and Interface Science, vol. 528, pp. 379-388.
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Dua, K, Rapalli, VK, Shukla, SD, Singhvi, G, Shastri, MD, Chellappan, DK, Satija, S, Mehta, M, Gulati, M, Pinto, TDJA, Gupta, G & Hansbro, PM 2018, 'Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: Emerging need for novel drug delivery approaches', Biomedicine & Pharmacotherapy, vol. 107, pp. 1218-1229.
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© 2018 Elsevier Masson SAS Tuberculosis (caused by Mycobacterium tuberculosis, Mtb) treatment involves multiple drug regimens for a prolonged period. However, the therapeutic benefit is often limited by poor patient compliance, subsequently leading to treatment failure and development of antibiotic resistance. Notably, oxidative stress is a crucial underlying factor that adversely influences the various treatment regimens in tuberculosis. Little information is available with advanced drug delivery systems that could be effectively utilized, in particular, for targeting the oxidative stress in tuberculosis. Thus, this presents an opportunity to review the utility of various available, controlled-release drug delivery systems (e.g., microspheres, liposomes, niosomes, solid lipid nanoparticles, dendrimers) that could be beneficial in tuberculosis treatments. This will help the biological and formulation scientists to pave a new path in formulating a treatment regimen for multi-drug resistant Mtb.

Fernández-Barrera, J, Bernabé-Rubio, M, Casares-Arias, J, Rangel, L, Fernández-Martín, L, Correas, I & Alonso, MA 2018, 'The actin-MRTF-SRF transcriptional circuit controls tubulin acetylation via α-TAT1 gene expression', The Journal of Cell Biology, vol. 217, no. 3, pp. 929-944.
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The role of formins in microtubules is not well understood. In this study, we have investigated the mechanism by which INF2, a formin mutated in degenerative renal and neurological hereditary disorders, controls microtubule acetylation. We found that silencing of INF2 in epithelial RPE-1 cells produced a dramatic drop in tubulin acetylation, increased the G-actin/F-actin ratio, and impaired myocardin-related transcription factor (MRTF)/serum response factor (SRF)–dependent transcription, which is known to be repressed by increased levels of G-actin. The effect on tubulin acetylation was caused by the almost complete absence of α-tubulin acetyltransferase 1 (α-TAT1) messenger RNA (mRNA). Activation of the MRTF-SRF transcriptional complex restored α-TAT1 mRNA levels and tubulin acetylation. Several functional MRTF-SRF–responsive elements were consistently identified in the α-TAT1 gene. The effect of INF2 silencing on microtubule acetylation was also observed in epithelial ECV304 cells, but not in Jurkat T cells. Therefore, the actin-MRTF-SRF circuit controls α-TAT1 transcription. INF2 regulates the circuit, and hence microtubule acetylation, in cell types where it has a prominent role in actin polymerization.

Ghorbani, S, Eyni, H, Tiraihi, T, Salari Asl, L, Soleimani, M, Atashi, A, Pour Beiranvand, S & Ebrahimi Warkiani, M 2018, 'Combined effects of 3D bone marrow stem cell-seeded wet-electrospun poly lactic acid scaffolds on full-thickness skin wound healing', International Journal of Polymeric Materials and Polymeric Biomaterials, vol. 67, no. 15, pp. 905-912.
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© 2017 Taylor & Francis. Tissue engineering has emerged as an alternative treatment to traditional grafts for skin wound healing. Three-dimensional nanofibers have been used extensively for this purpose due to their excellent biomedical-related properties. In this study, high porous 3D poly lactic acid nanofibrous scaffolds (PLA-S) were prepared by wet-electrospinning technique and seeded with rat bone-marrow stem cells (BMSCs) to characterize the biocompatibility and therapeutic efficacy of these fibers on the treating full-thickness dermal wounds. The results of in vitro andin vivo studies indicate that the 3D fibrous PLA-S can be a potential wound dressing for wound repair, particularly when seeded with BMSCs. GRAPHICAL ABSTRACT.

Guan, G, Zhao, M, Xu, X, Boczek, T, Mao, X, Li, Z, Gao, Q, Li, J, Zhao, D, Niu, W, Lei, L & Guo, F 2018, 'Abnormal changes in voltage-gated sodium channels subtypes Na V 1.1, Na V 1.2, Na V 1.3, Na V 1.6 and CaM/CaMKII pathway in low-grade astrocytoma', Neuroscience Letters, vol. 674, pp. 148-155.
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Han, W, Zhang, H-P, Tavakoli, J, Campbell, J & Tang, Y 2018, 'Polydopamine as sizing on carbon fiber surfaces for enhancement of epoxy laminated composites', Composites Part A: Applied Science and Manufacturing, vol. 107, pp. 626-632.
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Carbon fiber reinforced polymer (CFRP) laminate normally has plastic dominant crack propagation behavior, inducing potential insecurity in the safety and reliability of structures in practical applications. In this study, we report a simple process to increase the stability of crack growth by using polydopamine (PDA) as sizing on the surface of carbon fiber (CF) fabric. The crack propagation behavior changes from a saw-tooth-shaped curve in neat CFRP laminate to a relatively smooth trending curve in PDA coated CFRP laminate with increased Mode I interlaminar fracture toughness. Enhanced impact strength and interlaminar shear strength of PDA coated CFRP laminates is also observed. A single fiber pull-out experiment and morphological study reveal that, with PDA coating on CF fabrics, cracks tend to fracture through the epoxy matrix rather than between fiber and matrix interfaces. The use of PDA as sizing on the CF contributes to improving the load transfer between the CF and the polymer matrix by enhancing the interfaces between the epoxy and the CF, increasing the friction of the fractured interface, reducing unstable crack growth, and thereby enhancing interfacial fracture toughness and impact performance.

Hassanzadeh-Barforoushi, A, Law, AMK, Hejri, A, Asadnia, M, Ormandy, CJ, Gallego-Ortega, D & Ebrahimi Warkiani, M 2018, 'Static droplet array for culturing single live adherent cells in an isolated chemical microenvironment', Lab on a Chip, vol. 18, no. 15, pp. 2156-2166.
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Rapid and reliable capture and analysis of single cells in a chemically isolated static droplet array for fast-tracking single cell discoveries.

Ho, Y-J, Shih, C-P, Yeh, K-T, Shi, B, Gong, Z, Lin, Y-M & Lu, J-W 2018, 'Correlation between high expression levels of jumonji domain-containing 4 and short survival in cases of colon adenocarcinoma', Biochemical and Biophysical Research Communications, vol. 503, no. 3, pp. 1442-1449.
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Ho-Le, TP & Nguyen, TV 2018, 'Mathematics Research in Association of Southeast Asian Nations Countries: A Scientometric Analysis of Patterns and Impacts', Frontiers in Research Metrics and Analytics, vol. 3, p. 3.
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Ho-Le, TP, Pham, HM, Center, JR, Eisman, JA, Nguyen, HT & Nguyen, TV 2018, 'Prediction of changes in bone mineral density in the elderly: contribution of “osteogenomic profile”', Archives of Osteoporosis, vol. 13, no. 1.
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© 2018, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: The contribution of genetic variants to longitudinal bone loss has not been well documented. We constructed an “osteogenomic profile” based on 62 BMD-associated genetic variants and showed that the profile was significantly associated with bone loss, independently from baseline BMD and age. The osteogenomic profile can help predict bone loss in an individual. Introduction: The rate of longitudinal bone loss (ΔBMD) is a risk factor for fracture. The variation in ΔBMD is partly determined by genetic factors. This study sought to define the association between an osteogenomic profile and ΔBMD. Methods: The osteogenomic profile was created from 62 BMD-associated SNPs from genome-wide association studies (GWAS) that were genotyped in 1384 elderly men and women aged 60+ years. Weighted genetic risk scores (GRS) were constructed for each individual by summing the products of the number of risk alleles and the sex-specific regression coefficients [associated with BMD from GWAS]. ΔBMD, expressed as annual percent change-in-BMD, was determined by linear regression analysis for each individual who had had at least two femoral neck BMD measurements. Results: The mean ΔBMD was − 0.65% (SD 1.64%) for women and − 0.57% (SD 1.40%) for men, and this difference was not statistically significant (P = 0.32). In women, each unit increase in GRS was associated with 0.21% (SE 0.10) higher ΔBMD at the femoral neck (P = 0.036), and this association was independent of baseline BMD and age. In logistic regression analysis, each unit increase of GRS was associated with 41% odds (95%CI: 1.07–1.87) of rapid bone loss (ΔBMD ≤ − 1.2%/year; mean of rapid loss group = − 2.2%/year). There was no statistically significant association between ΔBMD and GRS in men. Conclusions: We conclude that the osteogenomic profile constructed from BMD-associated genetic variants is modestly associated with long-...

Ho-Pham, LT, Chau, PMN, Do, AT, Nguyen, HC & Nguyen, TV 2018, 'Type 2 diabetes is associated with higher trabecular bone density but lower cortical bone density: the Vietnam Osteoporosis Study', Osteoporosis International, vol. 29, no. 9, pp. 2059-2067.
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© 2018, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: It is not clear why type 2 diabetes (T2D) has an increased risk of fracture despite higher areal bone mineral density. This study showed that compared with controls, T2D patients had higher trabecular bone density but lower cortical bone density, resulting in a lower bone strength. Introduction: To define the association between type 2 diabetes and bone architecture and measures of bone strength. Methods: The study was part of the Vietnam Osteoporosis Study, in which 1115 women and 614 men aged ≥ 30 were randomly recruited from Ho Chi Minh City. HbA1c levels were measured with analyzers ADAMS™ A1c HA-8160 (Arkray, Kyoto, Japan). The diagnosis of T2D was made if HbA1c was ≥ 6.5%. Trabecular and cortical volumetric bone density (vBMD) was measured in the forearm and leg by a pQCT XCT2000 (Stratec, Germany). Polar stress strain index (pSSI) was derived from the pQCT measurements. Difference in bone parameters between T2D and non-diabetic individuals was assessed by the number of standard deviations (effect size [ES]) by the propensity score analysis. Results: The prevalence of T2D was ~ 8%. The results of propensity score matching for age, sex, and body mass index in 137 pairs of diabetic and non-diabetic individuals showed that T2D patients had significantly higher distal radius trabecular vBMD (ES 0.26; 95% CI, 0.02 to 0.50), but lower cortical vBMD (ES − 0.22; − 0.46 to 0.00) and reduced pSSI (ES − 0.23; − 0.47 to − 0.02) compared with non-diabetic individuals. Multiple linear regression analysis based on the entire sample confirmed the results of the propensity score analysis. Conclusion: Compared with non-diabetic individuals, patients with T2D have greater trabecular but lower cortical vBMD which leads to lower bone strength.

Ho-Pham, LT, Ho-Le, TP, Mai, LD, Do, TM, Doan, MC & Nguyen, TV 2018, 'Sex-difference in bone architecture and bone fragility in Vietnamese', Scientific Reports, vol. 8, no. 1.
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AbstractThis study sought to define the sex-difference in trabecular and cortical bone parameters in Vietnamese individuals. The study involved 1404 women and 864 men aged between 20 and 86 years who were recruited from Ho Chi Minh City, Vietnam. Trabecular and cortical volumetric BMD were measured at the proximal tibia and proximal radius at 4%, 38%, and 66% points, using a peripheral quantitative computed tomography XCT2000 (Stratec, Germany). Polar strength strain index was estimated from cortical bone parameters. Changes in bone parameters were assessed by the multiple linear regression model. Among individuals aged 20–39 years, women had significantly lower peak trabecular BMD at both the radius (40%) and tibia (16%) than men, but the age-related reduction in trabecular BMD were similar between two sexes. For cortical BMD, peak values in women and men were comparable, but the age-related diminution was greater in women than men. At any age, polar strength strain index in women was lower than men, and the difference was mainly attributable to cortical bone area and total bone mass. We conclude that in the elderly, sex-related difference in trabecular BMD is originated during growth, but sex-related difference in cortical BMD is determined by differential age-related bone loss.

Jia, P, Fang, G, Li, Z, Liang, H, Hong, Y, Liang, T & Xiong, J 2018, '“Bellows spring-shaped” ultrasensitive fiber-optic Fabry-Perot interferometric strain sensor', Sensors and Actuators A: Physical, vol. 277, pp. 85-91.
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© 2018 Elsevier B.V. All-silica fiber-optic Fabry-Perot strain sensor is rapidly gaining widespread adoption in many fields due to its compact structure, low cost and immunity to electromagnetic interference. However, the conventional configuration suffers from low sensitivity due to the limitation of its inherent structure feature. In this paper, we demonstrate an ultrasensitive fiber-optic Fabry-Perot interferometric strain sensor based on silica bellows spring structure. Utilizing the cascaded microbubbles, the sensitivity of the single-microbubble sensor is enhanced up to 203.8 pm/με and that of the cascaded two-microbubble sensor reaches 518.8 pm/με. The sensitivity is reinforced by 5-to-12 folds compared with the highest level ever reported, which could also be multiplied by increasing the microbubble number. The temperature-induced strain error is much low, less than 0.01 με/°C, showing great thermal stability and high-temperature application potential. Moreover, the strain sensor also provides high-quality spectrum, controllable free-spectral range and low cost.

