Publications

Hansen, T, Saleh, S, Figtree, GA & Gentile, C 2019, 'The Role of Redox Signalling in Cardiovascular Regeneration' in Oxidative Stress in Heart Diseases, Springer Singapore, pp. 19-37.
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© Springer Nature Singapore Pte Ltd. 2019. Cardiovascular disease (CVD) is a major public health problem, particularly in the industrialised world, with diverse causes. Central to these underlying aetiologies is a progressive loss of functional cardiomyocytes, maladaptive remodelling, and resultant cardiac dysfunction. The ageing heart is characterised by perturbations in numerous signalling pathways, impairing its ability to repair and replace injured cardiomyocytes. This is caused at least in part by dysregulation of redox signalling- both in regard to production of reactive oxygen species (ROS), and disruption of cellular protective mechanisms. Cardiac regeneration is one area of particular therapeutic promise, which seeks to ameliorate cardiac function by either (1) direct application of stem cells, (2) modification of molecular signalling pathways to restore the endogenous reparative capacity of the heart, or (3) a combination of these two approaches. Unravelling these molecular and cellular signalling pathways is paramount to unlocking the potential of cardiac regenerative therapies, and theoretically revolutionising the medical management of patients with heart failure. In this chapter, we will review the role of oxidative stress in cardiovascular disease, and the pathophysiological molecular signalling pathways that are involved in the transition from young to ageing heart. We will then provide an overview of the molecular therapies that are used to target these pathways to enhance heart regeneration, future directions involving cellular and novel ‘bio-printing’ based approaches, in addition to current promising clinical trials.

Kulasinghe, A, Warkiani, ME & Punyadeera, C 2019, 'The Isolation and Characterization of Circulating Tumor Cells from Head and Neck Cancer Patient Blood Samples Using Spiral Microfluidic Technology' in Methods in Molecular Biology, Springer New York, pp. 129-136.
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Metastasis is responsible for 90% of cancer-related deaths. The study of circulating tumor cells (CTCs) enables the study of the units of disease responsible for the process of metastasis. While the biology of the primary tissue is relatively known, little is understood about the cells en route to distant sites. Here we describe the isolation of CTCs using the spiral microfluidic technology for the efficient sorting of CTCs from head and neck cancer (HNC) patient blood samples. Furthermore, the molecular characterization of CTCs can aid in stratifying patients for targeted therapy such as immunotherapy, which is having a profound impact in the treatment of metastatic HNC.

Li, JJ & Zreiqat, H 2019, 'Tissue Response to Biomaterials' in Encyclopedia of Biomedical Engineering, Elsevier, pp. 270-277.
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Biomaterials are the central element of biomedical engineering solutions to replace, restore, or improve the function of diseased or damaged tissues or organs. All biomaterials placed inside the body will elicit tissue responses, the nature and extent of which depend on the biocompatibility and bioactivity of the biomaterial. This article will introduce the sequence of tissue responses to biomaterials, including the inflammatory and wound healing responses and the foreign body reaction, followed by a summary of the influence of biomaterial characteristics on directing the tissue response to different classes of biomaterials.

Rifai, A, Pirogova, E & Fox, K 2019, 'Diamond, Carbon Nanotubes and Graphene for Biomedical Applications' in Encyclopedia of Biomedical Engineering, Elsevier, pp. 97-107.
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Stratton-Powell, AA, Pasko, KM, Lal, S, Brockett, CL & Tipper, JL 2019, 'Biologic Responses to Polyetheretherketone (PEEK) Wear Particles' in Kurtz, SM (ed), PEEK Biomaterials Handbook, Elsevier, Cambridge MA, pp. 367-384.
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The biological response to wear particles is associated with failure and decreased longevity of total joint replacements. Particles in the size range of 0.1–10 μm are considered the most biologically reactive, particularly submicron-sized polymer particles. In bulk form, polyetheretherketone (PEEK) composites are generally considered to be biocompatible. In particulate form, however, the biological response remains unclear, with limited in vitro and in vivo studies defining the cellular reactions to particulates. Only three studies to date have analyzed retrieved periprosthetic human tissue samples to characterize the response to PEEK wear particles. In one study, PEEK particles were observed within macrophages, however, multinucleated giant cells were not present. In two other studies, rod-like carbon particulates and granular-shaped PEEK particles were identified in human tissue by histological analysis. A number of studies have quantified PEEK particles produced from PEEK bearings in joint replacement simulators. The mean particle size (i.e., Feret’s diameter) was reported to be between 0.23 and 2.0 μm, with a range of 0.01–50 μm. In vivo the biological response to PEEK-based particles was reported to be similar to ultrahigh-molecular-weight polyethylene (UHMWPE) particles. Inflammatory cytokine release [e.g., tumor necrosis factor-alpha (TNF)-α] was identified in more than one study without affecting macrophage viability. Only one study has investigated the effects of particle size on cytotoxicity and cytokine release and found unfilled PEEK particles (~ 13 μm) to have a toxic effect; UHMWPE particles in the same size range showed a similar cytotoxic effect. Further research is required to isolate and characterize PEEK-based particles from retrieved human tissue and, to elucidate the effect of particle characteristics, size, and dose on the biological response in both spinal and synovial joint models.

Abbasi, QH, Kiourti, A, Heidari, H, He, Y, Warkiani, M & Alomainy, A 2019, 'IEEE Access Special Section Editorial: Wearable and Implantable Devices and Systems', IEEE Access, vol. 7, pp. 139512-139517.
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© 2013 IEEE. Circuit techniques, sensors, antennas and communications systems are envisioned to help build new technologies over the next several years. Advances in the development and implementation of such technologies have already shown us their unique potential in realizing next-generation sensing systems. Applications include wearable consumer electronics, healthcare monitoring systems, and soft robotics, as well as wireless implants. There have been some interesting developments in the areas of circuits and systems, involving studies related to low-power electronics, wireless sensor networks, wearable circuit behaviour, security, real-time monitoring, connectivity of sensors, and Internet of Things (IoT). The direction for the current technology is electronics systems on large area electronics, integrated implantable systems and wearable sensors. So far, the research in the field has focused on materials, new processing techniques and one-off devices, such as diodes and transistors. However, current technology is not sufficient for future electronics to be useful in new applications; a great demand exists to scale up the research towards circuits and systems. Recent developments indicate that, in addition to fabrication technology, special attention should also be given to design, simulation and modeling of electronics, while keeping sensing system integration, power management, and sensors network under consideration.

Ajuyah, P, Hill, M, Ahadi, A, Lu, J, Hutvagner, G & Tran, N 2019, 'MicroRNA (miRNA)-to-miRNA Regulation of Programmed Cell Death 4 (PDCD4)', Molecular and Cellular Biology, vol. 39, no. 18, pp. 1-15.
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Copyright © 2019 Ajuyah et al. The regulation of tumor suppressor genes by microRNAs (miRNAs) is often demonstrated as a one-miRNA-to-one-target relationship. However, given the large number of miRNA sites within a 3= untranslated region (UTR), most targets likely undergo miRNA cooperation or combinatorial action. Programmed cell death 4 (PDCD4), an important tumor suppressor, prevents neoplastic events and is commonly downregulated in cancer. This study investigates the relationship between miRNA 21 (miR-21) and miR-499 in regulating PDCD4. This was explored using miRNA overexpression, mutational analysis of the PDCD4 3= UTR to assess regulation at each miRNA site, and 50% inhibitory concentration (IC50) calculations for combinatorial behavior. We demonstrate that the first miR-499 binding site within PDCD4 is inactive, but the two remaining sites are both required for PDCD4 suppression. Additionally, the binding of miR-21 to PDCD4 influenced miR-499 activity through an increase in its silencing potency and stabilization of its mature form. Furthermore, adjoining miRNA sites more than 35 nucleotides (nt) apart could potentially regulate thousands of 3= UTRs, similar to that observed between miR-21 and miR-499. The regulation of PDCD4 serves as a unique example of regulatory action by multiple miRNAs. This relationship was predicted to occur on thousands of targets and may represent a wider mode of miRNA regulation.

Ashtari, K, Nazari, H, Ko, H, Tebon, P, Akhshik, M, Akbari, M, Alhosseini, SN, Mozafari, M, Mehravi, B, Soleimani, M, Ardehali, R, Ebrahimi Warkiani, M, Ahadian, S & Khademhosseini, A 2019, 'Electrically conductive nanomaterials for cardiac tissue engineering', Advanced Drug Delivery Reviews, vol. 144, pp. 162-179.
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© 2019 Elsevier B.V. Patient deaths resulting from cardiovascular diseases are increasing across the globe, posing the greatest risk to patients in developed countries. Myocardial infarction, as a result of inadequate blood flow to the myocardium, results in irreversible loss of cardiomyocytes which can lead to heart failure. A sequela of myocardial infarction is scar formation that can alter the normal myocardial architecture and result in arrhythmias. Over the past decade, a myriad of tissue engineering approaches has been developed to fabricate engineered scaffolds for repairing cardiac tissue. This paper highlights the recent application of electrically conductive nanomaterials (carbon and gold-based nanomaterials, and electroactive polymers) to the development of scaffolds for cardiac tissue engineering. Moreover, this work summarizes the effects of these nanomaterials on cardiac cell behavior such as proliferation and migration, as well as cardiomyogenic differentiation in stem cells.

Azadi, S, Aboulkheyr Es, H, Razavi Bazaz, S, Thiery, JP, Asadnia, M & Ebrahimi Warkiani, M 2019, 'Upregulation of PD-L1 expression in breast cancer cells through the formation of 3D multicellular cancer aggregates under different chemical and mechanical conditions', Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1866, no. 12, pp. 118526-118526.
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© 2019 Elsevier B.V. Expression of programmed death-ligand 1 (PD-L1) in cancer cells plays an important role in cancer-immune cell interaction. The emerging evidence suggests regulation of PD-L1 expression by several tumor microenvironmental cues. However, the association of PD-L1 expression with chemical and mechanical features of the tumor microenvironment, specifically epidermal growth factor receptor (EGFR) signaling and matrix stiffness, remains elusive. Herein, we determine whether EGFR targeting and substrate stiffness affect the regulation of PD-L1 expression. Breast carcinoma cell lines, MCF7 and MDA-MB-231, were cultured under different conditions targeting EGFR and exposing cells to distinct substrate stiffness to evaluate PD-L1 expression. Furthermore, the ability to form aggregates in short-term culture of breast carcinoma cells and its effect on expression level of PD-L1 was probed. Our results indicated that PD-L1 expression was altered in response to both EGFR inhibition and substrate stiffness. Additionally, a positive association between the formation of multicellular aggregates and PD-L1 expression was observed. MDA-MB-231 cells expressed the highest PD-L1 level on a stiff substrate, while inhibition of EGFR reduced expression of PD-L1. The results suggested that both physical and chemical features of tumor microenvironment regulate PD-L1 expression through alteration of tumor aggregate formation potential. In line with these results, the in-silico study highlighted a positive correlation between PD-L1 expression, EGFR signaling, epithelial to mesenchymal transition related transcription factors (EMT-TFs) and stemness markers in metastatic breast cancer. These findings improve our understanding of regulation of PD-L1 expression by tumor microenvironment leading to evasion of tumor cells from the immune system.

Azadi, S, Tafazzoli‐Shadpour, M, Soleimani, M & Warkiani, ME 2019, 'Modulating cancer cell mechanics and actin cytoskeleton structure by chemical and mechanical stimulations', Journal of Biomedical Materials Research Part A, vol. 107, no. 8, pp. 1569-1581.
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AbstractTo date, a myriad of strategies has been suggested for targeting the chemical signaling of cancer cells. Also, biomechanical features are gaining much more attention. These features can be used as biomarkers which influence cancer progression. Current approaches on cancer treatment are mainly focused on changing the biochemical signaling of cancer cells, whereas less attention was devoted to their biomechanical properties. Herein, we propose targeting of cancer cell mechanics through the microenvironmental mechanical and chemical cues. As such, we examined the role of substrate stiffness as well as the effect of epidermal growth factor receptor (EGFR) blockade in the cell mechanics. As a mechanical stimulus, stiff and soft polydimethylsiloxane substrates were utilized, while as a chemical stimulus, EGFR blockade was considered. Thus, breast cancer cell lines, MCF7 and MDA‐MB‐231, were cultured among chemical and mechanical groups. The local elasticity of cancer cells was assessed by atomic force microscopy nanoindentation method. Furthermore, we evaluated the effect of mentioned mechanical and chemical treatments on the morphology, actin cytoskeleton structures, and cancer cell migration abilities. The stiffness and migration ability of cancer cells increased by substrate stiffening while Cetuximab treatment demonstrated an elevation in the elastic modulus of cells followed by a reduction in the migration ability. These findings indicate that cancer cell mechanics is modulated not only by the mechanical cues but also by the chemical ones through EGFR signaling pathway. Overall, our results illustrate that manipulation of cell mechanics allows for the possible modulation of tumor cell migration. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1569–1581, 2019.

Biglari, S, Le, TYL, Tan, RP, Wise, SG, Zambon, A, Codolo, G, De Bernard, M, Warkiani, M, Schindeler, A, Naficy, S, Valtchev, P, Khademhosseini, A & Dehghani, F 2019, 'Simulating Inflammation in a Wound Microenvironment Using a Dermal Wound‐on‐a‐Chip Model', Advanced Healthcare Materials, vol. 8, no. 1, pp. 1801307-1801307.
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AbstractConsiderable progress has been made in the field of microfluidics to develop complex systems for modeling human skin and dermal wound healing processes. While microfluidic models have attempted to integrate multiple cell types and/or 3D culture systems, to date they have lacked some elements needed to fully represent dermal wound healing. This paper describes a cost‐effective, multicellular microfluidic system that mimics the paracrine component of early inflammation close to normal wound healing. Collagen and Matrigel are tested as materials for coating and adhesion of dermal fibroblasts and human umbilical vein endothelial cells (HUVECs). The wound‐on‐chip model consists of three interconnecting channels and is able to simulate wound inflammation by adding tumor necrosis factor alpha (TNF‐α) or by triculturing with macrophages. Both the approaches significantly increase IL‐1β, IL‐6, IL‐8 in the supernatant (p < 0.05), and increases in cytokine levels are attenuated by cotreatment with an anti‐inflammatory agent, Dexamethasone. Incorporation of M1 and M2 macrophages cocultured with fibroblasts and HUVECs leads to a stimulation of cytokine production as well as vascular structure formation, particularly with M2 macrophages. In summary, this wound‐on‐chip system can be used to model the paracrine component of the early inflammatory phase of wound healing and has the potential for the screening of anti‐inflammatory compounds.