Jia, P, Liang, H, Fang, G, Qian, J, Feng, F, Liang, T & Xiong, J 2018, 'Batch-producible MEMS fiber-optic Fabry–Perot pressure sensor for high-temperature application', Applied Optics, vol. 57, no. 23, pp. 6687-6687.
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Jing, D, Huang, Y, Liu, X, Sia, KCS, Zhang, JC, Tai, X, Wang, M, Toscan, CE, McCalmont, H, Evans, K, Mayoh, C, Poulos, RC, Span, M, Mi, J, Zhang, C, Wong, JWH, Beck, D, Pimanda, JE & Lock, RB 2018, 'Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia', Cancer Cell, vol. 34, no. 6, pp. 906-921.e8.
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© 2018 Elsevier Inc. Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types. Jing et al. identified lymphocyte-specific open chromatin domains (LSOs) critical for glucocorticoid (GC)-induced acute lymphoblastic leukemia (ALL) apoptosis. GC receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by DNA methylation in GC-resistant ALL and non-lymphoid cell types.

Kapeleris, J, Kulasinghe, A, Warkiani, ME, Vela, I, Kenny, L, O'Byrne, K & Punyadeera, C 2018, 'The Prognostic Role of Circulating Tumor Cells (CTCs) in Lung Cancer', Frontiers in Oncology, vol. 8, no. AUG.
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© 2018 Kapeleris, Kulasinghe, Warkiani, Vela, Kenny, O'Byrne and Punyadeera. Lung cancer affects over 1. 8 million people worldwide and is the leading cause of cancer related mortality globally. Currently, diagnosis of lung cancer involves a combination of imaging and invasive biopsies to confirm histopathology. Non-invasive diagnostic techniques under investigation include 'liquid biopsies' through a simple blood draw to develop predictive and prognostic biomarkers. A better understanding of circulating tumor cell (CTC) dissemination mechanisms offers promising potential for the development of techniques to assist in the diagnosis of lung cancer. Enumeration and characterization of CTCs has the potential to act as a prognostic biomarker and to identify novel drug targets for a precision medicine approach to lung cancer care. This review will focus on the current status of CTCs and their potential diagnostic and prognostic utility in this setting.

Khan, H, Razmjou, A, Ebrahimi Warkiani, M, Kottapalli, A & Asadnia, M 2018, 'Sensitive and Flexible Polymeric Strain Sensor for Accurate Human Motion Monitoring', Sensors, vol. 18, no. 2, pp. 418-418.
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Flexible electronic devices offer the capability to integrate and adapt with human body. These devices are mountable on surfaces with various shapes, which allow us to attach them to clothes or directly onto the body. This paper suggests a facile fabrication strategy via electrospinning to develop a stretchable, and sensitive poly (vinylidene fluoride) nanofibrous strain sensor for human motion monitoring. A complete characterization on the single PVDF nano fiber has been performed. The charge generated by PVDF electrospun strain sensor changes was employed as a parameter to control the finger motion of the robotic arm. As a proof of concept, we developed a smart glove with five sensors integrated into it to detect the fingers motion and transfer it to a robotic hand. Our results shows that the proposed strain sensors are able to detect tiny motion of fingers and successfully run the robotic hand.

Kulasinghe, A, Schmidt, H, Perry, C, Whitfield, B, Kenny, L, Nelson, C, Warkiani, ME & Punyadeera, C 2018, 'A Collective Route to Head and Neck Cancer Metastasis', Scientific Reports, vol. 8, no. 1.
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AbstractDistant metastasis (DM) from head and neck cancers (HNC) portends a poor patient prognosis. Despite its important biological role, little is known about the cells which seed these DM. Circulating tumour cells (CTCs) represent a transient cancer cell population, which circulate in HNC patients’ peripheral blood and seed at distant sites. Capture and analysis of CTCs offers insights into tumour metastasis and can facilitate treatment strategies. Whilst the data on singular CTCs have shown clinical significance, the role of CTC clusters in metastasis remains limited. In this pilot study, we assessed 60 treatment naïve HNC patients for CTCs with disease ranging from early to advanced stages, for CTC clusters utilizing spiral CTC enrichment technology. Single CTCs were isolated in 18/60–30% (Ranging from Stage I-IV), CTC clusters in 15/60–25% (exclusively Stage IV) with 3/15–20% of CTC clusters also containing leukocytes. The presence of CTC clusters associated with the development of distant metastatic disease(P = 0.0313). This study demonstrates that CTC clusters are found in locally advanced patients, and this may be an important prognostic marker. In vivo and in vitro studies are warranted to determine the role of these CTC clusters, in particular, whether leukocyte involvement in CTC clusters has clinical relevance.

Kulasinghe, A, Wu, H, Punyadeera, C & Warkiani, ME 2018, 'The Use of Microfluidic Technology for Cancer Applications and Liquid Biopsy', Micromachines, vol. 9, no. 8, pp. 397-397.
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There is growing awareness for the need of early diagnostic tools to aid in point-of-care testing in cancer. Tumor biopsy remains the conventional means in which to sample a tumor and often presents with challenges and associated risks. Therefore, alternative sources of tumor biomarkers is needed. Liquid biopsy has gained attention due to its non-invasive sampling of tumor tissue and ability to serially assess disease via a simple blood draw over the course of treatment. Among the leading technologies developing liquid biopsy solutions, microfluidics has recently come to the fore. Microfluidic platforms offer cellular separation and analysis platforms that allow for high throughout, high sensitivity and specificity, low sample volumes and reagent costs and precise liquid controlling capabilities. These characteristics make microfluidic technology a promising tool in separating and analyzing circulating tumor biomarkers for diagnosis, prognosis and monitoring. In this review, the characteristics of three kinds of circulating tumor markers will be described in the context of cancer, circulating tumor cells (CTCs), exosomes, and circulating tumor DNA (ctDNA). The review will focus on how the introduction of microfluidic technologies has improved the separation and analysis of these circulating tumor markers.

Kumar, R, Arjuna, A, Diksha, Gupta, R, Mahajan, S, Satija, S & Mehta, M 2018, 'In vitro antioxidant and antimicrobial activity of polyherbal formulation', International Journal of Green Pharmacy, vol. 12, no. 2, pp. 80-84.
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Context: Antioxidants play a major role in protecting the body against oxidative stress that is associated with many chronic diseases and disorders including chronic wounds. Plants are the richest source for antioxidant and are effective in the management of oxidative stress, caused by free radical damage. Wound healing and antimicrobial potential are also attributed to the antioxidant potential of drugs. Aim: The aim of this study is to carry out the antioxidant and antimicrobial activity of given polyherbal formulation (PHF) to correlate with the wound healing potential of the formulation. Materials and Methods: Antioxidant potential of the PHF was evaluated by the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. Agar well diffusion method was used to determine its antimicrobial activity against the Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella aerogenes. Results: Results of the study demonstrated that PHF exhibited significant antioxidant activity. Antibacterial activity of polyherbal formula was evaluated against the four pathogenic microorganisms in which it showed mild-to-moderate antimicrobial activity against the E. coli and K. aerogenes, while mild antimicrobial activity against the P. aeruginosa and P. vulgaris. Conclusion: Results of this study suggested that PHF can be used for the treatment of wound infections due to its marked antioxidant and antimicrobial activity.

Lal, S, Caseley, EA, Hall, RM & Tipper, JL 2018, 'Biological Impact of Silicon Nitride for Orthopaedic Applications: Role of Particle Size, Surface Composition and Donor Variation', Scientific Reports, vol. 8, no. 1, pp. 9109-9109.
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AbstractThe adverse biological impact of orthopaedic wear debris currently limits the long-term safety of human joint replacement devices. We investigated the role of particle size, surface composition and donor variation in influencing the biological impact of silicon nitride as a bioceramic for orthopaedic applications. Silicon nitride particles were compared to the other commonly used orthopaedic biomaterials (e.g. cobalt-chromium and Ti-6Al-4V alloys). A novel biological evaluation platform was developed to simultaneously evaluate cytotoxicity, inflammatory cytokine release, oxidative stress, and genotoxicity potential of particles using peripheral blood mononuclear cells (PBMNCs) from individual human donors. Irrespective of the particle size, silicon nitride did not cause any adverse responses whereas cobalt-chromium wear particles caused donor-dependent cytotoxicity, TNF-α cytokine release, oxidative stress, and DNA damage in PBMNCs after 24 h. Despite being similar in size and morphology, silicon dioxide nanoparticles caused the release of significantly higher levels of TNF-α compared to silicon nitride nanoparticles, suggesting that surface composition influences the inflammatory response in PBMNCs. Ti-6Al-4V wear particles also released significantly elevated levels of TNF-α cytokine in one of the donors. This study demonstrated that silicon nitride is an attractive orthopaedic biomaterial due to its minimal biological impact on human PBMNCs.

Lan, C, Peng, H, McGowan, EM, Hutvagner, G & Li, J 2018, 'An isomiR expression panel based novel breast cancer classification approach using improved mutual information', BMC Medical Genomics, vol. 11, no. S6, pp. 118-118.
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BACKGROUND:Gene expression-based profiling has been used to identify biomarkers for different breast cancer subtypes. However, this technique has many limitations. IsomiRs are isoforms of miRNAs that have critical roles in many biological processes and have been successfully used to distinguish various cancer types. Biomarker isomiRs for identifying different breast cancer subtypes has not been investigated. For the first time, we aim to show that isomiRs are better performing biomarkers and use them to explain molecular differences between breast cancer subtypes. RESULTS:In this study, a novel method is proposed to identify specific isomiRs that faithfully classify breast cancer subtypes. First, as a null hypothesis method we removed the lowly expressed isomiRs from small sequencing data generated from diverse breast cancers types. Second, we developed an improved mutual information-based feature selection method to calculate the weight of each isomiR expression. The weight of isomiR measures the importance of a given isomiR in classifying breast cancer subtypes. The improved mutual information enables to apply the dataset in which the feature is continuous data and label is discrete data; whereby, the traditional mutual information cannot be applied in this dataset. Finally, the support vector machine (SVM) classifier is applied to find isomiR biomarkers for subtyping. CONCLUSIONS:Here we demonstrate that isomiRs can be used as biomarkers in the identification of different breast cancer subtypes, and in addition, they may provide new insights into the diverse molecular mechanisms of breast cancers. We have also shown that the classification of different subtypes of breast cancer based on isomiRs expression is more effective than using published gene expression profiling. The proposed method provides a better performance outcome than Fisher method and Hellinger method for discovering biomarkers to distinguish different breast cancer subtypes. This novel techniqu...

Lee, A, Rayner, SL, Gwee, SSL, De Luca, A, Shahheydari, H, Sundaramoorthy, V, Ragagnin, A, Morsch, M, Radford, R, Galper, J, Freckleton, S, Shi, B, Walker, AK, Don, EK, Cole, NJ, Yang, S, Williams, KL, Yerbury, JJ, Blair, IP, Atkin, JD, Molloy, MP & Chung, RS 2018, 'Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy', Cellular and Molecular Life Sciences, vol. 75, no. 2, pp. 335-354.
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Li, JJ, Akey, A, Dunstan, CR, Vielreicher, M, Friedrich, O, Bell, DC & Zreiqat, H 2018, 'Effects of Material–Tissue Interactions on Bone Regeneration Outcomes Using Baghdadite Implants in a Large Animal Model', Advanced Healthcare Materials, vol. 7, no. 15, pp. e1800218-1800218.
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AbstractExtensive bone loss due to trauma or disease leads to impaired healing. Current bone grafts and substitutes have major drawbacks that limit their effectiveness for treating large bone defects. A number of bone substitutes in development are undergoing preclinical testing, but few studies specifically investigate the in vivo material–tissue interactions that provide an important indicator to long‐term implant safety and efficacy. This study is the first of its kind to specifically investigate in vivo material–tissue interactions at the bone–implant interface. Baghdadite scaffolds implanted in critical‐sized segmental defects in sheep tibia for 26 weeks are analyzed by focused ion beam scanning electron microscopy, multiphoton microscopy, and histology. The scaffolds are seen to induce extensive bone formation that directly abut the implant surfaces with no evidence of chronic inflammation or fibrous capsule formation. Bone remodeling is influenced by slow in vivo degradation around and within the implant, causing portions of the implant to be incorporated into the newly formed bone. These findings have important implications for predicting the long‐term effects of baghdadite ceramics in promoting defect healing, and support the translation of baghdadite scaffolds as a new generation of bone graft substitutes with improved properties for the repair of large bone defects.

Li, JJ, Ebied, M, Xu, J & Zreiqat, H 2018, 'Current Approaches to Bone Tissue Engineering: The Interface between Biology and Engineering', Advanced Healthcare Materials, vol. 7, no. 6, pp. e1701061-1701061.
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AbstractThe successful regeneration of bone tissue to replace areas of bone loss in large defects or at load‐bearing sites remains a significant clinical challenge. Over the past few decades, major progress is achieved in the field of bone tissue engineering to provide alternative therapies, particularly through approaches that are at the interface of biology and engineering. To satisfy the diverse regenerative requirements of bone tissue, the field moves toward highly integrated approaches incorporating the knowledge and techniques from multiple disciplines, and typically involves the use of biomaterials as an essential element for supporting or inducing bone regeneration. This review summarizes the types of approaches currently used in bone tissue engineering, beginning with those primarily based on biology or engineering, and moving into integrated approaches in the areas of biomaterial developments, biomimetic design, and scalable methods for treating large or load‐bearing bone defects, while highlighting potential areas for collaboration and providing an outlook on future developments.

Li, W, Xu, X, Li, W, Zhao, Y & Chen, M 2018, 'Fabrication, characterization and in vitro evaluation of triboelectric nanogenerator based on 317 L stainless steel and polylactic acid', Nanotechnology, vol. 29, no. 20, pp. 205402-205402.
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Li, W, Xu, X, Li, W, Zhao, Y & Chen, M 2018, 'Green synthesis of micron-sized silver flakes and their application in conductive ink', Journal of Materials Science, vol. 53, no. 9, pp. 6424-6432.
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Li, Z, Jia, P, Fang, G, Liang, H, Liang, T, Liu, W & Xiong, J 2018, 'Microbubble-based fiber-optic Fabry–Perot pressure sensor for high-temperature application', Applied Optics, vol. 57, no. 8, pp. 1738-1738.
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Lin, M, Shan, S, Liu, P, Ma, L, Huang, L, Yang, M, Lawson, T, Wang, Z, Huang, Z, Shi, B, Yan, L & Liu, Y 2018, 'Hydroxyl-Functional Groups on Graphene Trigger the Targeted Delivery of Antitumor Drugs', Journal of Biomedical Nanotechnology, vol. 14, no. 8, pp. 1420-1429.
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© 2018 American Scientific Publishers. An efficient and targeted treatment for tumor cells is demonstrated. This targeting is based upon the strong affinity between hydroxyl-functional groups on graphene and acidic tumors. The hydroxylated graphene (GOH) with a unique 2D architecture further improve the targeting capacity of the system via an enhanced permeability and retention (EPR) process. Polyethylene glycol (PEG) was employed for better biocompatibility and the antitumor drug doxorubicin (DOX) was then incorporated. These additions created a biocompatible system with a superior pH-dependent drug release property. Its proficiency was due to its ability to pass through cell membranes via a process of endocytosis and exocytosis. The results from a Transwell co-culture system discovered that the PEG-GOH-DOX system had a large impact on tumor cell viability (less than 10% survived after treatment) and little influence on normal cells (more than 80% survived). An in vitro 3D tumor model study demonstrated that the size of the PEG-GOH-DOX treated tumor was 50% less than that of the pristine DOX treated tumor. In vivo data indicated that the PEG-GOH-DOX system was able to inhibit the size of tumors by a factor of 6.5 when compared to the untreated tumors.

Liu, Q, Thoms, JAI, Nunez, AC, Huang, Y, Knezevic, K, Packham, D, Poulos, RC, Williams, R, Beck, D, Hawkins, NJ, Ward, RL, Wong, JWH, Hesson, LB, Sloane, MA & Pimanda, JE 2018, 'Disruption of a −35 kb Enhancer Impairs CTCF Binding and MLH1 Expression in Colorectal Cells', Clinical Cancer Research, vol. 24, no. 18, pp. 4602-4611.
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Abstract Purpose: MLH1 is a major tumor suppressor gene involved in the pathogenesis of Lynch syndrome and various sporadic cancers. Despite their potential pathogenic importance, genomic regions capable of regulating MLH1 expression over long distances have yet to be identified. Experimental Design: Here, we use chromosome conformation capture (3C) to screen a 650-kb region flanking the MLH1 locus to identify interactions between the MLH1 promoter and distal regions in MLH1-expressing and nonexpressing cells. Putative enhancers were functionally validated using luciferase reporter assays, chromatin immunoprecipitation, and CRISPR-Cas9–mediated deletion of endogenous regions. To evaluate whether germline variants in the enhancer might contribute to impaired MLH1 expression in patients with suspected Lynch syndrome, we also screened germline DNA from a cohort of 74 patients with no known coding mutations or epimutations at the MLH1 promoter. Results: A 1.8-kb DNA fragment, 35 kb upstream of the MLH1 transcription start site enhances MLH1 gene expression in colorectal cells. The enhancer was bound by CTCF and CRISPR-Cas9–mediated deletion of a core binding region impairs endogenous MLH1 expression. A total of 5.4% of suspected Lynch syndrome patients have a rare single-nucleotide variant (G &gt; A; rs143969848; 2.5% in gnomAD European, non-Finnish) within a highly conserved CTCF-binding motif, which disrupts enhancer activity in SW620 colorectal carcinoma cells. Conclusions: A CTCF-bound region within the MLH1-35 enhancer regulates MLH1 expression in colorectal cells and is worthy of scrutiny in future genetic screening strategies for suspected Lynch syndrome associated with loss of MLH1 expression. Clin Cancer Res; 24(18); 4602–11. ©2018 AACR.

Mai, HT, Tran, TS, Ho-Le, TP, Pham, TT, Center, JR, Eisman, JA & Nguyen, TV 2018, 'Low-trauma rib fracture in the elderly: Risk factors and mortality consequence', Bone, vol. 116, pp. 295-300.
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© 2018 Elsevier Inc. Purpose: Low trauma rib fracture (hereinafter, rib fracture) is common in the elderly, but its risk factors and mortality consequence are rarely studied. We sought to define the epidemiology of rib fracture and the association between rib fracture and postfracture mortality. Methods: The study was part of the Dubbo Osteoporosis Epidemiology Study, which was designed as a population-based prospective study, and consisted of 2041 women and men (aged ≥ 60). The incidence of rib fracture was ascertained from X-ray reports. Bone mineral density (BMD) was measured by DXA (GE-Lunar). The time-dependent Cox model was used to access the relationship between rib fracture and mortality. Results: During the median follow-up of 13 years, 59 men and 78 women had sustained a rib fracture, making the annual incidence of 4.8/1000 person-years. Each SD (0.15 g/cm 2 ) lower in femoral neck BMD was associated with ~2-fold increase in the hazard of fracture (hazard ratio [HR] 1.9; 95% CI, 1.4 to 2.6 in men; and HR 2.1; 95% CI, 1.6 to 2.8 in women). Among those with a rib fracture, the incidence of subsequent fractures was 10.2/100 person-years. Compared with those without a fracture, the risk of mortality among those with a fracture was increased by ~7.8-fold (95% CI, 2.7 to 22.5) in men and 4.9-fold (95% CI 2.0 to 11.8) in women within the first year postfracture. Conclusions: A rib fracture signifies an increased risk of subsequent fractures and mortality. The increased risk of mortality during the first 2.5 years postfracture suggests a window of opportunity for treatment.

Marsavela, G, Aya-Bonilla, CA, Warkiani, ME, Gray, ES & Ziman, M 2018, 'Melanoma circulating tumor cells: Benefits and challenges required for clinical application', Cancer Letters, vol. 424, pp. 1-8.
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© 2018 The implementation of novel therapeutic interventions has improved the survival rates of melanoma patients with metastatic disease. Nonetheless, only 33% of treated cases exhibit long term responses. Circulating tumor cell (CTC) measurements are currently of clinical value in breast, prostate and colorectal cancers. However, the clinical utility of melanoma CTCs (MelCTCs) is still unclear due to challenges that appear intrinsic to MelCTCs (i.e. rarity, heterogeneity) and a lack of standardization in their isolation, across research laboratories. Here, we review the latest developments, pinpoint the challenges in MelCTC isolation and address their potential role in melanoma management.

Moazzam, P, Tavassoli, H, Razmjou, A, Warkiani, ME & Asadnia, M 2018, 'Mist harvesting using bioinspired polydopamine coating and microfabrication technology', Desalination, vol. 429, pp. 111-118.
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© 2017 Elsevier B.V. The fascinating biopolymer of polydopamine (PDA) and negative photolithography method was utilized to produce porous membrane surfaces with contrast wettabilities via creating hydrophilic patterns (nanoscale PDA coated SU-8 bumps) on the hydrophobic background of polypropylene (PP) membranes. The high rate of water collection (97 mg cm− 2 h− 1) highlighted the impact of hydrophilic patterns and wetting properties on mist-harvesting results. Modified samples exhibited droplet motion by coalescence rather than rolling which means created hydrophilic patterns also have a significant impact on the behavior of the droplets on these surfaces. Surface characterization including Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM) and contact angle as well as surface free energy measurement were performed to study the effect of topography and roughness on the system performance. This created structure has the great potential to be fabricated in large scale. Also, due to the porous nature of its hydrophobic background, water collection rate can be substantially increased by using vacuum pressure, makes it attractive for industry.

Moloudi, R, Oh, S, Yang, C, Ebrahimi Warkiani, M & Naing, MW 2018, 'Inertial particle focusing dynamics in a trapezoidal straight microchannel: application to particle filtration', Microfluidics and Nanofluidics, vol. 22, no. 3.
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© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Inertial microfluidics has emerged recently as a promising tool for high-throughput manipulation of particles and cells for a wide range of flow cytometric tasks including cell separation/filtration, cell counting, and mechanical phenotyping. Inertial focusing is profoundly reliant on the cross-sectional shape of channel and its impacts on not only the shear field but also the wall-effect lift force near the wall region. In this study, particle focusing dynamics inside trapezoidal straight microchannels was first studied systematically for a broad range of channel Re number (20 OpenSPiltSPi Re OpenSPiltSPi 800). The altered axial velocity profile and consequently new shear force arrangement led to a cross-lateral movement of equilibration toward the longer side wall when the rectangular straight channel was changed to a trapezoid; however, the lateral focusing started to move backward toward the middle and the shorter side wall, depending on particle clogging ratio, channel aspect ratio, and slope of slanted wall, as the channel Reynolds number further increased (Re CloseSPigtSPi 50). Remarkably, an almost complete transition of major focusing from the longer side wall to the shorter side wall was found for large-sized particles of clogging ratio K ~ 0.9 (K = a/Hmin) when Re increased noticeably to ~ 650. Finally, based on our findings, a trapezoidal straight channel along with a bifurcation was designed and applied for continuous filtration of a broad range of particle size (0.3 OpenSPiltSPi K OpenSPiltSPi 1) exiting through the longer wall outlet with ~ 99% efficiency (Re OpenSPiltSPi 100).

Moloudi, R, Oh, S, Yang, C, Teo, KL, Lam, AT-L, Warkiani, ME & Naing, MW 2018, 'Inertial-Based Filtration Method for Removal of Microcarriers from Mesenchymal Stem Cell Suspensions', Scientific Reports, vol. 8, no. 1.
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AbstractRapidly evolving cell-based therapies towards clinical trials demand alternative approaches for efficient expansion of adherent cell types such as human mesenchymal stem cells (hMSCs). Using microcarriers (100–300 µm) in a stirred tank bioreactor offers considerably enhanced surface to volume ratio of culture environment. However, downstream purification of the harvested cell product needs to be addressed carefully due to distinctive features and fragility of these cell products. This work demonstrates a novel alternative approach which utilizes inertial focusing to separate microcarriers (MCs) from the final cell suspension. First, we systematically investigated MC focusing dynamics inside scaled-up curved channels with trapezoidal and rectangular cross-sections. A trapezoidal spiral channel with ultra-low-slope (Tan(α) = 0.0375) was found to contribute to strong MC focusing (~300 < Re < ~400) while managing high MC volume fractions up to ~1.68%. Accordingly, the high-throughput trapezoidal spiral channel successfully separated MCs from hMSC suspension with total cell yield~94% (after two passes) at a high volumetric flow rate of ~30 mL/min (Re~326.5).

Moshksayan, K, Kashaninejad, N, Warkiani, ME, Lock, JG, Moghadas, H, Firoozabadi, B, Saidi, MS & Nguyen, N-T 2018, 'Spheroids-on-a-chip: Recent advances and design considerations in microfluidic platforms for spheroid formation and culture', Sensors and Actuators B: Chemical, vol. 263, pp. 151-176.
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© 2018 Elsevier B.V. A cell spheroid is a three-dimensional (3D) aggregation of cells. Synthetic, in-vitro spheroids provide similar metabolism, proliferation, and species concentration gradients to those found in-vivo. For instance, cancer cell spheroids have been demonstrated to mimic in-vivo tumor microenvironments, and are thus suitable for in-vitro drug screening. The first part of this paper discusses the latest microfluidic designs for spheroid formation and culture, comparing their strategies and efficacy. The most recent microfluidic techniques for spheroid formation utilize emulsion, microwells, U-shaped microstructures, or digital microfluidics. The engineering aspects underpinning spheroid formation in these microfluidic devices are therefore considered. In the second part of this paper, design considerations for microfluidic spheroid formation chips and microfluidic spheroid culture chips (μSFCs and μSCCs) are evaluated with regard to key parameters affecting spheroid formation, including shear stress, spheroid diameter, culture medium delivery and flow rate. This review is intended to benefit the microfluidics community by contributing to improved design and engineering of microfluidic chips capable of forming and/or culturing three-dimensional cell spheroids.