Bliuc, D, Tran, T, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, Josse, R, Kaiser, S, Kovacs, CS, Langsetmo, L, Prior, JC, Nguyen, TV & Center, JR 2019, 'Reduced Bone Loss Is Associated With Reduced Mortality Risk in Subjects Exposed to Nitrogen Bisphosphonates: A Mediation Analysis', Journal of Bone and Mineral Research, vol. 34, no. 11, pp. 2001-2011.
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ABSTRACT Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39–0.96] and 1.35 [95% CI 0.86–2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%–84%) of the nBP association with mortality was related to a redu...

Bliuc, D, Tran, T, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, Josse, RG, Kaiser, S, Kovacs, CS, Langsetmo, L, Prior, JC, Nguyen, TV & Center, JR 2019, 'Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study', Osteoporosis International, vol. 30, no. 4, pp. 817-828.
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© 2019, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. Introduction: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. Methods: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. Results: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48–0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66–1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031–0.70)] for n-BP vs. etidronate]. Conclusion: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonat...

Chacon, D, Braytee, A, Huang, Y, Thoms, J, Subramanian, S, Sauerland, MC, Bohlander, SK, Braess, J, Wörmann, BJ, Berdel, WE, Hiddemann, W, Gabrys, B, Metzeler, KH, Herold, T, Pimanda, J & Beck, D 2019, 'Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification', Blood, vol. 134, no. Supplement_1, pp. 1397-1397.
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Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal componen...

Chang, L, Ni, J, Zhu, Y, Pang, B, Graham, P, Zhang, H & Li, Y 2019, 'Liquid biopsy in ovarian cancer: recent advances in circulating extracellular vesicle detection for early diagnosis and monitoring progression', Theranostics, vol. 9, no. 14, pp. 4130-4140.
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The current biomarkers available in the clinic are not enough for early diagnosis or for monitoring disease progression of ovarian cancer. Liquid biopsy is a minimally invasive test and has the advantage of early diagnosis and real-time monitoring of treatment response. Although significant progress has been made in the usage of circulating tumor cells and cell-free DNA for ovarian cancer diagnosis, their potential for early detection or monitoring progression remains elusive. Extracellular vesicles (EVs) are a heterogeneous group of lipid membranous particles released from almost all cell types. EVs contain proteins, mRNA, DNA fragments, non-coding RNAs, and lipids and play a critical role in intercellular communication. Emerging evidence suggests that EVs have crucial roles in cancer development and metastasis, thus holding promise for liquid biopsy-based biomarker discovery for ovarian cancer diagnosis. In this review, we discuss the advantages of EV-based liquid biopsy, summarize the protein biomarkers identified from EVs in ovarian cancer, and highlight the utility of new technologies recently developed for EV detection with an emphasis on their use for diagnosing ovarian cancer, monitoring cancer progression, and developing personalized medicine.

Chen, X, Chamoli, U, Lapkin, S, Castillo, JV & Diwan, AD 2019, 'Complication rates of different discectomy techniques for the treatment of lumbar disc herniation: a network meta-analysis', European Spine Journal, vol. 28, no. 11, pp. 2588-2601.
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PURPOSE:The aim of this network meta-analysis (NMA) was to compare the complication rates of discectomy/microdiscectomy, percutaneous laser disc decompression (PLDD), percutaneous endoscopic lumbar discectomy (PELD), microendoscopic discectomy (MED), and tubular discectomy for symptomatic lumbar disc herniation (LDH). METHODS:We searched three online databases for randomized controlled trials (RCTs). Overall complication rates, complication rates per general and modified Clavien-Dindo classification schemes, and reoperation rates were considered as primary outcomes. Odds ratio with 95% confidence intervals for direct comparisons and 95% credible intervals for NMA results were reported. Surface under cumulative ranking curve (SUCRA) was used to estimate ranks for each discectomy technique based on the complication rates. RESULTS:In total, 18 RCTs with 2273 patients were included in this study. Our results showed that there was no significant difference in any of the pairwise comparisons. PELD (SUCRA: 0.856) ranked the lowest for overall complication rates. Discectomy/microdiscectomy (SUCRA: 0.599) and PELD (SUCRA: 0.939) ranked the lowest for intraoperative and post-operative complication rates, respectively. Concerning modified Clavien-Dindo classification scheme, PELD (SUCRA: 0.803), MED (SUCRA: 0.730), and PLDD (SUCRA: 0.605) ranked the lowest for the occurrence of type I, II, and III complications, respectively. Tubular discectomy (SUCRA: 0.699) ranked the lowest for reoperation rates. CONCLUSIONS:The results of this NMA suggest that discectomy/microdiscectomy and PELD are the safest procedures for LDH with minimal intraoperative and post-operative complications, respectively. PELD, MED, and PLDD are the safest procedures for LDH in terms of minimal rates for complications necessitating conservative, pharmacological, and surgical treatment, respectively. These slides can be retrieved under Electronic Supplementary Material.

Chen, Y, Ju, LA, Zhou, F, Liao, J, Xue, L, Su, QP, Jin, D, Yuan, Y, Lu, H, Jackson, SP & Zhu, C 2019, 'An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation', Nature Materials, vol. 18, no. 7, pp. 760-769.
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© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Integrins are membrane receptors that mediate cell adhesion and mechanosensing. The structure–function relationship of integrins remains incompletely understood, despite the extensive studies carried out because of its importance to basic cell biology and translational medicine. Using a fluorescence dual biomembrane force probe, microfluidics and cone-and-plate rheometry, we applied precisely controlled mechanical stimulations to platelets and identified an intermediate state of integrin αIIbβ3 that is characterized by an ectodomain conformation, ligand affinity and bond lifetimes that are all intermediate between the well-known inactive and active states. This intermediate state is induced by ligand engagement of glycoprotein (GP) Ibα via a mechanosignalling pathway and potentiates the outside-in mechanosignalling of αIIbβ3 for further transition to the active state during integrin mechanical affinity maturation. Our work reveals distinct αIIbβ3 state transitions in response to biomechanical and biochemical stimuli, and identifies a role for the αIIbβ3 intermediate state in promoting biomechanical platelet aggregation.

Chen, Y, Su, QP & Yu, L 2019, 'Studying Autophagic Lysosome Reformation in Cells and by an In Vitro Reconstitution System', vol. 1880, pp. 163-172.
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Autophagic lysosome reformation (ALR) is the terminal step of autophagy. ALR functions to recycle lysosomal membranes and maintain lysosome homeostasis. Maintaining a functional lysosome pool is critical for generating autolysosomes, in which cellular components are degraded and turned over during autophagy. This unit describes methods to visualize ALR in cells. In addition, this unit provides detailed protocols to establish in vitro systems which can be used to reconstitute ALR as well as to reconstitute mitochondrial tubulation/network formation, another process that is driven by motor proteins.

Chepurin, D, Chamoli, U, Sheldrick, K, Lapkin, S, Scott, D, Kuan, J & Diwan, AD 2019, 'Bony stress in the lumbar spine is associated with intervertebral disc degeneration and low back pain: a retrospective case–control MRI study of patients under 25 years of age', European Spine Journal, vol. 28, no. 11, pp. 2470-2477.
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PURPOSE:Abnormal stress in the lumbar vertebra, also known as bony stress, can be a precursor to degenerative changes which may manifest as low back pain (LBP). However, the prevalence of bony stress in the lumbar spine and its relationship with degenerative changes and LBP is unclear. The purpose of this study was to evaluate the prevalence of bony stress in the lumbar spine and its relationship with intervertebral disc (IVD) degeneration, facet osteoarthritis and LBP in patients under 25 years of age. METHODS:A retrospective case-control study of 130 patients under 25 years of age was conducted from a population of 493 patients who had lumbar MRI across three imaging centres over three years. A cohort of 55 consecutive patients with bony stress was identified. A control group of consecutive patients (n = 75) without bony stress was also selected from the population. RESULTS:Bony stress was prevalent in 11% (95% CI [8.4-14.5%]) of patients and was not diagnosed in 36% (95% CI [22-55%]) of these cases. Patients with bony stress had over twofold (OR 2.3, 95% CI [1.1-4.8]) and fivefold (OR 5.3, 95% CI [2.11-13.3]) higher likelihood of having IVD degeneration and LBP, respectively, when compared with the control group. Bony stress was not found to be associated with facet osteoarthritis. CONCLUSION:Bony stress in the lumbar spine was prevalent in 11% of patients under 25 years of age. It was commonly undiagnosed in radiology reports (not reported in 36% of the cases). Being significantly associated and with an increased likelihood of IVD degeneration and LBP, we posit that bony stress is likely a symptomatic and clinically meaningful diagnostic entity in the assessment of LBP. These slides can be retrieved under Electronic Supplementary Material.

Condina, MR, Dilmetz, BA, Razavi Bazaz, S, Meneses, J, Ebrahimi Warkiani, M & Hoffmann, P 2019, 'Rapid separation and identification of beer spoilage bacteria by inertial microfluidics and MALDI-TOF mass spectrometry', Lab on a Chip, vol. 19, no. 11, pp. 1961-1970.
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Microfluidics and MALDI-TOF MS is a rapid, high-throughput, and accurate method for the identification of beer spoilage bacteria.

Crowther, CA, Ashwood, P, Andersen, CC, Middleton, PF, Tran, T, Doyle, LW, Robinson, JS, Harding, JE, Crowther, C, Ashwood, P, Andersen, C, Middleton, P, Tran, T, Ball, V, Holst, C, Robinson, K, Zhang, S, Robinson, J, Khong, Y, McPhee, A, Groom, K, Alsweiler, J, Eaglen, D, Harding, J, Hauch, H, Vallely, A, Angus, S, Chenia, F, Drew, A, Gavranich, J, Green, A, Jack, S, Mahomed, K, Sebastian, R, Turner, L, Baldwin, M, Dennis, A, Fisher, E, Gee, K, Gee, M, Strong, D, Boord, D, Edge, N, Marsh, M, Staehr, C, Chaplin, J, Gardener, G, Gray, P, Hurrion, E, Jardine, L, Kan, J, Lynn, L, Poulsen, L, Tremellen, A, Codner, T, Cubis, W, Downward, S, Dunn, C, Furey, J, Hansen, D, Lampropoulos, B, Masson, E, Peek, M, Sellar, S, Butterley, K, Chadwick, M, Davis, C, DePaoli, T, Green, L, Matzolic, T, Woodhead, G, Biggs, V, Henry, A, Lainchbury, A, Nesbitt-Hawes, E, Oei, JL, Rodrigues, C, Shand, A, Sutton, L, Welsh, A, Bowen, J, Hayes-Cameron, L, Howard, G, Jacobs, C, Milligan, J, Morris, J, Rickard, K, Sedgley, J, White-Matthews, K, Blandthorn, J, Brownfoot, F, Burnett, A, Callanan, K, Davis, N, Deluca, C, Doyle, L, Duff, J, Howard, K, Hutchinson, E, Kelly, E, Kornman, L, Kuschel, C, Maxwell, D, McDonald, M, Poth, M, Co, J, Davis, G, Fonsesca, B, Khouri, J, Roberts, L, Rowe, C, Boniface, C, Boynton, C, Davies, C, Dickinson, C, Edmonds, L, Ireland, S, Koh, G, Kumar, P, Lawrence, A, Lock, R, Watson, D, Bahtia, V, Cash, S, Gagliardi, D, Gooding, M, Gowling, K, Grivell, R, Haslam, R, Headley, B, Johnson, M, Kobayashi, N, Kochar, A, Nikpoor, P, Simmonds, L, Siwicki, K, Stark, M & Trenowden, S 2019, 'Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial', The Lancet Child & Adolescent Health, vol. 3, no. 11, pp. 769-780.
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BACKGROUND: Antenatal corticosteroids given to women before preterm birth improve infant survival and health. However, whether dexamethasone or betamethasone have better maternal, neonatal, and childhood health outcomes remains unclear. We therefore aimed to assess whether administration of antenatal dexamethasone to women at risk of preterm birth reduced the risk of death or neurosensory disability in their children at age 2 years compared with betamethasone. We also aimed to assess whether dexamethasone reduced neonatal morbidity, had benefits for the mother, or affected childhood body size, blood pressure, behaviour, or general health compared with betamethasone. METHODS: In this multicentre, double-blind, randomised controlled trial, we recruited pregnant women from 14 maternity hospitals in Australia and New Zealand that could provide care to preterm babies. Women were eligible for study inclusion if they were at risk of preterm birth before 34 weeks of gestation, had a singleton or twin pregnancy, and had no contraindications to antenatal corticosteroids. We randomly assigned women (1:1) to receive two intramuscular injections of either 12 mg dexamethasone (dexamethasone sodium phosphate) or 11·4 mg betamethasone (Celestone Chronodose), 24 h apart. The randomisation schedule used balanced, variable blocks that were stratified by hospital, gestational age, and number of fetuses (singleton or twins). We masked all participants, staff, and assessors to treatment groups. Analyses were by intention to treat. The primary outcome was death or neurosensory disability at age 2 years (corrected for prematurity). This study is registered with ANZCTR, ACTRN12608000631303. FINDINGS: Between Jan 28, 2009, and Feb 1, 2013, we randomly assigned 1346 (78%) women who were pregnant with 1509 fetuses to groups: 679 (50%) women were assigned to receive dexamethasone and 667 (50%) women were assigned to receive betamethasone. 27 (4%) fetuses, infants, or children in th...