Motamedi, M, Warkiani, ME & Taylor, RA 2018, 'Transparent Surfaces Inspired by Nature', Advanced Optical Materials, vol. 6, no. 14, pp. 1800091-1800091.
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AbstractNature has long inspired scientists and engineers. As one ubiquitous example of this, nature has provided all with several clever methods to absorb, repel, and/or allow both sunlight and water to pass through surfaces. Moth's eyes (highly antireflective) and lotus leaves (highly hydrophobic and self‐cleaning) represent durable natural surfaces which exhibit nearly ideal physical and optical properties. Man‐made transparent surfaces must also be able to cope with water and dust while reaching the maximum possible light transmission for solar collectors, displays, and other optical devices. To explore the link between these – particularly for transparent surfaces – this review puts the physics, progress, and limitations of synthetic materials in context with natural materials. This perspective reveals that there is still much more to learn (and implement) if it is hoped to match the multifunctionality and resilience of natural materials.

Nguyen, LT, Nguyen, UDT, Nguyen, TDT, Ho-Pham, LT & Nguyen, TV 2018, 'Contribution of bone turnover markers to the variation in bone mineral density: a study in Vietnamese men and women', Osteoporosis International, vol. 29, no. 12, pp. 2739-2744.
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© 2018, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: The present cross-sectional study constructed reference ranges for bone resorption marker beta isomerized form of C-terminal crosslinking telopeptides of type I collagen (beta-CTX) and bone formation marker procollagen type 1 N-terminal propeptide (PINP) for the Vietnamese population. We have further shown that for a given age and weight, higher levels of beta-CTX were significantly associated with bone mineral density in men and women. Introduction: Normal bone is constantly renewed by two opposing processes of resorption and formation which can be reflected by bone turnover markers (BTMs). This study sought to define the contribution of BTMs to the variation in bone mineral density (BMD) in normal individuals. Methods: The study involved 205 men and 432 women aged between 18 and 87, who were randomly selected from various districts within Ho Chi Minh City, Vietnam. Fasting serum levels of PINP and beta-CTX were determined by electrochemiluminescence (Roche, ECLIA). BMD at the lumbar spine (LS) and femoral neck (FN) was measured by dual-energy x-ray absorptiometry (Hologic, Waltham, MA, USA). Results: Among those aged < 50 years, women had lower PINP and beta-CTX levels than men, but among those aged > 50 years, women had higher PINP and beta-CTX levels than men. In the multiple linear regression analysis, beta-CTX—but not PINP—was significantly associated with both femoral neck (P = 0.008) and lumbar spine BMD (P = 0.008) and the association was independent of gender, age, and body weight. The proportion of variance in BMD attributable to beta-CTX was 1% for femoral neck BMD and 2% for lumbar spine BMD. Conclusion: The elevation in bone formation marker PINP and bone resorption marker beta-CTX in postmenopausal women was greater than in elderly men. However, only beta-CTX was modestly but significantly associated with BMD.

Nguyen, TV 2018, 'Individualized fracture risk assessment: State-of-the-art and room for improvement', Osteoporosis and Sarcopenia, vol. 4, no. 1, pp. 2-10.
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Fragility fracture is a serious clinical event, because it is associated with increased risk of mortality and reduced quality of life. The risk of fracture is determined by multiple risk factors, and their effects may be interactional. Over the past 10 years, a number of predictive models (e.g., FRAX, Garvan Fracture Risk Calculator, and Qfracture) have been developed for individualized assessment of fracture risk. These models use different risk profiles to estimate the probability of fracture over 5- and 10-year period. The ability of these models to discriminate between those individuals who will and will not have a fracture (i.e., area under the receiver operating characteristic curve [AUC]) is generally acceptable-to-good (AUC, 0.6 to 0.8), and is highly variable between populations. The calibration of existing models is poor, particularly in Asian populations. There is a strong need for the development and validation of new prediction models based on Asian data for Asian populations. We propose approaches to improve the accuracy of existing predictive models by incorporating new markers such as genetic factors, bone turnover markers, trabecular bone score, and time-variant factors. New and more refined models for individualized fracture risk assessment will help identify those most likely to sustain a fracture, those most likely to benefit from treatment, and encouraging them to modify their risk profile to decrease risk.

Nguyen, TV & Eisman, JA 2018, 'Assessment of Fracture Risk: Population Association Versus Individual Prediction', Journal of Bone and Mineral Research, vol. 33, no. 3, pp. 386-388.
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Ooi, CY, Carter, DR, Liu, B, Mayoh, C, Beckers, A, Lalwani, A, Nagy, Z, De Brouwer, S, Decaesteker, B, Hung, T-T, Norris, MD, Haber, M, Liu, T, De Preter, K, Speleman, F, Cheung, BB & Marshall, GM 2018, 'Network Modeling of microRNA–mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN', Cancer Research, vol. 78, no. 12, pp. 3122-3134.
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Abstract Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. On the basis of a Bayesian learning network model in which we compared pretumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA–mRNA interaction network. Among the miRNA–mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis. Significance: Network modeling of miRNA–mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN. Cancer Res; 78(12); 3122–34. ©2018 AACR.

Partridge, S, Tipper, JL, Al‐Hajjar, M, Isaac, GH, Fisher, J & Williams, S 2018, 'Evaluation of a new methodology to simulate damage and wear of polyethylene hip replacements subjected to edge loading in hip simulator testing', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 106, no. 4, pp. 1456-1462.
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AbstractWear and fatigue of polyethylene acetabular cups have been reported to play a role in the failure of total hip replacements. Hip simulator testing under a wide range of clinically relevant loading conditions is important. Edge loading of hip replacements can occur following impingement under extreme activities and can also occur during normal gait, where there is an offset deficiency and/or joint laxity. This study evaluated a hip simulator method that assessed wear and damage in polyethylene acetabular liners that were subjected to edge loading. The liners tested to evaluate the method were a currently manufactured crosslinked polyethylene acetabular liner and an aged conventional polyethylene acetabular liner. The acetabular liners were tested for 5 million standard walking cycles and following this 5 million walking cycles with edge loading. Edge loading conditions represented a separation of the centers of rotation of the femoral head and the acetabular liner during the swing phase, leading to loading of the liner rim on heel strike. Rim damage and cracking was observed in the aged conventional polyethylene liner. Steady‐state wear rates assessed gravimetrically were lower under edge loading compared to standard loading. This study supports previous clinical findings that edge loading may cause rim cracking in liners, where component positioning is suboptimal or where material degradation is present. The simulation method developed has the potential to be used in the future to test the effect of aging and different levels of severity of edge loading on a range of cross‐linked polyethylene materials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1456–1462, 2018.

Patel, J, Lal, S, Nuss, K, Wilshaw, SP, von Rechenberg, B, Hall, RM & Tipper, JL 2018, 'Recovery of low volumes of wear debris from rat stifle joint tissues using a novel particle isolation method', Acta Biomaterialia, vol. 71, pp. 339-350.
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Less than optimal particle isolation techniques have impeded analysis of orthopaedic wear debris in vivo. The purpose of this research was to develop and test an improved method for particle isolation from tissue. A volume of 0.018 mm3 of clinically relevant CoCrMo, Ti-6Al-4V or Si3N4 particles was injected into rat stifle joints for seven days of in vivo exposure. Following sacrifice, particles were located within tissues using histology. The particles were recovered by enzymatic digestion of periarticular tissue with papain and proteinase K, followed by ultracentrifugation using a sodium polytungstate density gradient. Particles were recovered from all samples, observed using SEM and the particle composition was verified using EDX, which demonstrated that all isolated particles were free from contamination. Particle size, aspect ratio and circularity were measured using image analysis software. There were no significant changes to the measured parameters of CoCrMo or Si3N4 particles before and after the recovery process (KS tests, p > 0.05). Titanium particles were too few before and after isolation to analyse statistically, though size and morphologies were similar. Overall the method demonstrated a significant improvement to current particle isolation methods from tissue in terms of sensitivity and efficacy at removal of protein, and has the potential to be used for the isolation of ultra-low wearing total joint replacement materials from periprosthetic tissues. STATEMENT OF SIGNIFICANCE:This research presents a novel method for the isolation of wear particles from tissue. Methodology outlined in this work would be a valuable resource for future researchers wishing to isolate particles from tissues, either as part of preclinical testing, or from explants from patients for diagnostic purposes. It is increasingly recognised that analysis of wear particles is critical to evaluating the safety of an orthopaedic device.

Patel, J, Lal, S, Wilshaw, SP, Hall, RM & Tipper, JL 2018, 'Development and optimisation data of a tissue digestion method for the isolation of orthopaedic wear particles', Data in Brief, vol. 20, pp. 173-177.
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© 2018 The Authors The data contained within this article relate to several enzymatic tissue digestion experiments which were performed to produce an optimised protocol for the digestion of tissue samples. The digestion experiments involved a total of four different digestion protocols. The first protocol involved digestion with proteinase K, without the use of glycine. The second protocol involved digestion with proteinase K in the presence of glycine. The third protocol consisted of proteinase K digestion in the presence of glycine, with more frequent enzyme replenishment. The final protocol was similar to the third protocol but included a papain digestion stage prior to digestion with proteinase K. The data contained within this article are photographs of tissue samples which were captured at key stages of the four protocols and written descriptions based on visual observation of the tissue samples, which document the appearance of the tissue digests.

Patel, J, Lal, S, Wilshaw, SP, Hall, RM & Tipper, JL 2018, 'Recovery rate data for silicon nitride nanoparticle isolation using sodium polytungstate density gradients', Data in Brief, vol. 19, pp. 1474-1476.
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The average recovery rate of silicon nitride nanoparticles isolated from serum using the method detailed in previous article "A novel method for isolation and recovery of ceramic nanoparticles and metal wear debris from serum lubricants at ultra-low wear rate" (Lal et al., 2016) [1] was tested gravimetrically by weighing particles doped into serum before and after the isolation process. An average recovery rate of approximately 89.6% (± 7.1 SD) was achieved.

Patel, J, Lal, S, Wilshaw, SP, Hall, RM & Tipper, JL 2018, 'Validation of a novel particle isolation procedure using particle doped tissue samples', Data in Brief, vol. 18, pp. 1802-1807.
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A novel particle isolation method for tissue samples was developed and tested using particle-doped peri-articular tissues from ovine cadavers. This enabled sensitivity of the isolation technique to be established by doping tissue samples of 0.25 g with very low particle volumes of 2.5 µm3 per sample. Image analysis was used to verify that the method caused no changes to particle size or morphologies.

Pham, TT, Nguyen, DN, Dutkiewicz, E, Center, JR, Eisman, JA & Nguyen, TV 2018, 'A profiling analysis of contributions of cigarette smoking, dietary calcium intakes, and physical activity to fragility fracture in the elderly', Scientific Reports, vol. 8, no. 1.
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AbstractFragility fracture and bone mineral density (BMD) are influenced by common and modifiable lifestyle factors. In this study, we sought to define the contribution of lifestyle factors to fracture risk by using a profiling approach. The study involved 1683 women and 1010 men (50+ years old, followed up for up to 20 years). The incidence of new fractures was ascertained by X-ray reports. A “lifestyle risk score” (LRS) was derived as the weighted sum of effects of dietary calcium intake, physical activity index, and cigarette smoking. Each individual had a unique LRS, with higher scores being associated with a healthier lifestyle. Baseline values of lifestyle factors were assessed. In either men or women, individuals with a fracture had a significantly lower age-adjusted LRS than those without a fracture. In men, each unit lower in LRS was associated with a 66% increase in the risk of total fracture (non-adjusted hazard ratio [HR] 1.66; 95% CI, 1.26 to 2.20) and still significant after adjusting for age, weight or BMD. However, in women, the association was uncertain (HR 1.30; 95% CI, 1.11 to 1.53). These data suggest that unhealthy lifestyle habits are associated with an increased risk of fracture in men, but not in women, and that the association is mediated by BMD.

Pinho, AV, Van Bulck, M, Chantrill, L, Arshi, M, Sklyarova, T, Herrmann, D, Vennin, C, Gallego-Ortega, D, Mawson, A, Giry-Laterriere, M, Magenau, A, Leuckx, G, Baeyens, L, Gill, AJ, Phillips, P, Timpson, P, Biankin, AV, Wu, J & Rooman, I 2018, 'ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling', Nature Communications, vol. 9, no. 1.
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AbstractWhereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.

Qi, H, Niu, L, Zhang, J, Chen, J, Wang, S, Yang, J, Guo, S, Lawson, T, Shi, B & Song, C 2018, 'Large-area gold nanohole arrays fabricated by one-step method for surface plasmon resonance biochemical sensing', Science China Life Sciences, vol. 61, no. 4, pp. 476-482.
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Ren, W, Wen, S, Tawfik, SA, Su, QP, Lin, G, Ju, LA, Ford, MJ, Ghodke, H, van Oijen, AM & Jin, D 2018, 'Anisotropic functionalization of upconversion nanoparticles', Chemical Science, vol. 9, no. 18, pp. 4352-4358.
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Ligand competition directs heterogeneous bio-chemistry surface and self-assembly for upconversion nanoparticles.

Rifai, A, Tran, N, Lau, DW, Elbourne, A, Zhan, H, Stacey, AD, Mayes, ELH, Sarker, A, Ivanova, EP, Crawford, RJ, Tran, PA, Gibson, BC, Greentree, AD, Pirogova, E & Fox, K 2018, 'Polycrystalline Diamond Coating of Additively Manufactured Titanium for Biomedical Applications', ACS Applied Materials & Interfaces, vol. 10, no. 10, pp. 8474-8484.
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Rogers, S, McCloy, RA, Parker, BL, Gallego-Ortega, D, Law, AMK, Chin, VT, Conway, JRW, Fey, D, Millar, EKA, O’Toole, S, Deng, N, Swarbrick, A, Chastain, PD, Cesare, AJ, Timpson, P, Caldon, CE, Croucher, DR, James, DE, Watkins, DN & Burgess, A 2018, 'MASTL overexpression promotes chromosome instability and metastasis in breast cancer', Oncogene, vol. 37, no. 33, pp. 4518-4533.
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MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.

Sais, D, Zhang, X, Marques, TM, Rose, B, Khoury, S, Hill, M, Deutsch, F, Lyons, JG, Gama-Carvalho, M & Tran, N 2018, 'Human papillomavirus 16 E6 modulates the expression of miR-496 in oropharyngeal cancer', Virology, vol. 521, pp. 149-157.
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© 2018 Human papillomavirus (HPV), notably type 16, is a risk factor for up to 75% of oropharyngeal squamous cell carcinomas (SCC). It has been demonstrated that small non-coding RNAs known as microRNAs play a vital role in the cellular transformation process. In this study, we used an LNA array to further investigate the impact of HPV16 on the expression of microRNAs in oropharyngeal (tonsillar) cancer. A number of miRNAs were found to be deregulated, with miR-496 showing a four-fold decrease. Over-expression of the high risk E6 oncoprotein down-regulated miR-496, impacting upon the post-transcriptional control of the transcription factor E2F2. These HPV specific miRNAs were integrated with the HPV16 interactome to identify possible mechanistic pathways. These analyses provide insights into novel molecular interactions between HPV16 and miRNAs in oropharyngeal cancers.

Sarker, A, Tran, N, Rifai, A, Elambasseril, J, Brandt, M, Williams, R, Leary, M & Fox, K 2018, 'Angle defines attachment: Switching the biological response to titanium interfaces by modifying the inclination angle during selective laser melting', Materials & Design, vol. 154, pp. 326-339.
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Satija, S, Prince, Gupta, R, Mahajan, S, Sharma, N, Khurana, N, Kalsi, V, Duggal, N, Singh, A & Mehta, M 2018, 'Chromatographic fingerprinting, antioxidant, and anti-inflammatory potential of Dioscorea villosa (Wild Yam) leaves', International Journal of Green Pharmacy, vol. 12, no. 2, pp. 102-106.
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Context: Free radicals have been implicated in a wide range diversity of diseases and ailments, and therefore, the compounds having the ability to scavenge these free radicals are under extensive investigation, of which Dioscorea species have been actively involved. Objective: The current study assessed the anti-inflammatory and antioxidant potential of standardized leaf extracts of Dioscorea villosa. Material and Methods: Anti-inflammatory activity was carried out using carrageenan-induced paw edema assay, and antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Chromatographic fingerprinting of the crude methanolic extract was carried out using high-performance liquid chromatography (HPLC) whereby diosgenin was used as a standard marker compound. Results: Among all the crude successive extracts, methanolic extract showed significant anti-inflammatory activity in comparison with the standard whereby the extract showed maximum inhibition of paw edema after 3 h of carrageenan injection. The aqueous extract showed noticeable antioxidant activity with the half maximal inhibitory concentration of 21.36 μg/ml. Discussion: The preliminary phytochemical screening showed the presence of flavonoids and tannins that may be responsible for the observed effect. In addition, the presence of steroids marks toward the observed anti-inflammatory activity. In addition, the extract showed noticeable levels of diosgenin, which were marked and quantified using HPLC. Conclusion: The results strongly support the ethnobotanical use of the plant.

Scheltema, MJ, Chang, JI, Böhm, M, van den Bos, W, Blazevski, A, Gielchinsky, I, Kalsbeek, AMF, van Leeuwen, PJ, Nguyen, TV, de Reijke, TM, Siriwardana, AR, Thompson, JE, de la Rosette, JJ & Stricker, PD 2018, 'Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy', World Journal of Urology, vol. 36, no. 9, pp. 1383-1389.
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PURPOSE:The design, conduct and completion of randomized trials for curative prostate cancer (PCa) treatments are challenging. To evaluate the effect of robot-assisted radical prostatectomy (RARP) versus focal irreversible electroporation (IRE) on patient-reported quality of life (QoL) and early oncological control using propensity-scored matching. METHODS:Patients with T1c-cT2b significant PCa (high-volume ISUP 1 or any 2/3) who received unifocal IRE were pair-matched to patients who received nerve-sparing RARP. Patient-reported outcomes were prospectively assessed using the Expanded Prostate Cancer Index Composite (EPIC), AUA symptom score and Short Form of Health Survey (SF-12) physical and mental components. Oncological failure was defined as biochemical recurrence (RARP) or positive follow-up biopsies (IRE). Generalized mixed-effect models were used to compare IRE and RARP. RESULTS:50 IRE patients were matched to 50 RARP patients by propensity score. IRE was significantly superior to RARP in preserving pad-free continence (UC) and erections sufficient for intercourse (ESI). The absolute differences were 44, 21, 13, 14% for UC and 32, 46, 27, 22% for ESI at 1.5, 3, 6, and 12 months, respectively. The EPIC summary scores showed no statistically significant differences. Urinary symptoms were reduced for IRE and RARP patients at 12 months, although IRE patient initially had more complaints. IRE patients experienced more early oncological failure than RARP patients. CONCLUSIONS:These data demonstrated the superior preservation of UC and ESI with IRE compared to RARP up to 12 months after treatment. Long-term oncological data are warranted to provide ultimate proof for or against focal therapy.

Scheltema, MJ, Chang, JI, Bos, WVD, Gielchinsky, I, Nguyen, TV, Reijke, TMD, Siriwardana, AR, Böhm, M, Rosette, JJDL & Stricker, PD 2018, 'Impact on genitourinary function and quality of life following focal irreversible electroporation of different prostate segments', Diagnostic and Interventional Radiology, vol. 24, no. 5, pp. 268-275.
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© Turkish Society of Radiology 2018. PURPOSE We aimed to evaluate the genitourinary function and quality of life (QoL) following the ablation of different prostate segments with irreversible electroporation (IRE) for localized prostate cancer (PCa). METHODS Sixty patients who received primary focal IRE for organ-confined PCa were recruited for this study. Patients were evaluated for genitourinary function and QoL per prostate segment treated (anterior vs. posterior, apex vs. base vs. apex-to-base, unilateral vs. bilateral). IRE system settings and patient characteristics were compared between patients with preserved vs. those with impaired erectile function and urinary continence. Data were prospectively collected at baseline, 3, 6, and 12 months using the expanded prostate cancer index composite, American Urological Association symptom score, SF-12 physical and mental component summary surveys. Difference over time within segments per questionnaire was evaluated using the Wilcoxon’s signed rank test. Outcome differences between segments were assessed using covariance models. Baseline measurements included questionnaire scores, age, and prostate volume. RESULTS There were no statistically significant changes over time for overall urinary (P = 0.07-0.89), bowel (P = 0.06-0.79), physical (P = 0.18-0.71) and mental (P = 0.45-0.94) QoL scores within each segment. Deterioration of sexual function scores was observed at 6 months within each segment (P = 0.001-0.16). There were no statistically significant differences in QoL scores between prostate segments (P = 0.08-0.97). Older patients or those with poor baseline sexual function at time of treatment were associated with a greater risk of developing erectile dysfunction. CONCLUSION IRE is a feasible modality for all prostate segments without any significantly different effect on the QoL outcomes. Older patients and those with poor sexual function need to be counseled regarding the risk of erectile dysfunction.

Sheu, A, Chan, Y, Ferguson, A, Bakhtyari, MB, Hawke, W, White, C, Chan, YF, Bertolino, PJ, Woon, HG, Palendira, U, Sierro, F & Lau, SM 2018, 'A proinflammatory CD4+ T cell phenotype in gestational diabetes mellitus', Diabetologia, vol. 61, no. 7, pp. 1633-1643.
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Singh, A, Mukhtar, HM, Satija, S & Mehta, M 2018, 'DEVELOPMENT OF QUALITATIVE PHARMACOGNOSTIC AND HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHIC FINGERPRINTING OF MORPHOLOGICAL SIMILAR SPECIES OF GENUS FICUS', Asian Journal of Pharmaceutical and Clinical Research, vol. 11, no. 7, pp. 444-444.
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Objective: Ficus deltoidea (FD) and Ficus benjamina (FB), popularly known as “jack tree/mas cotek” and “pimpri/java fig,” respectively, in India and are used in folk medicine to treat the wound, ulcers, diabetes, microbial infections, and inflammatory disorders. Such therapeutic claims have also been justified in the literature by their rich chemical diversity. Both the plant species are morphologically similar and used unauthentically as the traditional medicinal product. Although these plants are sold in the local market by a traditional medicinal healer, we did not find any authenticated data on its quality.Methods: In the present study, quality standards of both the plant drugs have been developed and compared by performing morphological, microscopical, physicochemical, phytochemical, and high-performance thin-layer chromatographic (HPTLC) analysis. using CAMAG Linomat 5 instrument (Kindly delete the bold matter).Results: It was revealed that both the plant species have similar pharmacognostic features with some differences in type of stomata, presence of marked midrib, arrangement of the cell, cell structures, and meristele. HPTLC data revealed that the primary component in FD leaves (FDL) and FB leaves (FBL) extracts was found at Rf 0.67 and 0.37 with the respective peak area of 35.61% and 34.71%. The peaks at Rf 0.17 and 0.27 can be appeared as the chemical marker to highlight the quality of FDL, whereas peaks at Rf 0.87 and 0.95 can be considered to identify and chemically standardize the FBL.Conclusion: This study highlighted essential characters which contribute to the standardization, identification, and authentication of plant drugs.

Sofela, S, Sahloul, S, Rafeie, M, Kwon, T, Han, J, Warkiani, ME & Song, Y-A 2018, 'High-throughput sorting of eggs for synchronization ofC. elegansin a microfluidic spiral chip', Lab on a Chip, vol. 18, no. 4, pp. 679-687.
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High-throughput isolation ofC. eleganseggs from a mixed worm population in a spiral chip using inertial microfluidics.

Stefen, H, Hassanzadeh-Barforoushi, A, Brettle, M, Fok, S, Suchowerska, AK, Tedla, N, Barber, T, Warkiani, ME & Fath, T 2018, 'A Novel Microfluidic Device-Based Neurite Outgrowth Inhibition Assay Reveals the Neurite Outgrowth-Promoting Activity of Tropomyosin Tpm3.1 in Hippocampal Neurons', Cellular and Molecular Neurobiology, vol. 38, no. 8, pp. 1557-1563.
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© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Overcoming neurite inhibition is integral for restoring neuronal connectivity after CNS injury. Actin dynamics are critical for neurite growth cone formation and extension. The tropomyosin family of proteins is a regarded as master regulator of actin dynamics. This study investigates tropomyosin isoform 3.1 (Tpm3.1) as a potential candidate for overcoming an inhibitory substrate, as it is known to influence neurite branching and outgrowth. We designed a microfluidic device that enables neurons to be grown adjacent to an inhibitory substrate, Nogo-66. Results show that neurons, overexpressing hTpm3.1, have an increased propensity to overcome Nogo-66 inhibition. We propose Tpm3.1 as a potential target for promoting neurite growth in an inhibitory environment in the central nervous system.

Su, QP & Ju, LA 2018, 'Biophysical nanotools for single-molecule dynamics', Biophysical Reviews, vol. 10, no. 5, pp. 1349-1357.
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The focus of the cell biology field is now shifting from characterizing cellular activities to organelle and molecular behaviors. This process accompanies the development of new biophysical visualization techniques that offer high spatial and temporal resolutions with ultra-sensitivity and low cell toxicity. They allow the biology research community to observe dynamic behaviors from scales of single molecules, organelles, cells to organoids, and even live animal tissues. In this review, we summarize these biophysical techniques into two major classes: the mechanical nanotools like dynamic force spectroscopy (DFS) and the optical nanotools like single-molecule and super-resolution microscopy. We also discuss their applications in elucidating molecular dynamics and functionally mapping of interactions between inter-cellular networks and intra-cellular components, which is key to understanding cellular processes such as adhesion, trafficking, inheritance, and division.