Derakhshani, M, Abbaszadeh, H, Movassaghpour, AA, Mehdizadeh, A, Ebrahimi-Warkiani, M & Yousefi, M 2019, 'Strategies for elevating hematopoietic stem cells expansion and engraftment capacity', Life Sciences, vol. 232, pp. 116598-116598.
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© 2019 Elsevier Inc. Hematopoietic stem cells (HSCs) are a rare cell population in adult bone marrow, mobilized peripheral blood, and umbilical cord blood possessing self-renewal and differentiation capability into a full spectrum of blood cells. Bone marrow HSC transplantation has been considered as an ideal option for certain disorders treatment including hematologic diseases, leukemia, immunodeficiency, bone marrow failure syndrome, genetic defects such as thalassemia, sickle cell anemia, autoimmune disease, and certain solid cancers. Ex vivo proliferation of these cells prior to transplantation has been proposed as a potential solution against limited number of stem cells. In such culture process, MSCs have also been shown to exhibit high capacity for secretion of soluble mediators contributing to the principle biological and therapeutic activities of HSCs. In addition, endothelial cells have been introduced to bridge the blood and sub tissues in the bone marrow, as well as, HSCs regeneration induction and survival. Cell culture in the laboratory environment requires cell growth strict control to protect against contamination, symmetrical cell division and optimal conditions for maximum yield. In this regard, microfluidic systems provide culture and analysis capabilities in micro volume scales. Moreover, two-dimensional cultures cannot fully demonstrate extracellular matrix found in different tissues and organs as an abstract representation of three dimensional cell structure. Microfluidic systems can also strongly describe the effects of physical factors such as temperature and pressure on cell behavior.

Du, W & Su, QP 2019, 'Single-molecule in vitro reconstitution assay for kinesin-1-driven membrane dynamics', Biophysical Reviews, vol. 11, no. 3, pp. 319-325.
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© 2019, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature. Intracellular membrane dynamics, especially the nano-tube formation, plays important roles in vesicle transportation and organelle biogenesis. Regarding the regulation mechanisms, it is well known that during the nano-tube formation, motor proteins act as the driven force moving along the cytoskeleton, lipid composition and its associated proteins serve as the linkers and key mediators, and the vesicle sizes play as one of the important regulators. In this review, we summarized the in vitro reconstitution assay method, which has been applied to reconstitute the nano-tube dynamics during autophagic lysosomal regeneration (ALR) and the morphology dynamics during mitochondria network formation (MNF) in a mimic and pure in vitro system. Combined with the single-molecule microscopy, the advantage of the in vitro reconstitution system is to study the key questions at a single-molecule or single-vesicle level with precisely tuned parameters and conditions, such as the motor mutation, ion concentration, lipid component, ATP/GTP concentration, and even in vitro protein knockout, which cannot easily be achieved by in vivo or intracellular studies.

Ejeian, F, Azadi, S, Razmjou, A, Orooji, Y, Kottapalli, A, Ebrahimi Warkiani, M & Asadnia, M 2019, 'Design and applications of MEMS flow sensors: A review', Sensors and Actuators A: Physical, vol. 295, pp. 483-502.
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© 2019 Elsevier B.V. There is an indispensable need for fluid flow rate and direction sensors in various medical, industrial and environmental applications. Besides the critical demands on sensing range of flow parameters (such as rate, velocity, direction and temperature), the properties of different target gases or liquids to be sensed pose challenges to the development of reliable, inexpensive and low powered sensors. This paper presents an overview of the work done on design and development of Microelectromechanical system (MEMS)-based flow sensors in recent years. In spite of using some similar principles, diverse production methods, analysis strategies, and different sensing materials, MEMS flow sensors can be broadly categorized into three main types, namely thermal sensors, piezoresistive sensors and piezoelectric sensors. Additionally, some key challenges and future prospects for the use of the MEMS flow sensors are discussed briefly.

Entezari, A, Roohani, I, Li, G, Dunstan, CR, Rognon, P, Li, Q, Jiang, X & Zreiqat, H 2019, 'Architectural Design of 3D Printed Scaffolds Controls the Volume and Functionality of Newly Formed Bone', Advanced Healthcare Materials, vol. 8, no. 1, pp. 1801353-1801353.
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AbstractThe successful regeneration of functional bone tissue in critical‐size defects remains a significant clinical challenge. To address this challenge, synthetic bone scaffolds are widely developed, but remarkably few are translated to the clinic due to poor performance in vivo. Here, it is demonstrated how architectural design of 3D printed scaffolds can improve in vivo outcomes. Ceramic scaffolds with different pore sizes and permeabilities, but with similar porosity and interconnectivity, are implanted in rabbit calvaria for 12 weeks, and then the explants are harvested for microcomputed tomography evaluation of the volume and functionality of newly formed bone. The results indicate that scaffold pores should be larger than 390 µm with an upper limit of 590 µm to enhance bone formation. It is also demonstrated that a bimodal pore topology—alternating large and small pores—enhances the volume and functionality of new bone substantially. Moreover, bone formation results indicate that stiffness of new bone is highly influenced by the scaffold's permeability in the direction concerned. This study demonstrates that manipulating pore size and permeability in a 3D printed scaffold architecture provides a useful strategy for enhancing bone regeneration outcomes.

Entezari, A, Zhang, Z, Sue, A, Sun, G, Huo, X, Chang, C-C, Zhou, S, Swain, MV & Li, Q 2019, 'Nondestructive characterization of bone tissue scaffolds for clinical scenarios', Journal of the Mechanical Behavior of Biomedical Materials, vol. 89, pp. 150-161.
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Fang, G, Lu, H, Law, A, Gallego-Ortega, D, Jin, D & Lin, G 2019, 'Gradient-sized control of tumor spheroids on a single chip', Lab on a Chip, vol. 19, no. 24, pp. 4093-4103.
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Gradient-sized spheroids can be simultaneously generated on a single chip using a liquid-dome method assisted by the surface tension. The facile method can be used for investigation of the size-dependent behaviors of spheroids in biomedical research.

Feng, X, Bai, X, Ni, J, Wasinger, VC, Beretov, J, Zhu, Y, Graham, P & Li, Y 2019, 'CHTOP in Chemoresistant Epithelial Ovarian Cancer: A Novel and Potential Therapeutic Target', Frontiers in Oncology, vol. 9, no. JUN, pp. 1-13.
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Objective: Chemoresistance is a major challenge in epithelial ovarian cancer (EOC) treatment. Chromatin target of protein arginine methyltransferase (CHTOP) was identified as a potential biomarker in chemoresistant EOC cell lines using label-free LC-MS/MS quantitative proteomics. Thus, the aim of this study is to investigate the role of CHTOP in chemoresistant EOC and the underlying mechanism. Methods: The expression of CHTOP in human ovarian cancer cells and tissues was detected using immunofluorescence (IF), western blot (WB), and immunohistochemistry (IHC), respectively. Flow cytometry and TUNEL assay were employed to detect the effect of CHTOP knockdown (KD) in chemoresistant EOC cell apoptosis, while colony and sphere formation assays were used to evaluate its effect on cell stemness. The association of CHTOP with cell metastasis was determined using Matrigel invasion and wound-healing assays. Results: The higher level expression of CHTOP protein was found in chemoresistant EOC cells as compared to their sensitive parental cells or normal epithelial ovarian cells. Results from IHC and bioinformatic analysis showed CHTOP was highly expressed in human ovarian cancer tissues and associated with a poor progression-free survival in patients. In addition, CHTOP KD significantly enhanced cisplatin-induced apoptosis, reduced the stemness of chemoresistant EOC cells, and decreased their metastatic potential. Conclusion: Our findings suggest that CHTOP is associated with apoptosis, stemness, and metastasis in chemoresistant EOC cells and might be a promising target to overcome chemoresistance in EOC treatment.

Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Lasheras, SV, Pujol, R, Kiiski, JI, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomäki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmaña, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Beane Freeman, LE, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, NV, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Buys, SS, Caldés, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupré, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Léone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Noguès, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Révillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Vénat-Bouvet, L, Bézieau, S & et al. 2019, 'The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer', npj Breast Cancer, vol. 5, no. 1.
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AbstractBreast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM

Gamble, LD, Purgato, S, Murray, J, Xiao, L, Yu, DMT, Hanssen, KM, Giorgi, FM, Carter, DR, Gifford, AJ, Valli, E, Milazzo, G, Kamili, A, Mayoh, C, Liu, B, Eden, G, Sarraf, S, Allan, S, Di Giacomo, S, Flemming, CL, Russell, AJ, Cheung, BB, Oberthuer, A, London, WB, Fischer, M, Trahair, TN, Fletcher, JI, Marshall, GM, Ziegler, DS, Hogarty, MD, Burns, MR, Perini, G, Norris, MD & Haber, M 2019, 'Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma', Science Translational Medicine, vol. 11, no. 477.
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MYCN regulates polyamines in neuroblastoma, and combined inhibition of polyamine synthesis and transport has therapeutic effects in mouse models.

Gentile, C, Kesteven, S, Wu, J, Bursill, C, Davies, MJ & Figtree, G 2019, 'Abstract 138: A Novel Cellular and Genetic Approach to Investigate the Cardioprotective Role Played by Endothelial Nitric Oxide Synthase in Myocardial Infarction', Circulation Research, vol. 125, no. Suppl_1.
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The loss of regenerative properties in adult cardiomyocytes (CMs) is directly linked to their inability to proliferate. Following an extensive ischaemic event in an aged heart, fibrotic scar formation is the only repair process and eventually heart failure develops. However, molecular and cellular cues in the neonatal heart support that cardiac regeneration is possible in presence of proliferating CMs. Based on previous studies demonstrating that endothelial nitric oxide synthase (eNOS) regulates proliferation in both endothelial cells (ECs) and CMs, we hypothesized that eNOS signaling could play a cardioprotective role. To test our hypothesis, we injected different combinations of co-cultured ECs and CMs in the LV muscle wall of MI mice (permanent LAD ligation). First, injected cells were isolated from either WT or KO eNOS neonatal mice and then co-cultured to form 3D vascularized cardiac spheroids (VCSs), which were eventually transplanted in adult MI mice on the day of the procedure. Control infarcted animals received media-only (vehicle). Other mice received a suspension of co-cultured VCSs in media as follows: i ) WT CMs and ECs; ii ) WT CMs and KO ECs; iii ) KO CMs and WT ECs. Following 28 days, injection of WT cells increased the ejection fraction (EF%) by 20% compared with control animals (61%±4% and 41%±11%, respectively). When eNOS was absent in either CMs or ECs, the EF% was 40%±5% and 46%±2%, respectively, suggesting that the eNOS-mediated protection is dependent on its presence in both cells. Histological analyses confirmed the presence of WT VCSs in MI mice, contributing to a thicker wall thickness compared to vehicle MI mice. No VCSs were observed in the LV wall when KO cells were injected. Therefore, our results strongly suggest that eNOS may play a major role via bo...

Gerami, A, Alzahid, Y, Mostaghimi, P, Kashaninejad, N, Kazemifar, F, Amirian, T, Mosavat, N, Ebrahimi Warkiani, M & Armstrong, RT 2019, 'Microfluidics for Porous Systems: Fabrication, Microscopy and Applications', Transport in Porous Media, vol. 130, no. 1, pp. 277-304.
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© 2018, Springer Nature B.V. No matter how sophisticated the structures are and on what length scale the pore sizes are, fluid displacement in porous media can be visualized, captured, mimicked and optimized using microfluidics. Visualizing transport processes is fundamental to our understanding of complex hydrogeological systems, petroleum production, medical science applications and other engineering applications. Microfluidics is an ideal tool for visual observation of flow at high temporal and spatial resolution. Experiments are typically fast, as sample volume is substantially low with the use of miniaturized devices. This review first discusses the fabrication techniques for generating microfluidics devices, experimental setups and new advances in microfluidic fabrication using three-dimensional printing, geomaterials and biomaterials. We then address multiphase transport in subsurface porous media, with an emphasis on hydrology and petroleum engineering applications in the past few decades. We also cover the application of microfluidics to study membrane systems in biomedical science and particle sorting. Lastly, we explore how synergies across different disciplines can lead to innovations in this field. A number of problems that have been resolved, topics that are under investigation and cutting-edge applications that are emerging are highlighted.

Ghorbani, F, Abbaszadeh, H, Mehdizadeh, A, Ebrahimi-Warkiani, M, Rashidi, M-R & Yousefi, M 2019, 'Biosensors and nanobiosensors for rapid detection of autoimmune diseases: a review', Microchimica Acta, vol. 186, no. 12.
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© 2019, Springer-Verlag GmbH Austria, part of Springer Nature. This review (with 77 refs.) describes the progress that has been made in biosensors for the detection of autoimmune diseases, mainly via detection of autoantibodies. In addition, specific proteins, cytokines and ions have also been introduced as promising diagnostic biomarkers. Following an introduction into the various kinds of autoimmune diseases, we first discuss the state of the art in respective electrochemical biosensors and nanobiosensors (with subsections on amperometric, impedimetric, voltammetric and photoelectrochemical methods). The next large chapter covers optical methods (with subsections on electrochemiluminescence, fluorescence and surface plasmon resonance). We then make a critical comparison between commercially available kits used for detection of autoimmune diseases with the established biosensors. Several Tables are also presented that give an overview on the wealth of methods and nanomaterials. Finally, in the conclusion part, we summarize the current status, addresse present issues, and give an outlook on potential future opportunities. [Figure not available: see fulltext.].

Ghorbani, S, Eyni, H, Khosrowpour, Z, Salari Asl, L, Shabani, R, Nazari, H, Mehdizadeh, M, Ebrahimi Warkiani, M & Amjadi, F 2019, 'Spermatogenesis induction of spermatogonial stem cells using nanofibrous poly(l‐lactic acid)/multi‐walled carbon nanotube scaffolds and naringenin', Polymers for Advanced Technologies, vol. 30, no. 12, pp. 3011-3025.
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Spermatogenesis is a process in which animals generate spermatozoa from spermatogonial stem cells (SSCs). Successful in vitro differentiation of SSCs towards spermatids holds a significant promise for regeneration of impaired spermatogenesis. The present study aims to evaluate the efficiency of a 3D culture containing naringenin on proliferation and differentiation potentials of mouse SSCs. In this study, multi‐walled carbon nanotubes (MWCNTs) were incorporated into poly(l‐lactic acid) (PLLA) fibers via electrospinning technique. The fibrous PLLA/MWCNTs were studied by Fourier‐transform infrared spectroscopy (FTIR), transmission electron microscope (TEM), water contact angle measurements, electrical conductivity, and mechanical properties. Next, the SSCs were seeded into the PLLA/MWCNTs scaffolds and exhibited preferable survival and differentiation efficiency to subsequent cell lines. To shed more light on this matter, the immunocytochemistry, reverse‐transcription polymerase chain reaction (RT‐PCR), and qRT‐PCR results showed that the aforementioned cells on the 3D fabrics overexpressed the C‐kit and SYCP3 proteins. In addition, the reactive oxygen species (ROS) measurement data demonstrated that naringenin, an effective antioxidant, plays an important role in in vitro spermatogenesis. Taken together, the results of this study revealed the synergistic effects of 3D scaffolds and naringenin for efficient spermatogenesis in laboratories.