Sun, Y, Zhang, W, Wang, B, Xu, X, Chou, J, Shimoni, O, Ung, AT & Jin, D 2018, 'A supramolecular self-assembly strategy for upconversion nanoparticle bioconjugation', Chemical Communications, vol. 54, no. 31, pp. 3851-3854.
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An efficient surface modification and bioconjugation strategy for upconversion nanoparticles is reported via supramolecular host–guest self-assembly.

Suñer, S, Gowland, N, Craven, R, Joffe, R, Emami, N & Tipper, JL 2018, 'Ultrahigh molecular weight polyethylene/graphene oxide nanocomposites: Wear characterization and biological response to wear particles', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 106, no. 1, pp. 183-190.
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AbstractIn the field of total joint replacements, polymer nanocomposites are being investigated as alternatives to ultrahigh molecular weight polyethylene (UHMWPE) for acetabular cup bearings. The objective of this study was to investigate the wear performance and biocompatibility of UHMWPE/graphene oxide (GO) nanocomposites. This study revealed that low concentrations of GO nanoparticles (0.5 wt %) do not significantly alter the wear performance of UHMWPE. In contrast, the addition of higher concentrations (2 wt %) led to a significant reduction in wear. In terms of biocompatibility, UHMWPE/GO wear particles did not show any adverse effects on L929 fibroblast and PBMNC viability at any of the concentrations tested over time. Moreover, the addition of GO to a UHMWPE matrix did not significantly affect the inflammatory response to wear particles. Further work is required to optimize the manufacturing processes to improve the mechanical properties of the nanocomposites and additional biocompatibility testing should be performed to understand the potential clinical application of these materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 183–190, 2018.

Syed, MS, Rafeie, M, Vandamme, D, Asadnia, M, Henderson, R, Taylor, RA & Warkiani, ME 2018, 'Selective separation of microalgae cells using inertial microfluidics', Bioresource Technology, vol. 252, pp. 91-99.
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© 2017 Elsevier Ltd Microalgae represent the most promising new source of biomass for the world's growing demands. However, the biomass productivity and quality is significantly decreased by the presence of bacteria or other invading microalgae species in the cultures. We therefore report a low-cost spiral-microchannel that can effectively separate and purify Tetraselmis suecica (lipid-rich microalgae) cultures from Phaeodactylum tricornutum (invasive diatom). Fluorescent polystyrene-microbeads of 6 μm and 10 μm diameters were first used as surrogate particles to optimize the microchannel design by mimicking the microalgae cell behaviour. Using the optimum flowrate, up to 95% of the P. tricornutum cells were separated from the culture without affecting the cell viability. This study shows, for the first time, the potential of inertial microfluidics to sort microalgae species with minimal size difference. Additionally, this approach can also be applied as a pre-sorting technique for water quality analysis.

Tavakoli, J & Costi, JJ 2018, 'A method for visualization and isolation of elastic fibres in annulus fibrosus of the disc', Materials Science and Engineering: C, vol. 93, pp. 299-304.
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A simple and cost effective protocol for visualization and isolation of the elastic fibres network in the annulus fibrosus (AF) of the disc is explained, to provide other researchers a method that can be applied in disc ultra-structural analysis, biomechanical assessment of elastic fibre and tissue engineered scaffold fabrication. This protocol is developed based on simultaneous sonication and alkali digestion of tissue that eliminates all matrix constituents except for elastic fibres, which is applicable for different species including human. Thin samples harvested from ovine, bovine, porcine and human, which are commonly used in disc research, were exposed to 0.5 M sodium hydroxide solution along with sonication (25 kHz) in distilled water for defined periods of time at room temperature. Post heat treatment removed collagen fibres via the gelatinization process, for visualization of elastic fibres.

Tavakoli, J & Costi, JJ 2018, 'New findings confirm the viscoelastic behaviour of the inter-lamellar matrix of the disc annulus fibrosus in radial and circumferential directions of loading', Acta Biomaterialia, vol. 71, pp. 411-419.
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While few studies have improved our understanding of composition and organization of elastic fibres in the inter-lamellar matrix (ILM), its clinical relevance is not fully understood. Moreover, no studies have measured the direct tensile and shear failure and viscoelastic properties of the ILM. Therefore, the aim of this study was, for the first time, to measure the viscoelastic and failure properties of the ILM in both the tension and shear directions of loading. Using an ovine model, isolated ILM samples were stretched to 40% of their initial length at three strain rates of 0.1%s-1 (slow), 1%s-1 (medium) and 10%s-1 (fast) and a ramp test to failure was performed at a strain rate of 10%s-1. The findings from this study identified that the stiffness of the ILM was significantly larger at faster strain rates, and energy absorption significantly smaller, compared to slower strain rates, and the viscoelastic and failure properties were not significantly different under tension and shear loading. We found a strain rate dependent response of the ILM during dynamic loading, particularly at the fastest rate. The ILM demonstrated a significantly higher capability for energy absorption at slow strain rates compared to medium and fast strain rates. A significant increase in modulus was found in both loading directions and all strain rates, having a trend of larger modulus in tension and at faster strain rates. The finding of no significant difference in failure properties in both loading directions, was consistent with our previous ultra-structural studies that revealed a well-organized (±45°) elastic fibre orientation in the ILM. The results from this study can be used to develop and validate finite element models of the AF at the tissue scale, as well as providing new strategies for fabricating tissue engineered scaffolds. STATEMENT OF SIGNIFICANCE: While few studies have improved our understanding of composition and organization of elastic fibres in the inter-...

Tavakoli, J & Costi, JJ 2018, 'New insights into the viscoelastic and failure mechanical properties of the elastic fiber network of the inter-lamellar matrix in the annulus fibrosus of the disc', Acta Biomaterialia, vol. 77, pp. 292-300.
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The mechanical role of elastic fibers in the inter-lamellar matrix (ILM) is unknown; however, it has been suggested that they play a role in providing structural integrity to the annulus fibrosus (AF). Therefore, the aim of this study was to measure the viscoelastic and failure properties of the elastic fiber network in the ILM of ovine discs under both tension and shear directions of loading. Utilizing a technique, isolated elastic fibers within the ILM from ovine discs were stretched to 40% of their initial length at three strain rates of 0.1% s-1 (slow), 1% s-1 (medium) and 10% s-1 (fast), followed by a ramp test to failure at 10% s-1. A significant strain-rate dependent response was found, particularly at the fastest rate for phase angle and normalized stiffness (p < 0.001). The elastic fibers in the ILM demonstrated a significantly higher capability for energy absorption at slow compared to medium and fast strain rates (p < 0.001). These finding suggests that the elastic fiber network of the ILM exhibits nonlinear elastic behavior. When tested to failure, a significantly higher normalized failure force was found in tension compared to shear loading (p = 0.011), which is consistent with the orthotropic structure of elastic fibers in the ILM. The results of this study confirmed the mechanical contribution of the elastic fiber network to the ILM and the structural integrity of the AF. This research serves as a foundation for future studies to investigate the relationship between degeneration and ILM mechanical properties. STATEMENT OF SIGNIFICANCE: The mechanical role of elastic fibres in the inter-lamellar matrix (ILM) of the disc is unknown. The viscoelastic and failure properties of the elastic fibre network in the ILM in both tension and shear directions of loading was measured for the first time. We found a strain-rate dependent response for the elastic fibres in the ILM. The elastic fibres in the ILM demonstrated a significantly higher capabilit...

Tavakoli, J & Costi, JJ 2018, 'Ultrastructural organization of elastic fibres in the partition boundaries of the annulus fibrosus within the intervertebral disc', Acta Biomaterialia, vol. 68, pp. 67-77.
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The relationship between elastic fibre disorders and disc degeneration, aging and progression of spine deformity have been discussed in a small number of studies. However, the clinical relevance of elastic fibres in the annulus fibrosus (AF) of the disc is poorly understood. Ultrastructural visualization of elastic fibres is an important step towards understanding their structure-function relationship. In our previous studies, a novel technique for visualization of elastic fibres across the AF was presented and their ultrastructural organization in intra- and inter-lamellar regions was compared. Using the same novel technique in the present study, the ultrastructural organization of elastic fibres in the partition boundaries (PBs), which are located between adjacent collagen bundles, is presented for the first time. Visualization of elastic fibres in the PBs in control and partially digested (digested) samples was compared, and their orientation in two different cutting planes (transverse and oblique) were discussed. The ultrastructural analysis revealed that elastic fibres in PBs were a well-organized dense and complex network having different size and shape. Adjacent collagen bundles in a cross section (CS) lamella appear to be connected to each other, where elastic fibres in the PBs were merged in parallel or penetrated into the collagen bundles. There was no significant difference in directional coherency coefficient of elastic fibres between the two different cutting planes (p = .35). The present study revealed that a continuous network of elastic fibres may provide disc integrity by connecting adjacent bundles of CS lamellae together. Compared to our previous studies, the density of the elastic fibre network in PBs was lower, and fibre orientation was similar to the intra-lamellar space and inter-lamellar matrix. STATEMENT OF SIGNIFICANCE: A detailed ultrastructural study in the partition boundaries of the annulus fibrosus within the disc revealed...

Tavakoli, J & Khosroshahi, ME 2018, 'Surface morphology characterization of laser-induced titanium implants: lesson to enhance osseointegration process', Biomedical Engineering Letters, vol. 8, no. 3, pp. 249-257.
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The surface properties of implant are responsible to provide mechanical stability by creating an intimate bond between the bone and implant; hence, play a major role on osseointegration process. The current study was aimed to measure surface characteristics of titanium modified by a pulsed Nd:YAG laser. The results of this study revealed an optimum density of laser energy (140 Jcm-2), at which improvement of osteointegration process was seen. Significant differences were found between arithmetical mean height (Ra), root mean square deviation (Rq) and texture orientation, all were lower for 140 Jcm-2 samples compared to untreated one. Also it was identified that the surface segments were more uniformly distributed with a more Gaussian distribution for treated samples at 140 Jcm-2. The distribution of texture orientation at high laser density (250 and 300 Jcm-2) were approximately similar to untreated sample. The skewness index that indicates how peaks and valleys are distributed throughout the surface showed a positive value for laser treated samples, compared to untreated one. The surface characterization revealed that Kurtosis index, which tells us how high or flat the surface profile is, for treated sample at 140 Jcm-2 was marginally close to 3 indicating flat peaks and valleys in the surface profile.

Tavakoli, J, Amin, DB, Freeman, BJC & Costi, JJ 2018, 'The Biomechanics of the Inter-Lamellar Matrix and the Lamellae During Progression to Lumbar Disc Herniation: Which is the Weakest Structure?', Annals of Biomedical Engineering, vol. 46, no. 9, pp. 1280-1291.
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While microstructural observations have improved our understanding of possible pathways of herniation progression, no studies have measured the mechanical failure properties of the inter-lamellar matrix (ILM), nor of the adjacent lamellae during progression to herniation. The aim of this study was to employ multiscale, biomechanical and microstructural techniques to evaluate the effects of progressive induced herniation on the ILM and lamellae in control, pre-herniated and herniated discs (N = 7), using 2 year-old ovine spines. Pre-herniated and herniated (experimental) groups were subjected to macroscopic compression while held in flexion (13°), before micro-mechanical testing. Micro-tensile testing of the ILM and the lamella from anterior and posterolateral regions was performed in radial and circumferential directions to measure failure stress, modulus, and toughness in all three groups. The failure stress of the ILM was significantly lower for both experimental groups compared to control in each of radial and circumferential loading directions in the posterolateral region (p < 0.032). Within each experimental group in both loading directions, the ILM failure stress was significantly lower by 36% (pre-herniation), and 59% (herniation), compared to the lamella (p < 0.029). In pre-herniated compared to control discs, microstructural imaging revealed significant tissue stretching and change in orientation (p < 0.003), resulting in a loss of distinction between respective lamellae and ILM boundaries.

Tavakoli, J, Mirzaei, S & Tang, Y 2018, 'Cost-Effective Double-Layer Hydrogel Composites for Wound Dressing Applications', Polymers, vol. 10, no. 3, pp. 305-305.
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Although poly vinyl alcohol-poly acrylic acid (PVA-PAA) composites have been widely used for biomedical applications, their incorporation into double-layer assembled thin films has been limited because the interfacial binding materials negatively influence the water uptake capacity of PVA. To minimize the effect of interfacial binding, a simple method for the fabrication of a double-layered PVA-PAA hydrogel was introduced, and its biomedical properties were evaluated in this study. Our results revealed that the addition of PAA layers on the surface of PVA significantly increased the swelling properties. Compared to PVA, the equilibrium swelling ratio of the PVA-PAA hydrogel increased (p = 0.035) and its water vapour permeability significantly decreased (p = 0.04). Statistical analysis revealed that an increase in pH value from 7 to 10 as well as the addition of PAA at pH = 7 significantly increased the adhesion force (p < 0.04). The mechanical properties—including ultimate tensile strength, modulus, and elongation at break—remained approximately untouched compared to PVA. A significant increase in biocompatibility was found after day 7 (p = 0.016). A higher release rate for tetracycline was found at pH = 8 compared to neutral pH.

Tavassoli, H, Alhosseini, SN, Tay, A, Chan, PPY, Weng Oh, SK & Warkiani, ME 2018, 'Large-scale production of stem cells utilizing microcarriers: A biomaterials engineering perspective from academic research to commercialized products', Biomaterials, vol. 181, pp. 333-346.
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© 2018 Elsevier Ltd Human stem cells, including pluripotent, embryonic and mesenchymal, stem cells play pivotal roles in cell-based therapies. Over the past decades, various methods for expansion and differentiation of stem cells have been developed to satisfy the burgeoning clinical demands. One of the most widely endorsed technologies for producing large cell quantities is using microcarriers (MCs) in bioreactor culture systems. In this review, we focus on microcarriers properties that can manipulate the expansion and fate of stem cells. Here, we provide an overview of commercially available MCs and focus on novel stimulus responsive MCs controlled by temperature, pH and field changes. Different features of MCs including composition, surface coating, morphology, geometry/size, surface functionalization, charge and mechanical properties, and their cellular effects are also highlighted. We then conclude with current challenges and outlook on this promising technology.

Tavassoli, H, Javadpour, J, Taheri, M, Mehrjou, M, Koushki, N, Arianpour, F, Majidi, M, Izadi-Mobarakeh, J, Negahdari, B, Chan, P, Ebrahimi Warkiani, M & Bonakdar, S 2018, 'Incorporation of Nanoalumina Improves Mechanical Properties and Osteogenesis of Hydroxyapatite Bioceramics', ACS Biomaterials Science & Engineering, vol. 4, no. 4, pp. 1324-1336.
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© 2018 American Chemical Society. A handful of work focused on improving the intrinsic low mechanical properties of hydroxyapatite (HA) by various reinforcing agents. However, the big challenge regarding improving mechanical properties is maintaining bioactivity. To address this issue, we report fabrication of apatite-based composites by incorporation of alumina nanoparticles (n-Al2O3). Although numerous studies have used micron or submicron alumina for reinforcing hydroxyapatite, only few reports are available about the use of n-Al2O3. In this study, spark plasma sintering (SPS) method was utilized to develop HA-nAl2O3 dense bodies. Compared to the conventional sintering, decomposition of HA and formation of calcium aluminates phases are restricted using SPS. Moreover, n-Al2O3 acts as a bioactive agent while its conventional form is an inert bioceramics. The addition of n-Al2O3 resulted in 40% improvement in hardness along with a 110% increase in fracture toughness, while attaining nearly full dense bodies. The in vitro characterization of nanocomposite demonstrated improved bone-specific cell function markers as evidenced by cell attachment and proliferation, alkaline phosphatase activity, calcium and collagen detection and nitric oxide production. Specifically, gene expression analysis demonstrated that introduction of n-Al2O3 in HA matrix resulted in accelerated osteogenic differentiation of osteoblast and mesenchymal stem cells, as expression of Runx-2 and OSP showed 2.5 and 19.6 fold increase after 2 weeks (p < 0.05). Moreover, protein adsorption analysis showed enhanced adsorption of plasma proteins to HA-nAl2O3 sample compared to HA. These findings suggest that HA-nAl2O3 could be a prospective candidate for orthopedic applications due to its improved mechanical and osteogenic properties.

Tran, T, Bliuc, D, Hansen, L, Abrahamsen, B, van den Bergh, J, Eisman, JA, van Geel, T, Geusens, P, Vestergaard, P, Nguyen, TV & Center, JR 2018, 'Persistence of Excess Mortality Following Individual Nonhip Fractures: A Relative Survival Analysis', The Journal of Clinical Endocrinology & Metabolism, vol. 103, no. 9, pp. 3205-3214.
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© 2018 Endocrine Society. Context: Little is known about long-term excess mortality following fragility nonhip fractures. Objective: The study aimed to determine which fracture was associated with excess mortality and for how long the postfracture excess mortality persisted. Design, Setting, and Patients: This nationwide registry-based follow-up study included all individuals in Denmark aged 50+ years who first experienced fragility fractures in 2001 and were followed up for up to 10 years for their mortality risk. Main Outcome Measure: The contribution of fracture to mortality at precise postfracture time intervals was examined using relative survival analysis, accounting for time-related mortality changes in the background population. Results: There were 21,123 women (aged 72 ± 13 years) and 9481 men (aged 67 ± 12 years) with an incident fragility fracture in 2001, followed by 10,668 and 4745 deaths, respectively. Excess mortality was observed following all proximal and lower leg fractures. The majority of deaths occurred within the first year after fracture, and thereafter excess mortality gradually declined. Hip fractures were associated with the highest excess mortality (33% and 20% at 1 year after fracture in men and women, respectively). One-year excess mortality after fracture of a femur or pelvis was 20% to 25%; vertebrae, 10%; humerus, rib, or clavicle, 5% to 10%; and lower leg, 3%. A significant although smaller excess mortality was still observed until 10 years for hip fractures and ∼5 years after femur, other proximal, and lower leg fractures. Conclusion: This study highlights the important contribution of a wide variety of fragility fractures to long-term excess mortality and thus the potential for benefit from early intervention.

Valdes-Mora, F, Handler, K, Law, AMK, Salomon, R, Oakes, SR, Ormandy, CJ & Gallego-Ortega, D 2018, 'Single-Cell Transcriptomics in Cancer Immunobiology: The Future of Precision Oncology', Frontiers in Immunology, vol. 9.
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Viardot, A, Purtell, L, Nguyen, TV & Campbell, LV 2018, 'Relative Contributions of Lean and Fat Mass to Bone Mineral Density: Insight From Prader-Willi Syndrome', Frontiers in Endocrinology, vol. 9, no. AUG.
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© 2018 Viardot, Purtell, Nguyen and Campbell. Context: Low bone mineral density (BMD) is the most important risk factor for fragility fracture. Body weight is a simple screening predictor of difference in BMD between individuals. However, it is not clear which component of body weight, lean (LM), or fat mass (FM), is associated with BMD. People with the genetic disorder of Prader-Willi syndrome (PWS) uniquely have a reduced LM despite increased FM. Objective: We sought to define the individual impact of LM and FM on BMD by investigating subjects with and without PWS. Design, Setting and Participants: This cross-sectional study was conducted at the Clinical Research Facility of the Garvan Institute of Medical Research, with PWS and control participants recruited from a specialized PWS clinic and from the general public by advertisement, respectively. The study involved 11 adults with PWS, who were age- and sex-matched with 12 obese individuals (Obese group) and 10 lean individuals (Lean group). Main Outcome Measures: Whole body BMD was measured by dual-energy X-ray absorptiometry. Total body FM and LM were derived from the whole body scan. Differences in BMD between groups were assessed by the analysis of covariance model, taking into account the effects of LM and FM. Results: The PWS group had significantly shorter height than the lean and obese groups. As expected, there was no significant difference in FM between the Obese and PWS group, and no significant difference in LM between the Lean and PWS group. However, obese individuals had greater LM than lean individuals. BMD in lean individuals was significantly lower than in PWS individuals (1.13 g/cm2 vs. 1.21 g/cm2, p < 0.05) and obese individuals (1.13 g/cm2 vs. 1.25 g/cm2, p < 0.05). After adjusting for both LM and FM, there was no significant difference in BMD between groups, and the only significant predictor of BMD was LM. Conclusions: These data from the human genetic model Prader-Willi syndrome...

Wang, J, Zhao, L, Zhang, A, Huang, Y, Tavakoli, J & Tang, Y 2018, 'Novel Bacterial Cellulose/Gelatin Hydrogels as 3D Scaffolds for Tumor Cell Culture', Polymers, vol. 10, no. 6, pp. 581-581.
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Three-dimensional (3D) cells in vitro culture are becoming increasingly popular in cancer research because some important signals are lost when cells are cultured in a two-dimensional (2D) substrate. In this work, bacterial cellulose (BC)/gelatin hydrogels were successfully synthesized and were investigated as scaffolds for cancer cells in vitro culture to simulate tumor microenvironment. Their properties and ability to support normal growth of cancer cells were evaluated. In particular, the human breast cancer cell line (MDA-MD-231) was seeded into BC/gelatin scaffolds to investigate their potential in 3D cell in vitro culture. MTT proliferation assay, scanning electron microscopy, hematoxylin and eosin staining and immunofluorescence were used to determine cell proliferation, morphology, adhesion, infiltration, and receptor expression. The in vitro MDA-MD-231 cell culture results demonstrated that cells cultured on the BC/gelatin scaffolds had significant adhesion, proliferation, ingrowth and differentiation. More importantly, MDA-MD-231 cells cultured in BC/gelatin scaffolds retained triple-negative receptor expression, demonstrating that BC/gelatin scaffolds could be used as ideal in vitro culture scaffolds for tumor cells.

Winter, M, Hardy, T, Rezaei, M, Nguyen, V, Zander‐Fox, D, Ebrahimi Warkiani, M & Thierry, B 2018, 'Isolation of Circulating Fetal Trophoblasts Using Inertial Microfluidics for Noninvasive Prenatal Testing', Advanced Materials Technologies, vol. 3, no. 7, pp. 1800066-1800066.
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AbstractWhile noninvasive prenatal testing based on cell‐free fetal DNA has recently revolutionized the field of aneuploidy screening in pregnancy, it remains limited to aneuploidy and microdeletion screening, and is unable to reliably detect single gene disorders. A number of recent studies have demonstrated the potential of circulating trophoblastic cells in providing cell‐based noninvasive diagnosis with sequencing or array‐based assays. However, considering the extreme rarity of these cells in blood, efficient, high‐throughput, and clinically applicable enrichment technologies are yet to be developed. This study demonstrates for the first time the utility of inertial microfluidics for efficient isolation of trophoblastic cells from maternal peripheral blood. Under optimal operating conditions, high‐recovery yields (79%) are obtained using a trophoblastic cell‐line, which is subsequently confirmed with analysis of maternal blood. Feasibility of obtaining a diagnosis from cells isolated from a maternal sample is demonstrated in a case of confirmed fetal trisomy 21 in which six fetal cells are found in a 7 mL blood sample using fluorescence in situ hybridization. Finally, it is demonstrated that trophoblastic cells isolated using inertial microfluidics could be picked and subjected to a clinically validated sequencing assay, paving the way for further validation of this technology and larger clinical studies.

Wu, Y, Li, S, Liu, J, Liu, X, Ruan, W, Lu, J, Liu, Y, Lawson, T, Shimoni, O, Lovejoy, DB, Walker, AK, Cong, Y & Shi, B 2018, 'Stilbenes from Veratrum maackii Regel Protect against Ethanol-Induced DNA Damage in Mouse Cerebellum and Cerebral Cortex', ACS Chemical Neuroscience, vol. 9, no. 7, pp. 1616-1624.
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© Copyright 2018 American Chemical Society. Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as 'Lilu' and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3′-O-β-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5-O-β-d-diglucopyranoside (5), oxyresveratrol- 4′-O-β-d-glucopyranoside (6), oxyresveratrol-3-O-β-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development.

Young, AIJ, Timpson, P, Gallego-Ortega, D, Ormandy, CJ & Oakes, SR 2018, 'Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion', Cell Adhesion & Migration, vol. 12, no. 6, pp. 513-523.
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Zhao, B, Dong, K, Lin, M, Dong, G, Shan, S, Lawson, T, Yan, L, Zhang, W, Shi, B, Chou, S, Baker, MS & Liu, Y 2018, 'A Transferrin Triggered Pathway for Highly Targeted Delivery of Graphene‐Based Nanodrugs to Treat Choroidal Melanoma', Advanced Healthcare Materials, vol. 7, no. 16.
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AbstractThe synthesis of transferrin (Tf)‐modified pegylated graphene (PG) and its application as a highly efficient drug delivery carrier for therapy of Ocular Choroidal Melanoma‐1 (OCM‐1) cells is presented. For the first reported time, nanoscaled PG is prepared using an environmentally friendly ball‐milling technique. The unique 2D nanostructure obtained using this PG synthesis approach offers considerable advantages in terms of drug loading and delivery, as well as the conjugation of Tf to PG providing a more targeted delivery vehicle. A highly efficient targeted pathway toward OCM‐1 cells triggered by an affinity between Tf and Tf receptors expressed on the surface of OCM‐1 cells is reported first here. PG‐Tf is observed to easily anchor anticancer drugs such as doxorubicin via π–π stacking. This work performs a Transwell two cells coculture experiment, a 3D in vitro tumor model, and an in vivo mouse model with OCM‐1 tumors to demonstrate the composite's therapeutic superiority over conventional systems for the targeted delivery and controlled release of antitumor drugs.