Guo, D, Lui, GYL, Lai, SL, Wilmott, JS, Tikoo, S, Jackett, LA, Quek, C, Brown, DL, Sharp, DM, Kwan, RYQ, Chacon, D, Wong, JH, Beck, D, van Geldermalsen, M, Holst, J, Thompson, JF, Mann, GJ, Scolyer, RA, Stow, JL, Weninger, W, Haass, NK & Beaumont, KA 2019, 'RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes', International Journal of Cancer, vol. 144, no. 12, pp. 3070-3085.
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Despite recent advances in targeted and immune‐based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A‐replete exosomes, but not RAB27A‐knockdown exosomes, indicating that RAB27A is responsible for the generation of pro‐invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro‐invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.

Guo, Z, Yang, C, Maritz, MF, Wu, H, Wilson, P, Warkiani, ME, Chien, C, Kempson, I, Aref, AR & Thierry, B 2019, 'Validation of a Vasculogenesis Microfluidic Model for Radiobiological Studies of the Human Microvasculature', Advanced Materials Technologies, vol. 4, no. 4, pp. 1800726-1800726.
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AbstractThe therapeutic ratio of radiotherapy is limited by acute or chronic side effects with often severe consequences to patients. The microvasculature is a central player involved in both tumor responses and healthy tissue/organ radiological injuries. However, current preclinical vascular models based on 2D culture offer only limited radiobiological insight due to their failure in recapitulating the 3D nature experienced by endothelial cells within the human microvasculature. To address this issue, the use of a 3D microvasculature‐on‐a‐chip microfluidic technology is demonstrated in radiobiological studies. Within this vasculogenesis model a perfusable network that structurally mimics the human microvasculature is formed and the biological response to ionizing radiation including cellular apoptosis, vessel tight adherens junction breakage, DNA double strand break, and repair is systematically investigated. In comparison to cells grown in a 2D environment, human umbilical vein endothelial cells in the 3D microvasculature‐on‐a‐chip displays significant differences in biological responses, especially at high X‐ray dose. This data confirms the feasibility of using microvascular‐on‐a‐chip models for radiobiological studies. Such vasculogenesis models have strong potential to yield more accurate prediction of healthy tissue responses to ionizing radiation as well as to guide the development of risk‐reducing strategies to prevent radiation‐induced acute and long‐term side‐effects.

Hadzhiev, Y, Qureshi, HK, Wheatley, L, Cooper, L, Jasiulewicz, A, Van Nguyen, H, Wragg, JW, Poovathumkadavil, D, Conic, S, Bajan, S, Sik, A, Hutvàgner, G, Tora, L, Gambus, A, Fossey, JS & Müller, F 2019, 'A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation', Nature Communications, vol. 10, no. 1.
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AbstractMost metazoan embryos commence development with rapid, transcriptionally silent cell divisions, with genome activation delayed until the mid-blastula transition (MBT). However, a set of genes escapes global repression and gets activated before MBT. Here we describe the formation and the spatio-temporal dynamics of a pair of distinct transcription compartments, which encompasses the earliest gene expression in zebrafish. 4D imaging of pri-miR430and zinc-finger-gene activities by a novel, native transcription imaging approach reveals transcriptional sharing of nuclear compartments, which are regulated by homologous chromosome organisation. These compartments carry the majority of nascent-RNAs and active Polymerase II, are chromatin-depleted and represent the main sites of detectable transcription before MBT. Transcription occurs during the S-phase of increasingly permissive cleavage cycles. It is proposed, that the transcription compartment is part of the regulatory architecture of embryonic nuclei and offers a transcriptionally competent environment to facilitate early escape from repression before global genome activation.

Ho-Pham, LT, Tran, B, Do, AT & Nguyen, TV 2019, 'Association between pre-diabetes, type 2 diabetes and trabecular bone score: The Vietnam Osteoporosis Study', Diabetes Research and Clinical Practice, vol. 155, pp. 107790-107790.
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© 2019 Aims: Trabecular bone score (TBS) is a surrogate indicator of bone microarchitecture. The present study sought to examine the association between type 2 diabetes (T2D) and trabecular bone score (TBS) in adult Vietnamese men and women. Methods: The study was part of the Vietnam Osteoporosis Study, in which 2702 women and 1398 men aged ≥30 years were recruited from the general community in Ho Chi Minh City. HbA1c levels were measured by the ADAMS™ A1c HA-8160 (Arkray, Kyoto, Japan), and classified into 3 groups: normal if HbA1c < 5.7%; pre-diabetes (5.7–6.4%); and diabetes (>6.4%). TBS was evaluated by iNsight Software, version 2.1 (Medimaps, Merignac, France) on lumbar spine BMD scan (Hologic Horizon). Differences in TBS between diabetic status were analyzed by the multivariable regression model with adjustment for age and body mass index. Results: The prevalence of pre-diabetes and diabetes in men and women was 30.2% and 8.3%, respectively. In women, TBS was lower in pre-diabetes (−0.02; P < 0.001) and diabetes (−0.02; P < 0.001) compared with normal individuals. In men, there was no statistically significant difference in TBS between diabetic status. Moreover, TBS was significantly inversely correlated with HbA1c levels in women (P = 0.01), but not in men (P = 0.89). Conclusion: Women, but not men, with type 2 diabetes and pre-diabetes have lower TBS than individuals without diabetes. These data suggest that diabetes and prediabetes are associated with deterioration of bone microarchitecture.

Houshyar, S, Kumar, GS, Rifai, A, Tran, N, Nayak, R, Shanks, RA, Padhye, R, Fox, K & Bhattacharyya, A 2019, 'Nanodiamond/poly-ε-caprolactone nanofibrous scaffold for wound management', Materials Science and Engineering: C, vol. 100, pp. 378-387.
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Hu, X, Zheng, W, Zhu, Q, Gu, L, Du, Y, Han, Z, Zhang, X, Carter, DR, Cheung, BB, Qiu, A & Jiang, C 2019, 'Increase in DNA Damage by MYCN Knockdown Through Regulating Nucleosome Organization and Chromatin State in Neuroblastoma', Frontiers in Genetics, vol. 10, no. JUL.
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© 2019 Hu, Zheng, Zhu, Gu, Du, Han, Zhang, Carter, Cheung, Qiu and Jiang. As a transcription factor, MYCN regulates myriad target genes including the histone chaperone FACT. Moreover, FACT and MYCN expression form a forward feedback loop in neuroblastoma. It is unclear whether MYCN is involved in chromatin remodeling in neuroblastoma through regulation of its target genes. We showed here that MYCN knockdown resulted in loss of the nucleosome-free regions through nucleosome assembly in the promoters of genes functionally enriched for DNA repair. The active mark H3K9ac was removed or replaced by the repressive mark H3K27me3 in the promoters of double-strand break repair-related genes upon MYCN knockdown. Such chromatin state alterations occurred only in MYCN-bound promoters. Consistently, MYCN knockdown resulted in a marked increase in DNA damage in the treatment with hydroxyurea. In contrast, nucleosome reorganization and histone modification changes in the enhancers largely included target genes with tumorigenesis-related functions such as cell proliferation, cell migration, and cell-cell adhesion. The chromatin state significantly changed in both MYCN-bound and MYCN-unbound enhancers upon MYCN knockdown. Furthermore, MYCN knockdown independently regulated chromatin remodeling in the promoters and the enhancers. These findings reveal the novel epigenetic regulatory role of MYCN in chromatin remodeling and provide an alternative potential epigenetic strategy for MYCN-driven neuroblastoma treatment.

Khorsand, M, Tavakoli, J, Kamanya, K & Tang, Y 2019, 'Simulation of high-output and lightweight sliding-mode triboelectric nanogenerators', Nano Energy, vol. 66, pp. 104115-104115.
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In light of the rapid growth in microelectronic technology, triboelectric nanogenerators (TENGs) have been exploited as securely sustainable substitutes for energy scavenging purposes as well as self-powered sensory utilization. In essence, TENGs’ energy output and average power distribution depend highly on certain key parameters including contact area, the thickness of electric films and external resistance. This study attempts to predict the behavior of TENGs based on variation of those key parameters and tries to optimize the associated characteristics leading to high-output and light-weight sliding-mode TENGs. To meet this problem, an artificial intelligence approach is taken into consideration and solutions for load resistance and geometry are presented. Furthermore, an experimental setup is designed to evaluate the accuracy of the simulation results, demonstrating the precision of the applied theory. The results revealed that the predefined sliding-mode TENG can harvest 0.25 mJ at each cycle in an open-circuit condition where the weight is almost 42.91 g. Moreover, simulation proves that an appropriate value for the external resistor can increase the scavenged energy up to 3.65 mJ at each reciprocal movement. Finally, temporal responses for charge, current, voltage, power output, and harvested energy are plotted and discussed, facilitating understanding of the relationship between scavenged energy and optimized parameters.

Koach, J, Holien, JK, Massudi, H, Carter, DR, Ciampa, OC, Herath, M, Lim, T, Seneviratne, JA, Milazzo, G, Murray, JE, McCarroll, JA, Liu, B, Mayoh, C, Keenan, B, Stevenson, BW, Gorman, MA, Bell, JL, Doughty, L, Hüttelmaier, S, Oberthuer, A, Fischer, M, Gifford, AJ, Liu, T, Zhang, X, Zhu, S, Gustafson, WC, Haber, M, Norris, MD, Fletcher, JI, Perini, G, Parker, MW, Cheung, BB & Marshall, GM 2019, 'Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface', Cancer Research, vol. 79, no. 21, pp. 5652-5667.
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Abstract MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. Significance: Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Krivtsov, AV, Evans, K, Gadrey, JY, Eschle, BK, Hatton, C, Uckelmann, HJ, Ross, KN, Perner, F, Olsen, SN, Pritchard, T, McDermott, L, Jones, CD, Jing, D, Braytee, A, Chacon, D, Earley, E, McKeever, BM, Claremon, D, Gifford, AJ, Lee, HJ, Teicher, BA, Pimanda, JE, Beck, D, Perry, JA, Smith, MA, McGeehan, GM, Lock, RB & Armstrong, SA 2019, 'A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia', Cancer Cell, vol. 36, no. 6, pp. 660-673.e11.
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© 2019 Elsevier Inc. Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

Kulasinghe, A, Kapeleris, J, Cooper, C, Warkiani, ME, O’Byrne, K & Punyadeera, C 2019, 'Phenotypic Characterization of Circulating Lung Cancer Cells for Clinically Actionable Targets', Cancers, vol. 11, no. 3, pp. 380-380.
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Objectives: In non-small cell lung cancers (NSCLC), tumour biopsy can often be an invasive procedure. The development of a non-invasive methodology to study genetic changes via circulating tumour cells (CTCs) is an appealing concept. Whilst CTCs typically remain as rare cells, improvements in epitope-independent CTC isolation techniques has given rise to a greater capture of CTCs. In this cross sectional study, we demonstrate the capture and characterization of NSCLC CTCs for the clinically actionable markers epidermal growth factor receptor (EGFR) alterations, anaplastic lymphoma kinase (ALK) rearrangements and programmed death ligand-1 (PD-L1) expression. The study identified CTCs/CTC clusters in 26/35 Stage IV NSCLC patients, and subsequently characterized the CTCs for EGFR mutation, ALK status and PD-L1 status. This pilot study demonstrates the potential of a non-invasive fluid biopsy to determine clinically relevant biomarkers in NSCLC.

Kumar, P, Beck, D, Galeev, R, Thoms, JAI, Talkhoncheh, MS, de Jong, I, Unnikrishnan, A, Baudet, A, Subramaniam, A, Pimanda, JE & Larsson, J 2019, 'HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells', Blood Advances, vol. 3, no. 4, pp. 681-691.
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Abstract Identification of determinants of fate choices in hematopoietic stem cells (HSCs) is essential to improve the clinical use of HSCs and to enhance our understanding of the biology of normal and malignant hematopoiesis. Here, we show that high-mobility group AT hook 2 (HMGA2), a nonhistone chromosomal-binding protein, is highly and preferentially expressed in HSCs and in the most immature progenitor cell subset of fetal, neonatal, and adult human hematopoiesis. Knockdown of HMGA2 by short hairpin RNA impaired the long-term hematopoietic reconstitution of cord blood (CB)–derived CB CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ cells led to overall enhanced reconstitution in serial transplantation assays accompanied by a skewing toward the myeloerythroid lineages. RNA-sequencing analysis showed that enforced HMGA2 expression in CD34+ cells induced gene-expression signatures associated with differentiation toward megakaryocyte-erythroid and myeloid lineages, as well as signatures associated with growth and survival, which at the protein level were coupled with strong activation of AKT. Taken together, our findings demonstrate a key role of HMGA2 in regulation of both proliferation and differentiation of human HSPCs.

Lan, C, Peng, H, Hutvagner, G & Li, J 2019, 'Construction of competing endogenous RNA networks from paired RNA-seq data sets by pointwise mutual information', BMC Genomics, vol. 20, no. S9, p. 943.
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Abstract Background A long noncoding RNA (lncRNA) can act as a competing endogenous RNA (ceRNA) to compete with an mRNA for binding to the same miRNA. Such an interplay between the lncRNA, miRNA, and mRNA is called a ceRNA crosstalk. As an miRNA may have multiple lncRNA targets and multiple mRNA targets, connecting all the ceRNA crosstalks mediated by the same miRNA forms a ceRNA network. Methods have been developed to construct ceRNA networks in the literature. However, these methods have limits because they have not explored the expression characteristics of total RNAs. Results We proposed a novel method for constructing ceRNA networks and applied it to a paired RNA-seq data set. The first step of the method takes a competition regulation mechanism to derive candidate ceRNA crosstalks. Second, the method combines a competition rule and pointwise mutual information to compute a competition score for each candidate ceRNA crosstalk. Then, ceRNA crosstalks which have significant competition scores are selected to construct the ceRNA network. The key idea, pointwise mutual information, is ideally suitable for measuring the complex point-to-point relationships embedded in the ceRNA networks. Conclusion Computational experiments and results demonstrate that the ceRNA networks can capture important regulatory mechanism of breast cancer, and have also revealed new insights into the treatment of breast cancer. The proposed method can be directly applied to other RNA-seq data sets for deeper disease understanding.