Zheng, M, Tao, W, Zou, Y, Farokhzad, OC & Shi, B 2018, 'Nanotechnology-Based Strategies for siRNA Brain Delivery for Disease Therapy', Trends in Biotechnology, vol. 36, no. 5, pp. 562-575.
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Zou, Y, Liu, Y, Yang, Z, Zhang, D, Lu, Y, Zheng, M, Xue, X, Geng, J, Chung, R & Shi, B 2018, 'Effective and Targeted Human Orthotopic Glioblastoma Xenograft Therapy via a Multifunctional Biomimetic Nanomedicine', Advanced Materials, vol. 30, no. 51.
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AbstractGlioblastoma multiforme (GBM) is a fatal central nervous system tumor without effective treatment. Chemotherapeutic agents are mainstays in the treatment of glioblastoma. However, the effectiveness of these is seriously hindered by poor blood–brain‐barrier (BBB) penetrance and tumor targeting, together with short biological half‐life. Improved chemotherapy is thus urgently needed for GBM. Multifunctional nanoparticle delivery systems offer much promise in overcoming current limitations. Accordingly, a multifunctional biomimetic nanomedicine is developed by functionalizing the surface of red blood cell membranes (RBCms) with angiopep‐2 and loading pH‐sensitive nanoparticles (polymer, doxorubicin (Dox), and lexiscan (Lex)) using the functionalized cell membrane to generate the novel nanomedicine, Ang‐RBCm@NM‐(Dox/Lex). The studies toward orthotopic U87MG human glioblastoma tumor‐bearing nude mice show that the Ang‐RBCm@NM‐(Dox/Lex) nanomedicine has much improved blood circulation time, superb BBB penetration, superior tumor accumulation and retention. Moreover, effective suppression of tumor growth and significantly improved medium survival time are also observed after Ang‐RBCm@NM‐(Dox/Lex) treatment. The results show that this biomimetic nanoplatform can serve as a flexible and powerful system for GBM treatment which can be readily adapted for the treatment of other central nervous system (CNS) disorders.

Barua, PD, Zhou, X, Gururajan, R & Chan, KC 1970, 'Determination of Factors Influencing Student Engagement Using a Learning Management System in a Tertiary Setting', 2018 IEEE/WIC/ACM International Conference on Web Intelligence (WI), 2018 IEEE/WIC/ACM International Conference on Web Intelligence (WI), IEEE.
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Chan, KC, Zhou, X, Gururajan, R & Barua, P 1970, 'A Set of Quality Metrics for the Evaluation of Voice Termination Services', 2018 5th International Conference on Behavioral, Economic, and Socio-Cultural Computing (BESC), 2018 5th International Conference on Behavioral, Economic, and Socio-Cultural Computing (BESC), IEEE, pp. 138-143.
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Chan, KC, Zhou, X, Gururajan, R & Barua, P 1970, 'A Set of Quality Metrics for the Evaluation of Voice Termination Services', 2018 5TH INTERNATIONAL CONFERENCE ON BEHAVIORAL, ECONOMIC, AND SOCIO-CULTURAL COMPUTING (BESC), 5th International Conference on Behavioral, Economic, and Socio-Cultural Computing (BESC), IEEE, PEOPLES R CHINA, Natl Univ Kaohsiung, Kaohsiung, pp. 138-143.
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Clement, S, Chen, W, Deng, W & Goldys, E 1970, 'Biodegradable nanoconstructs for targeted deep tumour therapy (Conference Presentation)', Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVII, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVII, SPIE.
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Deng, W, Kautzka, Z, Clement, S & Goldys, E 1970, 'Light-triggered liposomal cargo delivery platform incorporating photosensitizers and gold nanoparticles for enhanced singlet oxygen generation and increased cytotoxicity', Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVII, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVII, SPIE, San Francisco, CA, pp. 9-9.
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Du, F, Rafeie, M, Warkiani, ME & Barber, T 1970, 'A systematic investigation of 3D-printed micromixers, applied to red blood cell lysis', 22nd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2018, pp. 2124-2126.
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Micromixer, mixing fluid samples or reactants, is an important microfluidic device that can be applied in the fields of micro total analysis system and biomedical applications. In this paper, 3D micromixers featured with various mixing strategies are designed, simulated and fabricated with the cost-effective wax printing. Experiments are made to validate the simulation results. Using the best performed micromixer, the lysis of red blood cell is conducted. The results presented here demonstrate a systematic method of optimizing the structure of 3D micromixers by integrating different mixing units.

Kottapalli, AGP, Asadnia, M, Karavitaki, KD, Warkiani, ME, Miao, J, Corey, DP & Triantafyllou, M 1970, 'Engineering biomimetic hair bundle sensors for underwater sensing applications', AIP Conference Proceedings, TO THE EAR AND BACK AGAIN - ADVANCES IN AUDITORY BIOPHYSICS: Proceedings of the 13th Mechanics of Hearing Workshop, Author(s), St Catharines, Canada, pp. 160003-160003.
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© 2018 Author(s). We present the fabrication of an artificial MEMS hair bundle sensor designed to approximate the structural and functional principles of the flow-sensing bundles found in fish neuromast hair cells. The sensor consists of micro-pillars of graded height connected with piezoelectric nanofiber 'tip-links' and encapsulated by a hydrogel cupula-like structure. Fluid drag force actuates the hydrogel cupula and deflects the micro-pillar bundle, stretching the nanofibers and generating electric charges. These biomimetic sensors achieve an ultrahigh sensitivity of 0.286 mV/(mm/s) and an extremely low threshold detection limit of 8.24 μm/s. A complete version of this paper has been published [1].

Kulasinghe, A, Perry, C, Kenny, L, Blick, T, Warkiani, M, Vela, I, O'Byrne, K, Thiery, J-P, Thompson, E, Nelson, C & Punyadeera, C 1970, 'Abstract 5572: Circulating tumor cells: The tumor trail left in the blood', Cancer Research, Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL, American Association for Cancer Research (AACR), Chicago, IL, pp. 5572-5572.
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Abstract Background: Metastasis in HNC patients is reflected by measurable levels of circulating tumor cells (CTCs) in the peripheral blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. For patients without CTCs at presentation, the detection of CTCs in the blood and analysis of biomarkers within them provide an opportunity to identify patients 'at risk' of developing overt metastasis, accelerating targeted treatment in addition to routing care with the clear aim of improving cure. Methods: Our study aimed to assess whether CTCs from the blood of HNC patients attending the Princess Alexandra Hospital and Royal Brisbane and Women's Hospital provided early cues of distant metastases (n=250). Results: With significant advances in CTC isolation technologies, we could demonstrate a higher CTC capture efficiency using epitope-independent platforms. By assessment of single and clustered CTCs, our data showed that HNC patients can be identified 4-6 months prior to developing clinical/radiographically evident metastasis. In these patients, a window for treatment escalation could become a possibility. In a proof-of-principle study, using novel culture formulations and hypoxic conditions (1-2% O2), we were able to demonstrate, for the first time, short-term patient-derived CTC cultures ex vivo from 7/18 HNC samples (4/7 HPV-positive, oropharyngeal) in a clinically relevant time period. Recent advancements have shown that PD-1 immune checkpoint therapies have durable responses in metastatic HNC patients that fail 1st- and 2nd-line therapy. Our preliminary data suggest PD-L1 is frequently expressed on HNC CTCs, and an immunoscore may be able to stratify patients likely to respond to immunotherapy. <...

Moloudi, R, Oh, S, Yang, C, Teo, KL, Lam, ATL, Warkiani, ME & Naing, MW 1970, 'Separation of microcarriers from mesenchymal stem cell suspensions using inertial focusing', 22nd International Conference on Miniaturized Systems for Chemistry and Life Sciences Microtas 2018, pp. 2082-2083.
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Rapidly evolving cell-based therapies in clinical trials demand alternative approaches for efficient expansion of adherent cell types such as human mesenchymal stem cells (hMSCs). Using microcarriers (MCs) suspended in a bioreactor provides a higher surface-to-volume ratio for cell culture. Following cell expansion and detachment from microcarriers, a novel approach which utilizes inertial focusing to separate MCs from the final cell suspensions is demonstrated.

Pinho, AV, Bulck, MV, Chantrill, L, Arshi, M, Sklyarova, T, Herrmann, D, Vennin, C, Gallego-Ortega, D, Mawson, A, Giry-Laterriere, M, Magenau, A, Baeyens, L, Gill, AJ, Phillips, P, Timpson, P, Biankin, AV, Wu, J & Rooman, I 1970, 'ROBO2 is a Stroma Suppressor Gene in the Pancreas Through Regulation of TGF-beta', PANCREAS, LIPPINCOTT WILLIAMS & WILKINS, pp. 1417-1417.

Polonchuk, L, Chabria, M, Badi, L, Hoflack, J-C, Davies, MJ, Figtree, G & Gentile, C 1970, 'Cardiac spheroid co-cultures as a novel in vitro model to study human heart microenvironment', Journal of Pharmacological and Toxicological Methods, Elsevier BV, pp. 167-167.
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Rana, R, Gururajan, R, McKenzie, G, Dunn, J, Gray, A, Zhou, X, Barua, PD, Epps, J & Humphris, GM 1970, 'A Novel Framework for Distress Detection through an Automated Speech Processing System', 2018 IEEE/WIC/ACM International Conference on Web Intelligence (WI), 2018 IEEE/WIC/ACM International Conference on Web Intelligence (WI), IEEE, pp. 610-614.
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Raoufi, MA, Mashhadian, A, Asadnia, M & Warkiani, ME 1970, 'Experimental and numerical study of viscoelasticity effects on particle focusing within a straight trapezoidal channel', 22nd International Conference on Miniaturized Systems for Chemistry and Life Sciences Microtas 2018, pp. 468-471.
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This paper investigates the effect of viscoelastic force on the focusing behaviour of 5.1µm particles in a straight trapezoidal channel and elucidates fundamentals of elasto-inertial microfluidics dynamic using both experimental and computational approaches. To date, numerous studies have been conducted to improve particle sorting by altering microchannel structures, flow rates and properties of solutions; however, none of these studies have fundamentally investigated the effects of viscoelasticity on particle movements through microchannels with nonlinear cross-section. The results revealed that, at each cross section the inertial lift and elastic forces are unidirectional everywhere except around corners and the channel center which causes the particles to focus in these areas.

Zhao, M, Yang, Z, Sun, B, Dai, B, Liu, H, Yao, J, Xu, X, Ding, G & Zhao, X 1970, 'A micro electromagnetically-driven scanner by 2-DOF second-order resonance to extend scanning scale for ultra-thin single-fiber endoscope application', 2018 IEEE Micro Electro Mechanical Systems (MEMS), 2018 IEEE Micro Electro Mechanical Systems (MEMS), IEEE, Belfast, UK, pp. 575-578.
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© 2018 IEEE. This paper presents an electromagnetically-driven single-fiber scanner utilizing 2 degree-of-freedom (DOF) second-order resonance to realize a larger field scanning scale in narrow space of the human body. We design a reasonable 2-DOF system structure including fiber, magnet and weight, which can conveniently execute high-order resonance modal to extend the scanning angle in the limited dimensional tube of the ultra-thin endoscope. A low-cost flexible microcoil embedded in polyimide film is also fabricated to drive the fiber-magnet-weight 2-DOF system to vibrate. The magnetic field distributions of the microcoil with different structural parameters are simulated. The test result shows that the scanner with the second-order resonance model successfully realizes 9.47° scanning scale, which is much larger than that (2.98°) obtained at the traditional first-order resonance model. Finally, the scanning locus of fiber tip in the scanner probe has been measured in xoy-plane by standard position sensitive detector (PSD).

Gee, A & Xu, X 2018, 'Surface Functionalisation of Upconversion Nanoparticles with Different Moieties for Biomedical Applications', MDPI AG.
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Gentile, C, Kesteven, S, Wu, J, Bursill, C, Davies, M, Feneley, M & Figtree, G 2018, 'Endothelial nitric oxide synthase plays a protective role against myocardial infarction', Elsevier BV, pp. S26-S26.
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Hadzhiev, Y, Qureshi, HK, Wheatley, L, Cooper, L, Jasiulewicz, A, Nguyen, HV, Wragg, J, Poovathumkadavil, D, Conic, S, Bajan, S, Sik, A, Hutvàgner, G, Tora, L, Gambus, A, Fossey, JS & Müller, F 2018, 'A cell cycle-coordinated nuclear compartment for Polymerase II transcription encompasses the earliest gene expression before global genome activation', Cold Spring Harbor Laboratory.
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Ho-Le, TP, Tran, TS, Center, JR, Eisman, JA & Nguyen, TV 2018, 'Contribution of Multimorbility to Post-Fracture Mortality: Result of a Long Term Population Based Study', WILEY, pp. 271-271.

Lan, C, Peng, H, McGowan, EM, Hutvagner, G & Li, J 2018, 'An isomIR expression panel based novel breast cancer classification approach using improved mutual information'.

Tran, TS & Nguyen, TV 2018, 'Association Between Alendronate and All-Cause Mortality and Cardiovascular Mortality Among Hip Fracture: An Alternative Explanation', Oxford University Press (OUP), pp. 1906-1907.
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