Li, J & Little, C 2019, 'Role of stem cells and bioactive scaffold in chronic joint injury: Working towards a regenerative medicine approach to stop osteoarthritis progression', Osteoarthritis and Cartilage, vol. 27, pp. S82-S83.
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Li, J, Hosseini-Beheshti, E, Grau, G, Zreiqat, H & Little, C 2019, 'Stem Cell-Derived Extracellular Vesicles for Treating Joint Injury and Osteoarthritis', Nanomaterials, vol. 9, no. 2, pp. 261-261.
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Extracellular vesicles (EVs) are nanoscale particles secreted by almost all cell types to facilitate intercellular communication. Stem cell-derived EVs theoretically have the same biological functions as stem cells, but offer the advantages of small size, low immunogenicity, and removal of issues such as low cell survival and unpredictable long-term behaviour associated with direct cell transplantation. They have been an area of intense interest in regenerative medicine, due to the potential to harness their anti-inflammatory and pro-regenerative effects to induce healing in a wide variety of tissues. However, the potential of using stem cell-derived EVs for treating joint injury and osteoarthritis has not yet been extensively explored. The pathogenesis of osteoarthritis, with or without prior joint injury, is not well understood, and there is a longstanding unmet clinical need to develop new treatments that provide a therapeutic effect in preventing or stopping joint degeneration, rather than merely relieving the symptoms of the disease. This review summarises the current evidence relating to stem cell-derived EVs in joint injury and osteoarthritis, providing a concise discussion of their characteristics, advantages, therapeutic effects, limitations and outlook in this exciting new area.

Li, JJ, Dunstan, CR, Entezari, A, Li, Q, Steck, R, Saifzadeh, S, Sadeghpour, A, Field, JR, Akey, A, Vielreicher, M, Friedrich, O, Roohani‐Esfahani, S & Zreiqat, H 2019, 'A Novel Bone Substitute with High Bioactivity, Strength, and Porosity for Repairing Large and Load‐Bearing Bone Defects', Advanced Healthcare Materials, vol. 8, no. 13, pp. e1900641-1900641.
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Adv. Healthcare Mater. 2019, 8, 1801298 In the initially published version of this article, the author list and affiliations were incorrect. The correct author list is as follows: Jiao Jiao Li, Colin R. Dunstan, Ali Entezari, Qing Li, Roland Steck, Siamak Saifzadeh, Ameneh Sadeghpour, John R. Field, Austin Akey, David C. Bell, Martin Vielreicher, Oliver Friedrich, Seyed-Iman Roohani-Esfahani, and Hala Zreiqat* The correct affiliation for D.C.B. is as follows: Dr. A. Akey, Prof. D. C. Bell Center for Nanoscale Systems Harvard University Cambridge, MA 02138, USA.

Li, JJ, Dunstan, CR, Entezari, A, Li, Q, Steck, R, Saifzadeh, S, Sadeghpour, A, Field, JR, Akey, A, Vielreicher, M, Friedrich, O, Roohani‐Esfahani, S & Zreiqat, H 2019, 'A Novel Bone Substitute with High Bioactivity, Strength, and Porosity for Repairing Large and Load‐Bearing Bone Defects', Advanced Healthcare Materials, vol. 8, no. 8, pp. e1801298-1801298.
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AbstractAchieving adequate healing in large or load‐bearing bone defects is highly challenging even with surgical intervention. The clinical standard of repairing bone defects using autografts or allografts has many drawbacks. A bioactive ceramic scaffold, strontium‐hardystonite‐gahnite or “Sr‐HT‐Gahnite” (a multi‐component, calcium silicate‐based ceramic) is developed, which when 3D‐printed combines high strength with outstanding bone regeneration ability. In this study, the performance of purely synthetic, 3D‐printed Sr‐HT‐Gahnite scaffolds is assessed in repairing large and load‐bearing bone defects. The scaffolds are implanted into critical‐sized segmental defects in sheep tibia for 3 and 12 months, with bone autografts used for comparison. The scaffolds induce substantial bone formation and defect bridging after 12 months, as indicated by X‐ray, micro‐computed tomography, and histological and biomechanical analyses. Detailed analysis of the bone‐scaffold interface using focused ion beam scanning electron microscopy and multiphoton microscopy shows scaffold degradation and maturation of the newly formed bone. In silico modeling of strain energy distribution in the scaffolds reveal the importance of surgical fixation and mechanical loading on long‐term bone regeneration. The clinical application of 3D‐printed Sr‐HT‐Gahnite scaffolds as a synthetic bone substitute can potentially improve the repair of challenging bone defects and overcome the limitations of bone graft transplantation.

Li, JJ, Dunstan, CR, Entezari, A, Li, Q, Steck, R, Saifzadeh, S, Sadeghpour, A, Field, JR, Akey, A, Vielreicher, M, Friedrich, O, Roohani‐Esfahani, S & Zreiqat, H 2019, 'Bone Regeneration: A Novel Bone Substitute with High Bioactivity, Strength, and Porosity for Repairing Large and Load‐Bearing Bone Defects (Adv. Healthcare Mater. 8/2019)', Advanced Healthcare Materials, vol. 8, no. 8, pp. 1970031-1970031.
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Mahmoodi, Z, Mohammadnejad, J, Razavi Bazaz, S, Abouei Mehrizi, A, Ghiass, MA, Saidijam, M, Dinarvand, R, Ebrahimi Warkiani, M & Soleimani, M 2019, 'A simple coating method of PDMS microchip with PTFE for synthesis of dexamethasone-encapsulated PLGA nanoparticles', Drug Delivery and Translational Research, vol. 9, no. 3, pp. 707-720.
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© 2019, Controlled Release Society. Dexamethasone is a widely used drug in medical and biological applications. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this anti-inflammatory drug in poly(lactic-co-glycolic acid) (PLGA) nanoparticles can minimize uncontrolled issues. As dexamethasone-encapsulated PLGA nanoparticles are synthesized in the presence of organic solvents, poly(dimethylsiloxane) (PDMS)-based microchannels collapse due to the swelling problem. In present study, PTFE nanoparticles were used for the surface modification of the microchannels to prevent absorption and adhesion of solvents into the microchannels’ wall. The contact angle analysis of microchips after coating showed that the surface of microchannels bear the superhydrophobicity feature (140.30°) and SEM images revealed that PTFE covered the surface of PDMS, favorably. Then, the prepared microchip was tested for the synthesis of dexamethasone-loaded nanoparticles. SEM and atomic force microscopy (AFM) images of the synthesized nanoparticles represented that there was not any evidence of adhesion or absorption of nanoparticles. Furthermore, the monodispersity of nanoparticles was discernible. As AFM results revealed, the average diameters of 47, 63, and 82 nm were achieved for flow ratios of 0.01, 0.05, and 0.1, respectively. To evaluate the drug efficiency, cumulative release and encapsulation efficiency were analyzed which showed much more efficiency than the synthesized nanoparticles in the bulk mode. In addition, MTT test revealed that nanoparticles could be considered as a non-toxic material. Since the synthesis of drug-loaded nanoparticles is ubiquitous in laboratory experiments, the approach presented in this study can render more versatility in this regard.

Mai, HT, Tran, TS, Ho-Le, TP, Center, JR, Eisman, JA & Nguyen, TV 2019, 'Response to Letter to the Editor: “Two-Thirds of All Fractures Are Not Attributable to Osteoporosis and Advancing Age: Implication for Fracture Prevention”', The Journal of Clinical Endocrinology & Metabolism, vol. 104, no. 9, pp. 3605-3606.
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Mai, HT, Tran, TS, Ho-Le, TP, Center, JR, Eisman, JA & Nguyen, TV 2019, 'Response to Letter to the Editor: “Two-Thirds of All Fractures Are Not Attributable to Osteoporosis and Advancing Age: Implications for Fracture Prevention”', The Journal of Clinical Endocrinology & Metabolism, vol. 104, no. 12, pp. 5866-5866.
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Mai, HT, Tran, TS, Ho-Le, TP, Center, JR, Eisman, JA & Nguyen, TV 2019, 'Two-Thirds of All Fractures Are Not Attributable to Osteoporosis and Advancing Age: Implications for Fracture Prevention', The Journal of Clinical Endocrinology & Metabolism, vol. 104, no. 8, pp. 3514-3520.
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Abstract Context Although bone mineral density (BMD) is strongly associated with fracture and postfracture mortality, the burden of fractures attributable to low BMD has not been investigated. Objectives We sought to estimate the population attributable fraction of fractures and fracture-related mortality that can be attributed to low BMD. Design and Setting This study is a part of an ongoing population-based prospective cohort study, the Dubbo Osteoporosis Epidemiology study. In total, 3700 participants aged ≥50 years participated in the study. Low-trauma fracture was ascertained by X-ray reports, and mortality was ascertained from the Birth, Death and Marriage Registry. Results Overall, 21% of women and 11% of men had osteoporotic BMD. In univariable analysis, 21% and 16% of total fractures in women and men, respectively, were attributable to osteoporosis. Osteoporosis combined with advancing age (>70 years) accounted for 34% and 35% of fractures in women and men, respectively. However, these two factors accounted for ∼60% of hip fractures. About 99% and 66% of postfracture mortality in women and men, respectively, were attributable to advancing age, osteoporosis, and fracture; however, most of the attributable proportion was accounted for by advancing age. Conclusions A substantial health care burden of fracture is ...

Mofradnia, SR, Ashouri, R, Tavakoli, Z, Shahmoradi, F, Rashedi, H, Yazdian, F & Tavakoli, J 2019, 'Effect of zero-valent iron/starch nanoparticle on nitrate removal using MD simulation', International Journal of Biological Macromolecules, vol. 121, pp. 727-733.
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In this study, the efficacy of zero-valent iron nanostructure modified by starch for removal of nitrate was investigated. Effect of zero-valent iron/starch nanoparticle in the presence of Thiobacillus dinitrificans for removal of nitrate was simulated via material studio software. Thermodynamic principles and proper equations were used via molecular dynamic (MD) simulation. The results of software predictions were demonstrated by radial distribution function (RDF), density, potential energy and temperature graphs. According to the graphs, the simultaneous in the presence of zero-valent iron/starch nanoparticle and Thiobacillus dinitrificans increase the removal efficiency of nitrate reached 91% and in the absence of nanoparticle was 44.44%.

Moloudi, R, Oh, S, Yang, C, Teo, KL, Lam, AT, Ebrahimi Warkiani, M & Win Naing, M 2019, 'Scaled‐Up Inertial Microfluidics: Retention System for Microcarrier‐Based Suspension Cultures', Biotechnology Journal, vol. 14, no. 5, pp. 1800674-1800674.
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Recently, particle concentration and filtration using inertial microfluidics have drawn attention as an alternative to membrane and centrifugal technologies for industrial applications, where the target particle size varies between 1 µm and 500 µm. Inevitably, the bigger particle size (>50 µm) mandates scaling up the channel cross‐section or hydraulic diameter (DH > 0.5 mm). The Dean‐coupled inertial focusing dynamics in spiral microchannels is studied broadly; however, the impacts of secondary flow on particle migration in a scaled‐up spiral channel is not fully elucidated. The mechanism of particle focusing inside scaled‐up rectangular and trapezoidal spiral channels (i.e., 5–10× bigger than conventional microchannels) with an aim to develop a continuous and clog‐free microfiltration system for bioprocessing is studied in detail. Herein, a unique focusing based on inflection point without the aid of sheath flow is reported. This new focusing mechanism, observed in the scaled‐up channels, out‐performs the conventional focusing scenarios in the previously reported trapezoidal and rectangular channels. Finally, as a proof‐of‐concept, the utility of this device is showcased for the first time as a retention system for a cell–microcarrier (MC) suspension culture.

Moradi, A, Zhand, S, Hosseini, S, Tabarraei, A & Saeidi, M 2019, 'Analysis of poliovirus receptor, CD155 expression in different human colorectal cancer cell lines: Implications for poliovirus virotherapy', Journal of Cancer Research and Therapeutics, vol. 15, no. 1, pp. 61-61.
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© 2019 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow. Context: Poliovirus (PV) receptor (CD155) is expressed on several kinds of cells and exerts diverse functions. Various investigations have confirmed that changes in CD155 expression in cancer cell lines affect metastasis, proliferation, and migration. Aims: The purpose of the present study was to investigate the CD155 transcript and protein expression in human colon adenocarcinoma cell lines in comparison to normal fetal human colon (FHC) cells. Materials and Methods: The CD155 expression level in four human adenocarcinoma cell lines and normal colon cell line were assessed using the SYBR green quantitative real-time polymerase chain reaction (PCR) and flowcytometry. Results: The results of real-time PCR indicated that CD155 was significantly overexpressed in all human adenocarcinoma cell lines (P = 0.000). The highest and the lowest expression level of CD155 messenger RNA was observed in SW480 and HT29 cell lines by 491.14, and 12.04 fold changes, respectively, in comparison with the human normal cell line (FHC). Results of flowcytometry indicate that protein was strongly expressed in cancer cell lines. SW480 cells showed the highest CD155 protein expression level of 98.1%, whereas this protein expression was 1.3% in human normal colon cell line (FHC). Totally, these data indicate that CD155 expression is significantly elevated in cancer cell lines. Conclusions: The preferential expression of CD155 on cancer cell lines rather than on normal cell line suggests that CD155 could be targeted for future PV virotherapy.

Movassaghi, S, Nadia Sharifi, Z, Koosha, M, Abdollahifar, MA, Fathollahipour, S, Tavakoli, J & Abdi, S 2019, 'Effect of Honey/PVA Hydrogel Loaded by Erythromycin on Full-Thickness Skin Wound Healing in Rats; Stereological Study.', Galen Med J, vol. 8, p. e1362.
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BACKGROUND: Skin wounds are a significant public health risk, and treatment of wound remains a challenging clinical problem for medical teams and researchers. MATERIALS AND METHODS: In the present study, we aimed to investigate the healing effects of honey/polyvinyl alcohol (PVA) hydrogel loaded with erythromycin as wound dressing on skin wounds in rats, based on histological studies. In this study, 60 male Wistar rats, with a 1.5 ×1.5 cm2 diameter full-thickness wounds on the backs were divided into four groups: honey/PVA with the erythromycin hydrogel group, honey group, PVA group, and the control group, with no treatment. Skin biopsies were prepared at days 4, 7, and 14 for microscopic analyses. The stereological analysis, including the mean area of the wound, length of vessels, numerical density of fibroblast, macrophage, basal cell and volume of the epidermis, dermis, and fibrous tissue were performed. RESULTS: Wounds area in the honey/PVA hydrogel with the erythromycin group were significantly (P<0.05) smaller than in the other group. The numerical density of fibroblast, macrophage, basal cell and volume of the epidermis in the honey/PVA hydrogel with the erythromycin group were significantly higher than other groups. CONCLUSION: According to our results, honey/PVA hydrogel with erythromycin may promote early wound healing and has a positive influence on fibroblast proliferation and re-epithelialization, and its administration is recommended after further validation of clinical data.

Nguyen, LT, Pham, VN, Chau, PMN, Ho-Pham, LT & Nguyen, TV 2019, 'Association between carotid intima-media thickness and bone mineral density: a cross-sectional study in Vietnamese men and women aged 50 years and older', BMJ Open, vol. 9, no. 9, pp. e028603-e028603.
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ObjectivesThe association between osteoporosis and atherosclerosis remains controversial. We sought to define the relationship between carotid intima-media thickness and bone mineral density (BMD) in individuals of Vietnamese background.Design and settingCross-sectional study in Ho Chi Minh City, Vietnam.ParticipantsThe study involved 1460 individuals (559 men) aged 50 years and older (average age 59 years) who were randomly recruited from the community.Outcome measuresBMD at the femoral neck and lumbar spine was measured by dual-energy X-ray absorptiometry (Hologic, Waltham, Massachusetts, USA). Carotid intima-media thickness (cIMT) was measured using a Philips Ultrasonography (HD7XE). The presence of atherosclerotic plaque was ascertained for each individual. The association between cIMT and BMD was analysed by a multiple linear regression model.ResultsIn unadjusted analysis, cIMT was positively associated with femoral neck BMD in men (p=0.005), but not in women (p=0.242). After adjusting for age, smoking, diabetes and hypertension, the association remained statistically significant in men (partial R2=0.005; p=0.015) but not in women (partial R2=0.008; p=0.369). When the analysis was limited to individuals aged 60 years and older, the association between cIMT and BMD was no longer statistically significant. There was no statistically significant association between cIMT and lumbar spine BMD in either men or women.ConclusionsIn Vietnamese individuals aged 50 years and older, there is a clinically non-significant but statistically significant association betwee...

Nguyen, PTK, Tran, HT, Fitzgerald, DA, Tran, TS, Graham, SM & Marais, BJ 2019, 'Characterisation of children hospitalised with pneumonia in central Vietnam: a prospective study', European Respiratory Journal, vol. 54, no. 1, pp. 1802256-1802256.
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Pneumonia is the most common reason for paediatric hospital admission in Vietnam. The potential value of using the World Health Organization (WHO) case management approach in Vietnam has not been documented.We performed a prospective descriptive study of all children (2–59 months) admitted with “pneumonia” (as assessed by the admitting clinician) to the Da Nang Hospital for Women and Children to characterise their disease profiles and assess risk factors for an adverse outcome. The disease profile was classified using WHO pneumonia criteria, with tachypnoea or chest indrawing as defining clinical signs. Adverse outcome was defined as death, intensive care unit admission, tertiary care transfer or hospital stay >10 days.Of 4206 admissions, 1758 (41.8%) were classified as “no pneumonia” using WHO criteria and only 252 (6.0%) met revised criteria for “severe pneumonia”. The inpatient death rate was low (0.4% of admissions) with most deaths (11 out of 16; 68.8%) occurring in the “severe pneumonia” group. An adverse outcome was recorded in 18.7% of all admissions and 60.7% of the “severe pneumonia” group. Children were hospitalised for a median of 7 days at an average cost of 253 USD per admission. Risk factors for adverse outcome included WHO-classified “severe pneumonia”, age <1 year, low birth weight, previous recent admission with an acute respiratory infection and recent tuberculosis exposure. Breastfeeding, day-care attendance and pre-admission antibiotic use were associated with reduced risk.Few hospital admissions met WHO criteria for “severe pneumonia”, suggesting potential unnecessary hospitalisation and use of intravenous antibiotics. Better characterisation of the underlying diagnosis requires careful consideration.

Ni, J, Bongers, A, Chamoli, U, Bucci, J, Graham, P & Li, Y 2019, 'In Vivo 3D MRI Measurement of Tumour Volume in an Orthotopic Mouse Model of Prostate Cancer', Cancer Control, vol. 26, no. 1, pp. 107327481984659-107327481984659.
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Prostate cancer (CaP) is the most commonly diagnosed cancer in males in western countries. Orthotopic implantation is considered as an ideal xenograft model for CaP study, and noninvasive measurement of tumor volume changes is important for monitoring responses to anticancer therapies. In this study, the T2-weighted fast spin echo sequence magnetic resonance imaging (MRI) was performed on a CaP orthotopic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model weekly for 6 weeks post PC-3 CaP cell inoculation, and the fat signal was suppressed using a chemical shift-selective pulse. Subsequently, the MRI data were imported into the image processing software Avizo Standard and stacked into three-dimensional (3D) volumes. Our results demonstrate that MRI, combined with 3D reconstruction, is a feasible and sensitive method to assess tumor growth in a PC-3 orthotopic CaP mouse model and this established monitoring approach is promising for longitudinal observation of CaP xenograft development after anticancer therapy in vivo. Further investigation is needed to validate this protocol in a larger cohort of mice to generate enough statistical power.

Pham, DD, Lee, SK, Shin, C, Kim, NH, Eisman, JA, Center, JR, Nguyen, TV & Leem, CH 2019, 'Koreans Do Not Have Higher Percent Body Fat than Australians: Implication for the Diagnosis of Obesity in Asians', Obesity, vol. 27, no. 11, pp. 1892-1897.
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ObjectiveIt has been assumed that, for a given BMI, Asians have higher percent body fat (PBF) than Caucasians. As a result, it has been suggested that the BMI threshold for diagnosing obesity in Asians be lowered to less than  30 kg/m2. This study sought to compare PBF between Koreans and Australians.MethodsWhole‐body fat mass and PBF were measured in 1,211 Koreans and 1,006 Australians using dual‐energy x‐ray absorptiometry (Lunar Prodigy; GE Healthcare, Madison, Wisconsin). The two groups were then matched for age and BMI by the propensity score method.ResultsFor a given age and BMI, Koreans had lower PBF than Australians, and the difference was statistically significant in women (mean difference: −2.13%; 95% CI: −2.61% to −1.65%) but not in men (difference: −0.54%; 95% CI: −1.22% to 0.14%). Matched‐pair analysis (423 pairs of women and 208 pairs of men) also showed that Korean women had statistically lower PBF than their Australian counterparts (P < 0.001).ConclusionsIn individuals aged 60 years and older, Koreans do not have higher PBF than Australians after adjusting for BMI. These results suggest that there is no evidence for lowering the BMI threshold for the diagnosis of obesity in elderly Koreans.

Piya, R, Zhu, Y, Soeriyadi, AH, Silva, SM, Reece, PJ & Gooding, JJ 2019, 'Micropatterning of porous silicon Bragg reflectors with poly(ethylene glycol) to fabricate cell microarrays: Towards single cell sensing', Biosensors and Bioelectronics, vol. 127, pp. 229-235.
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The work presented here describes the development of an optical label-free biosensor based on a porous silicon (PSi) Bragg reflector to study heterogeneity in single cells. Photolithographic patterning of a poly(ethylene glycol) (PEG) hydrogel with a photoinitiator was employed on RGD peptide-modified PSi to create micropatterns with cell adhesive and cell repellent areas. Macrophage J774 cells were incubated to form cell microarrays and single cell arrays. Moreover, cells on the microarrays were lysed osmotically with Milli-Q™ water and the infiltration of cell lysate into the porous matrix was monitored by measuring the red shift in the reflectivity. On average, the magnitude of red shift increased with the increase in the number of cells on the micropatterns. The red shift from the spots with single cells varied from spot to spot emphasizing the heterogeneous nature of the individual cells.

Rafeie, M, Hosseinzadeh, S, Huang, J, Mihandoust, A, Warkiani, ME & Taylor, RA 2019, 'New insights into the physics of inertial microfluidics in curved microchannels. II. Adding an additive rule to understand complex cross-sections', Biomicrofluidics, vol. 13, no. 3, pp. 034118-034118.
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Curved microchannels allow controllable microparticle focusing, but a full understanding of particle behavior has been limited—even for simple rectangular and trapezoidal shapes. At present, most microfluidic particle separation literature is dedicated to adding “internal” complexity (via sheath flow or obstructions) to relatively simple cross-sectional channel shapes. We propose that, with sufficient understanding of particle behavior, an equally viable pathway for microparticle focusing could utilize complex “external” cross-sectional shapes. By investigating three novel, complex spiral microchannels, we have found that it is possible to passively focus (6, 10, and 13 μm) microparticles in the middle of a convex channel. Also, we found that in concave and jagged channel designs, it is possible to create multiple, tight focusing bands. In addition to these performance benefits, we report an “additive rule” herein, which states that complex channels can be considered as multiple, independent, simple cross-sectional shapes. We show with experimental and numerical analysis that this new additive rule can accurately predict particle behavior in complex cross-sectional shaped channels and that it can help to extract general inertial focusing tendencies for suspended particles in curved channels. Overall, this work provides simple, yet reliable, guidelines for the design of advanced curved microchannel cross sections.

Rafeie, M, Hosseinzadeh, S, Taylor, RA & Warkiani, ME 2019, 'New insights into the physics of inertial microfluidics in curved microchannels. I. Relaxing the fixed inflection point assumption', Biomicrofluidics, vol. 13, no. 3, pp. 034117-034117.
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Inertial microfluidics represents a powerful new tool for accurately positioning cells and microparticles within fluids for a variety of biomedical, clinical, and industrial applications. In spite of enormous advancements in the science and design of these devices, particularly in curved microfluidic channels, contradictory experimental results have confounded researchers and limited progress. Thus, at present, a complete theory which describes the underlying physics is lacking. We propose that this bottleneck is due to one simple mistaken assumption—the locations of inflection points of the Dean velocity profile in curved microchannels are not fixed, but can actually shift with the flow rate. Herein, we propose that the dynamic distance (δ) between the real equilibrium positions and their nearest inflection points can clearly explain several (previously) unexplained phenomena in inertial microfluidic systems. More interestingly, we found that this parameter, δ, is a function of several geometric and operational parameters, all of which are investigated (in detail) here with a series of experiments and simulations of different spiral microchannels. This key piece of understanding is expected to open the door for researchers to develop new and more effective inertial microfluidic designs.

Rangel, L, Bernabé-Rubio, M, Fernández-Barrera, J, Casares-Arias, J, Millán, J, Alonso, MA & Correas, I 2019, 'Caveolin-1α regulates primary cilium length by controlling RhoA GTPase activity', Scientific Reports, vol. 9, no. 1.
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AbstractThe primary cilium is a single non-motile protrusion of the plasma membrane of most types of mammalian cell. The structure, length and function of the primary cilium must be tightly controlled because their dysfunction is associated with disease. Caveolin 1 (Cav1), which is best known as a component of membrane invaginations called caveolae, is also present in non-caveolar membrane domains whose function is beginning to be understood. We show that silencing of α and β Cav1 isoforms in different cell lines increases ciliary length regardless of the route of primary ciliogenesis. The sole expression of Cav1α, which is distributed at the apical membrane, restores normal cilium size in Cav1 KO MDCK cells. Cells KO for only Cav1α, which also show long cilia, have a disrupted actin cytoskeleton and reduced RhoA GTPase activity at the apical membrane, and a greater accumulation of Rab11 vesicles at the centrosome. Subsequent experiments showed that DIA1 and ROCK help regulate ciliary length. Since MDCK cells lack apical caveolae, our results imply that non-caveolar apical Cav1α is an important regulator of ciliary length, exerting its effect via RhoA and its effectors, ROCK and DIA1.

Raoufi, MA, Mashhadian, A, Niazmand, H, Asadnia, M, Razmjou, A & Warkiani, ME 2019, 'Experimental and numerical study of elasto-inertial focusing in straight channels', Biomicrofluidics, vol. 13, no. 3, pp. 034103-034103.
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Elasto-inertial microfluidics has drawn significant attention in recent years due to its enhanced capabilities compared to pure inertial systems in control of small microparticles. Previous investigations have focused mainly on the applications of elasto-inertial sorting, rather than studying its fundamentals. This is because of the complexity of simulation and analysis, due to the presence of viscoelastic force. There have been some investigative efforts on the mechanisms of elasto-inertial focusing in straight channels; however, these studies were limited to simple rectangular channels and neglected the effects of geometry and flow rates on focusing positions. Herein, for the first time, we experimentally and numerically explore the effects of elasticity accompanying channel cross-sectional geometry and sample flow rates on the focusing phenomenon in elasto-inertial systems. The results reveal that increasing the aspect ratio weakens the elastic force more than inertial force, causing a transition from one focusing position to two. In addition, they show that increasing the angle of a channel corner causes the elastic force to push the particles more efficiently toward the center over a larger area of the channel cross section. Following on from this, we proposed a new complex straight channel which demonstrates a tighter focusing band compared to other channel geometries. Finally, we focused Saccharomyces cerevisiae cells (3–5 μm) in the complex channel to showcase its capability in focusing small-size particles. We believe that this research work improves the understanding of focusing mechanisms in viscoelastic solutions and provides useful insights into the design of elasto-inertial microfluidic devices.

Raoufi, MA, Moshizi, SA, Razmjou, A, Wu, S, Ebrahimi Warkiani, M & Asadnia, M 2019, 'Development of a Biomimetic Semicircular Canal With MEMS Sensors to Restore Balance', IEEE Sensors Journal, vol. 19, no. 23, pp. 11675-11686.
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© 2001-2012 IEEE. A third of adults over the age of 50 suffer from chronic impairment of balance, posture, and/or gaze stability due to partial or complete impairment of the sensory cells in the inner ear responsible for these functions. The consequences of impaired balance organ can be dizziness, social withdrawal, and acceleration of the further functional decline. Despite the significant progress in biomedical sensing technologies, current artificial vestibular systems fail to function in practical situations and in very low frequencies. Herein, we introduced a novel biomechanical device that closely mimics the human vestibular system. A microelectromechanical systems (MEMS) flow sensor was first developed to mimic the vestibular haircell sensors. The sensor was then embedded into a three-dimensional (3D) printed semicircular canal and tested at various angular accelerations in the frequency range from 0.5Hz to 1.5Hz. The miniaturized device embedded into a 3D printed model will respond to mechanical deflections and essentially restore the sense of balance in patients with vestibular dysfunctions. The experimental and simulation studies of semicircular canal presented in this work will pave the way for the development of balance sensory system, which could lead to the design of a low-cost and commercially viable medical device with significant health benefits and economic potential.

Razavi Bazaz, S, Kashaninejad, N, Azadi, S, Patel, K, Asadnia, M, Jin, D & Ebrahimi Warkiani, M 2019, 'Microfluidics: Rapid Softlithography Using 3D‐Printed Molds (Adv. Mater. Technol. 10/2019)', Advanced Materials Technologies, vol. 4, no. 10, pp. 1970056-1970056.
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Razavi Bazaz, S, Kashaninejad, N, Azadi, S, Patel, K, Asadnia, M, Jin, D & Ebrahimi Warkiani, M 2019, 'Rapid Softlithography Using 3D‐Printed Molds', Advanced Materials Technologies, vol. 4, no. 10, pp. 1900425-1900425.
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AbstractPolydimethylsiloxane (PDMS) is a long‐standing material of significant interest in microfluidics due to its unique features. As such, rapid prototyping of PDMS‐based microchannels is of great interest. The most prevalent and conventional method for fabrication of PDMS‐based microchips relies on softlithography, the main drawback of which is the preparation of a master mold, which is costly and time‐consuming. To prevent the attachment of PDMS to the master mold, silanization is necessary, which can be detrimental for cellular studies. Additionally, using coating the mold with a cell‐compatible surfactant adds extra preprocessing time. Recent advances in 3D printing have shown great promise in expediting microfabrication. Nevertheless, current 3D printing techniques are sub‐optimal for PDMS softlithography. The feasibility of producing master molds suitable for rapid softlithography is demonstrated using a newly developed 3D‐printing resin. Moreover, the utility of this technique is showcased for a number of widely used applications, such as concentration gradient generation, particle separation, cell culture (to show biocompatibility of the process), and fluid mixing. This can open new opportunities for biologists and scientists with minimum knowledge of microfabrication to build functional microfluidic devices for their basic and applied research.

Rezaei, M, Winter, M, Zander-Fox, D, Whitehead, C, Liebelt, J, Warkiani, ME, Hardy, T & Thierry, B 2019, 'A Reappraisal of Circulating Fetal Cell Noninvasive Prenatal Testing', Trends in Biotechnology, vol. 37, no. 6, pp. 632-644.
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© 2018 Elsevier Ltd New tools for higher-resolution fetal genome analysis including microarray and next-generation sequencing have revolutionized prenatal screening. This article provides commentary on this rapidly advancing field and a future perspective emphasizing circulating fetal cell (CFC) utility. Despite the tremendous technological challenges associated with their reliable and cost-effective isolation from maternal blood, CFCs have a strong potential to bridge the gap between the diagnostic sensitivity of invasive procedures and the desirable noninvasive nature of cell-free fetal DNA (cffDNA). Considering the rapid advances in both rare cell isolation and low-input DNA analysis, we argue here that CFC-based noninvasive prenatal testing is poised to be implemented clinically in the near future.

Rifai, A, Tran, N, Reineck, P, Elbourne, A, Mayes, E, Sarker, A, Dekiwadia, C, Ivanova, EP, Crawford, RJ, Ohshima, T, Gibson, BC, Greentree, AD, Pirogova, E & Fox, K 2019, 'Engineering the Interface: Nanodiamond Coating on 3D-Printed Titanium Promotes Mammalian Cell Growth and Inhibits Staphylococcus aureus Colonization', ACS Applied Materials & Interfaces, vol. 11, no. 27, pp. 24588-24597.
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Sabnis, AB, Chamoli, U & Diwan, AD 2019, 'Answer to the Letter to the Editor of Miao Yu et al. concerning “Is L5-S1 motion segment different from the rest? A radiographic kinematic assessment of 72 patients with chronic low back pain” by AB Sabnis et al. (Eur. Spine J; 27(5):1127–1135)', European Spine Journal, vol. 28, no. 5, pp. 1249-1249.
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Salomon, R, Kaczorowski, D, Valdes-Mora, F, Nordon, RE, Neild, A, Farbehi, N, Bartonicek, N & Gallego-Ortega, D 2019, 'Droplet-based single cell RNAseq tools: a practical guide', Lab on a Chip, vol. 19, no. 10, pp. 1706-1727.
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A step-by-step guide for droplet-based single cell RNAseq experiments, practical considerations and technical notes.

Sarker, A, Tran, N, Rifai, A, Brandt, M, Tran, PA, Leary, M, Fox, K & Williams, R 2019, 'Rational design of additively manufactured Ti6Al4V implants to control Staphylococcus aureus biofilm formation', Materialia, vol. 5, pp. 100250-100250.
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Sheldrick, K, Chamoli, U, Masuda, K, Miyazaki, S, Kato, K & Diwan, AD 2019, 'A novel magnetic resonance imaging postprocessing technique for the assessment of intervertebral disc degeneration—Correlation with histological grading in a rabbit disc degeneration model', JOR SPINE, vol. 2, no. 3.
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AbstractIntroductionEstimation of intervertebral disc degeneration on magnetic resonance imaging (MRI) is challenging. Qualitative schemes used in clinical practice correlate poorly with pain and quantitative techniques have not entered widespread clinical use.MethodsAs part of a prior study, 25 New Zealand white rabbits underwent annular puncture to induce disc degeneration in 50 noncontiguous lumbar discs. At 16 weeks, the animals underwent multi‐echo T2 MRI scanning and were euthanized. The discs were stained and examined histologically. Quantitative T2 relaxation maps were prepared using the nonlinear least squares method. Decay Variance maps were created using a novel technique of aggregating the deviation in the intensity of each echo signal from the expected intensity based on the previous rate of decay.ResultsDecay Variance maps showed a clear and well demarcated nucleus pulposus with a consistent rate of decay (low Decay Variance) in healthy discs that showed progressively more variable decay (higher Decay Variance) with increasing degeneration. Decay Variance maps required significantly less time to generate (1.0 ± 0.0 second) compared with traditional T2 relaxometry maps (5 (±0.9) to 1788.9 (±116) seconds). Histology scores correlated strongly with Decay Variance scores (r = 0.82, P < .01) and weakly with T2 signal intensity (r = 0.32, P < .01) and quantitative T2 relaxometry (r = 0.39, P < .01). Decay Variance had superior sensitivity and specificity for the detection of degenerate discs when compared to T2 signal intensity or Quantitative T2 mapping.ConclusionOur results show that using a multi‐echo ...

Shrestha, J, Ghadiri, M, Shanmugavel, M, Razavi Bazaz, S, Vasilescu, S, Ding, L & Ebrahimi Warkiani, M 2019, 'A rapidly prototyped lung-on-a-chip model using 3D-printed molds', Organs-on-a-Chip, vol. 1, pp. 100001-100001.
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Si, L, Eisman, JA, Winzenberg, T, Sanders, KM, Center, JR, Nguyen, TV & Palmer, AJ 2019, 'Microsimulation model for the health economic evaluation of osteoporosis interventions: study protocol', BMJ Open, vol. 9, no. 2, pp. e028365-e028365.
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IntroductionOsteoporosis is a systemic skeletal disease that is characterised by reduced bone strength and increased fracture risk. Osteoporosis-related fractures impose enormous disease and economic burden to the society. Although many treatments and health interventions are proven effective to prevent fractures, health economic evaluation adds evidence to their economic merits. Computer simulation modelling is a useful approach to extrapolate clinical and economic outcomes from clinical trials and it is increasingly used in health economic evaluation. Many osteoporosis health economic models have been developed in the past decades; however, they are limited to academic use and there are no publicly accessible health economic models of osteoporosis.Methods and analysisWe will develop the Australian osteoporosis health economic model based on our previously published microsimulation model of osteoporosis in the Chinese population. The development of the model will follow the recommendations for the conduct of economic evaluations in osteoporosis by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the US branch of the International Osteoporosis Foundation. The model will be a state-transition semi-Markov model with memory. Clinical parameters in the model will be mainly obtained from the Dubbo Osteoporosis Epidemiology Study and the health economic parameters will be collected from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study. Model transparency and validates will be tested using the recommendations from Good Research Practices in Modelling Task Forces. The model will be used in economic evaluations of osteoporosis interventions including pharmaceutical treatments and primary care interventions. A user-friendly graphical user ...

Smith, CM, Catchpoole, D & Hutvagner, G 2019, 'Non-Coding RNAs in Pediatric Solid Tumors', Frontiers in Genetics, vol. 10.
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© Copyright © 2019 Smith, Catchpoole and Hutvagner. Pediatric solid tumors are a diverse group of extracranial solid tumors representing approximately 40% of childhood cancers. Pediatric solid tumors are believed to arise as a result of disruptions in the developmental process of precursor cells which lead them to accumulate cancerous phenotypes. In contrast to many adult tumors, pediatric tumors typically feature a low number of genetic mutations in protein-coding genes which could explain the emergence of these phenotypes. It is likely that oncogenesis occurs after a failure at many different levels of regulation. Non-coding RNAs (ncRNAs) comprise a group of functional RNA molecules that lack protein coding potential but are essential in the regulation and maintenance of many epigenetic and post-translational mechanisms. Indeed, research has accumulated a large body of evidence implicating many ncRNAs in the regulation of well-established oncogenic networks. In this review we cover a range of extracranial solid tumors which represent some of the rarer and enigmatic childhood cancers known. We focus on two major classes of ncRNAs, microRNAs and long non-coding RNAs, which are likely to play a key role in the development of these cancers and emphasize their functional contributions and molecular interactions during tumor formation.

Styrkarsdottir, U, Stefansson, OA, Gunnarsdottir, K, Thorleifsson, G, Lund, SH, Stefansdottir, L, Juliusson, K, Agustsdottir, AB, Zink, F, Halldorsson, GH, Ivarsdottir, EV, Benonisdottir, S, Jonsson, H, Gylfason, A, Norland, K, Trajanoska, K, Boer, CG, Southam, L, Leung, JCS, Tang, NLS, Kwok, TCY, Lee, JSW, Ho, SC, Byrjalsen, I, Center, JR, Lee, SH, Koh, J-M, Lohmander, LS, Ho-Pham, LT, Nguyen, TV, Eisman, JA, Woo, J, Leung, P-C, Loughlin, J, Zeggini, E, Christiansen, C, Rivadeneira, F, van Meurs, J, Uitterlinden, AG, Mogensen, B, Jonsson, H, Ingvarsson, T, Sigurdsson, G, Benediktsson, R, Sulem, P, Jonsdottir, I, Masson, G, Holm, H, Norddahl, GL, Thorsteinsdottir, U, Gudbjartsson, DF & Stefansson, K 2019, 'GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures', Nature Communications, vol. 10, no. 1.
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AbstractBone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.

Sutton, SK, Cheung, BB, Massudi, H, Tan, O, Koach, J, Mayoh, C, Carter, DR & Marshall, GM 2019, 'Heterozygous loss of keratinocyte TRIM16 expression increases melanocytic cell lesions and lymph node metastasis', Journal of Cancer Research and Clinical Oncology, vol. 145, no. 9, pp. 2241-2250.
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© 2019, The Author(s). Purpose: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. Methods: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. Results: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. Conclusion: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.

Tavakoli, J, Gascooke, J, Xie, N, Tang, BZ & Tang, Y 2019, 'Enlightening Freeze–Thaw Process of Physically Cross-Linked Poly(vinyl alcohol) Hydrogels by Aggregation-Induced Emission Fluorogens', ACS Applied Polymer Materials, vol. 1, no. 6, pp. 1390-1398.
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Tavakoli, J, Laisak, E, Gao, M & Tang, Y 2019, 'AIEgen quantitatively monitoring the release of Ca2+ during swelling and degradation process in alginate hydrogels', Materials Science and Engineering: C, vol. 104, pp. 109951-109951.
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© 2019 Elsevier B.V. Alginate-based hydrogels are extensively used for different biomedical applications. While the swelling and degradation of alginate-based hydrogels affect their structure-property relationship, many studies employed gravimetric analysis to characterize the swelling-degradation process. Accurate or not, this traditional method is difficult to be consistently performed with minimized errors, especially at the late stage of the process. For the first time, this study introduced a reliable, accurate and cost-effective method to minimize the human-sourced errors during repetitive measurement of swelling and degradation of alginate-based hydrogels based on Ca2+ specified aggregation-induced emission fluorogen technology. This study provides an approach for characterization of different properties of alginate-based tissue engineered scaffolds. The established relation between the changes in released Ca2+ into the swelling environment and its relative intensity identified the potential application of the proposed method for prediction of swelling and degradation behaviour in alginate-based hydrogels.

Tavakoli, J, Zhang, H-P, Tang, BZ & Tang, Y 2019, 'Aggregation-induced emission lights up the swelling process: a new technique for swelling characterisation of hydrogels', Materials Chemistry Frontiers, vol. 3, no. 4, pp. 664-667.
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The characterization of the swelling properties in hydrogels suffers uncertainty due to the limitations that occur during weight change measurement.

Thoms, JAI, Beck, D & Pimanda, JE 2019, 'Transcriptional networks in acute myeloid leukemia', Genes, Chromosomes and Cancer, vol. 58, no. 12, pp. 859-874.
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AbstractAcute myeloid leukemia (AML) is a complex disease characterized by a diverse range of recurrent molecular aberrations that occur in many different combinations. Components of transcriptional networks are a common target of these aberrations, leading to network‐wide changes and deployment of novel or developmentally inappropriate transcriptional programs. Genome‐wide techniques are beginning to reveal the full complexity of normal hematopoietic stem cell transcriptional networks and the extent to which they are deregulated in AML, and new understandings of the mechanisms by which AML cells maintain self‐renewal and block differentiation are starting to emerge. The hope is that increased understanding of the network architecture in AML will lead to identification of key oncogenic dependencies that are downstream of multiple network aberrations, and that this knowledge will be translated into new therapies that target these dependencies. Here, we review the current state of knowledge of network perturbation in AML with a focus on major mechanisms of transcription factor dysregulation, including mutation, translocation, and transcriptional dysregulation, and discuss how these perturbations propagate across transcriptional networks. We will also review emerging mechanisms of network disruption, and briefly discuss how increased knowledge of network disruption is already being used to develop new therapies.

Thomson, S, Lu, W, Zreiqat, H, Li, JJ, Tetsworth, K & Al Muderis, M 2019, 'Proximal Bone Remodeling in Lower Limb Amputees Reconstructed With an Osseointegrated Prosthesis', Journal of Orthopaedic Research, vol. 37, no. 12, pp. 2524-2530.
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ABSTRACTMobility outcomes and changes in bone mineral density (BMD) of the spine and femoral necks in response to unilateral osseointegrated implants was investigated over a 3‐year period. A total of 48 unilateral amputees who received an osseointegrated implant, comprising 33 trans‐femoral amputees (TFA) and 15 trans‐tibial amputees (TTA), underwent dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (L2–L4) and femoral necks at baseline, 1‐, and 3‐years follow‐ups. Mobility outcomes, including the Six‐Minute‐Walk Test (6MWT) and Timed‐Up‐and‐Go (TUG), were measured before surgery, at 1 year, and more than 2 years following the osseointegration procedure. We observed a significant increase (p < 0.05) in Z‐score values in the femoral neck of the amputated side in TFA patients without a femoral neck lag screw at the 1‐ and 3‐year follow‐ups, as well as in TFA patients with a lag screw present at 3‐year follow‐up. The BMD at 1‐year follow‐up was found to be positively correlated with pre‐surgery 6MWT values in patients who were mobile using a traditional socket prosthesis before receiving an osseointegrated implant. These results suggest that osseointegrated implants induce a physiological response in the femoral neck of recipients and appear to be evidence of restored biomechanical loading in the proximal femur. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2524–2530, 2019

Tran, HV, Tran‐Le, PT & Nguyen, TV 2019, 'Treatment of vocal cord paralysis by autologous fat injection: Our experience with 41 patients', Clinical Otolaryngology, vol. 44, no. 1, pp. 76-80.
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Wang, B, Xing, D, Li, JJ, Zhu, Y, Dong, S & Zhao, B 2019, 'Lateral or medial approach for valgus knee in total knee arthroplasty - which one is better? A systematic review', Journal of International Medical Research, vol. 47, no. 11, pp. 5400-5413.
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ObjectiveTo identify whether the medial or lateral approach is superior for patients with valgus knees undergoing primary total knee arthroplasty (TKA).MethodsStudies evaluating the 2 approaches were sourced from the PUBMED, EMBASE, Web of Science, and OVID databases. The quality of included studies was assessed using a modified quality evaluation method, and differences between approaches were systematically reviewed.ResultsSeventeen observational studies were included. The studies were published between 1991 and 2016, and included 5 retrospective studies and 12 prospective studies. Sixteen evaluation methods for the study outcomes were identified. Twelve and eight complication types were identified by studies reporting the lateral and medial approaches for valgus knee, respectively. Several studies showed that pain scores and knee function were superior using a lateral approach.ConclusionThe lateral approach (combined with a tibial tubercle osteotomy or proximal quadriceps snip) was more useful and safer than the medial approach in the treatment of severe uncorrectable valgus knee deformity in patients undergoing TKA. Most of the available evidence supports the use of a lateral approach provided that the surgeon is familiar with the pathological anatomy of the valgus knee.

Wang, J, Tavakoli, J & Tang, Y 2019, 'Bacterial cellulose production, properties and applications with different culture methods – A review', Carbohydrate Polymers, vol. 219, pp. 63-76.
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© 2019 Elsevier Ltd Bacterial cellulose (BC) is an organic compound produced by certain types of bacteria. In natural habitats, the majority of bacteria synthesize extracellular polysaccharides, such as cellulose, which form protective envelopes around the cells. Many methods are currently being investigated to enhance cellulose growth. The various celluloses produced by different bacteria possess different morphologies, structures, properties, and applications. However, the literature lacks a comprehensive review of the different methods of BC production, which are critical to BC properties and their final applications. The aims of this review are to provide an overview of the production of BC from different culture methods, to analyze the characteristics of particular BC productions, to indicate existing problems associated with different methods, and to choose suitable culture approaches for BC applications in different fields. The main goals for future studies have also been discussed here.

Winter, M, Cai, Z, Winkler, K, Georgiou, K, Inglis, D, Lavranos, T, Rezaei, M, Warkiani, M & Thierry, B 2019, 'Circulating tumour cell RNA characterisation from colorectal cancer patient blood after inertial microfluidic enrichment', MethodsX, vol. 6, pp. 1512-1520.
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© 2019 The Authors The detection and molecular analysis of circulating tumour cells (CTCs) potentially provides a significant insight to the characterisation of disease, stage of progression and therapeutic options for cancer patients. Following on from the protocol by Warkiani et al. 2016, which describes a method of enriching CTCs from cancer patient blood with inertial microfluidics, we describe a method to measure the CTC RNA expression in the enriched fraction using droplet digital PCR and compare transcript detection with and without RNA pre-amplification. • Inertial microfluidics combined with droplet digital PCR is advantageous as it allows for CTC enrichment and subsequent RNA analysis from patient blood. This allows for patient tumour analysis with increased sensitivity and precision compared to quantitative Real Time PCR and enables the direct quantification of nucleic acids without the need for tumour biopsy. • This method demonstrates an efficient approach providing important insights into the analysis of colorectal cancer patients’ CTCs using a specific gene subset or biomarkers, an approach that may be tailored to tumour type or expanded to larger panels.

Xu, X, Zhou, Z, Liu, Y, Wen, S, Guo, Z, Gao, L & Wang, F 2019, 'Optimising passivation shell thickness of single upconversion nanoparticles using a time-resolved spectrometer', APL Photonics, vol. 4, no. 2, pp. 026104-026104.
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© 2019 Author(s). Lanthanide-doped upconversion nanoparticles (UCNPs) are the most efficient multi-photon probe that can be used for deep tissue bio-imaging, fluorescence microscopy, and single molecule sensing applications. Passivating UCNPs with inert shell has been demonstrated to be an effective method to significantly enhance their brightness. However, this method also increases the overall size of the nanoparticles, which limited their cellular applications. Current reports to optimise the thickness of the shell are based on the spectrum measurement of ensembles of UCNPs, which are less quantitative. The characterisation of single UCNPs would be desirable, but is limited by the sensitivity of conventional spectrometers. We developed an optical filter-based spectrometer coupled to a laser scanning microscopy system and achieved a high degree of sensitivity - seven times more than the traditional amount. Through highly controlled syntheses of a range Yb 3+ and Tm 3+ doped UCNPs with different shell thickness, quantitative characterization of the emission intensity and lifetime on single UCNPs were comprehensively studied using a home-made optical system. We found that the optimal shell thickness was 6.3 nm. We further demonstrated that the system was sensitive enough to measure the time-resolved spectrum from a single UCNP, which is significantly useful for a comprehensive study of the energy transfer process of UCNPs.

Zhang, H-P, Han, W, Tavakoli, J, Zhang, Y-P, Lin, X, Lu, X, Ma, Y & Tang, Y 2019, 'Understanding interfacial interactions of polydopamine and glass fiber and their enhancement mechanisms in epoxy-based laminates', Composites Part A: Applied Science and Manufacturing, vol. 116, pp. 62-71.
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Interfacial behavior greatly affects the bulk mechanical performance of fiber reinforced polymer laminates. In this study, polydopamine modified glass fiber was used to fabricate short glass fiber reinforced polymer (GFRP) laminates. The interactions between glass fiber and polydopamine were studied experimentally and theoretically by X-ray photoelectron spectroscopy (XPS) and density functional calculation respectively. Theoretical study clearly demonstrated that electronic interactions existed between polydopamine and glass fiber, indicating the hydrogen bonds/chemical interactions between them that were also demonstrated by XPS results. The enhanced interfacial interaction significantly benefited GFRP laminates, as demonstrated by various mechanical characterizations such as single fiber pull-out and Mode I interlaminar fracture toughness tests. Combining the theoretical and experimental studies indicated that polydopamine modification of glass fiber could be an easy and effective way to significantly improve the interfacial interactions between glass fiber and matrix and enhance the mechanical properties of GFRP laminates.

Zhang, X, Xiang, X, Wang, Y, Ding, G, Xu, X & Yang, Z 2019, 'A Heterogeneous Integrated MEMS Inertial Switch With Compliant Cantilevers Fixed Electrode and Electrostatic Locking to Realize Stable On-State', Journal of Microelectromechanical Systems, vol. 28, no. 6, pp. 977-986.
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© 1992-2012 IEEE. A novel heterogeneous integrated inertial micro-switch has been designed with adjustable acceleration threshold and a stable 'on'-state due to a predefined bias voltage. The bias voltage is applied onto the large-area parallel-plate electrodes, which endows the movable proof-mass with electrostatic forces. With an external excitation acceleration, the movable electrode moves to the fixed electrode and it can be locked by the electrostatic force onto the compliant electrical contacts, which are composed of micro-cantilever array to eliminate the contact rebound during electrostatic pull-in process. Both the dynamic response of the proof-mass and the relationship between the bias voltage and the inertial excitation acceleration were analyzed using theoretical model and finite element simulation. A unique heterogeneous integration process including both the silicon-based and non-silicon surface micromachining processes was adopted to fabricate the switch. The tests using a standard dropping hammer system demonstrated that the switch could keep a stable switch-on at the 57 g excitation acceleration and 38 V bias voltage. As wide as 52% adjustment range of the acceleration threshold was obtained when the applied bias voltage was from 38 V to 44 V. The tested relationship between the bias voltage and the external acceleration was very consistent with the simulated relationship. [2019-0038].

Alarkawi, D, Bliuc, D, Tran, T, Ahmed, LA, Emaus, N, Nguyen, TV, Eisman, JA & Center, JR 1970, 'IMPACT OF OSTEOPOROTIC FRACTURE TYPE AND SUBSEQUENT FRACTURE ON MORTALITY IN TROMSO, NORWAY', OSTEOPOROSIS INTERNATIONAL, IOF-Regional 7th Asia-Pacific Osteoporosis Conference, SPRINGER LONDON LTD, Sydney, AUSTRALIA, pp. S105-S106.

Bai, X, Feng, X, Ni, J, Beretov, J, Deng, J, Zhu, Y, Graham, P & Li, Y 1970, 'Abstract 4754: CHTOP is a novel therapeutic target for chemoresistant epithelial ovarian cancer therapy', Experimental and Molecular Therapeutics, Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA, American Association for Cancer Research.
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Deng, W, Chen, W, Clement, S, Guller, A, Zhao, Z, Engel, A & Goldys, EM 1970, 'Controlled drug release from a X-ray triggered liposomal delivery platform for colorectal cancer treatment (Conference Presentation)', Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVIII, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVIII, SPIE.
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Ding, L, Fardjahromi, MA, Bazaz, SR, Asadnia, M, Vesey, G & Warkiani, ME 1970, 'A 3D printed modular microfluidic device for large scale cell harvesting from bioreactors', 23rd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2019, pp. 604-605.
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Mesenchymal stem cell (MSC) therapy is a research hotspot nowadays due to its multiple therapeutic effects and novel application in diseases treatments. However, the current industrial technologies for their culture and harvesting are labour-intensive, time-consuming and very expensive. Herein, we presented a 3D printed modular microfluidic system consisting of micromixers and spiral channel units for cell harvesting which will greatly reduce the time and cost needed for cell harvesting, washing and cultivation. At the meantime, this system is automatic, making it compatible to the current Good Manufacturing Practice (cGMP).

Hadgraft, R, Francis, B, Lawson, J, Jarman, R & Araci, JT 1970, 'Summer studios - Lessons from a 'small bet' in student-led learning', Proceedings of the 46th SEFI Annual Conference 2018: Creativity, Innovation and Entrepreneurship for Engineering Education Excellence, SEFI Annual Conference, SEDI, Copenhagen, Denmark, pp. 815-823.

Kulasinghe, A, Kapeleris, J, Kenny, L, Warkiani, M, Vela, I, Thiery, J-P, O'Byrne, K & Punyadeera, C 1970, 'Abstract 1333: Isolation, characterization and expansion of circulating tumor cells in solid cancers', Cancer Research, American Association for Cancer Research (AACR), pp. 1333-1333.
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Abstract Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the 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. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=300) and lung cancer (n=80) patients were recruited to investigate the prognostic role of CTCs. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, inertial microfluidics) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (PFS) (Hazard ratio [HR]: 4.946; 95% confidence internal [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Recently, we have preliminary data that suggests that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit ...

Ngo, CQ, Chai, R, Nguyen, TV, Jones, TW & Nguyen, HT 1970, 'Nocturnal Hypoglycemia Detection using Optimal Bayesian Algorithm in an EEG Spectral Moments Based System', 2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2019 41st Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), IEEE, Berlin, Germany, pp. 5439-5442.
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This paper presents a hypoglycemia detection system using electroencephalogram (EEG) spectral moments from 8 patients with type 1 diabetes (T1D) at night time. Four channels (C3, C4, O1, and O2) associated with glycemic episodes were analyzed. Spectral moments were applied to EEG signal and its corresponding speed and acceleration. During hypoglycemia, theta moments increased significantly (P<; 0.001) and alpha moments decreased significantly (P<; 0.001). The system used an optimal Bayesian neural network for detecting hypoglycemic episodes. Based on the optimal network architecture with the highest log evidence, the final classification results for the test set were 79% and 51% in sensitivity and specificity, respectively. Essentially, the estimated blood glucose profiles correlated significantly to actual values in the test set (P<; 0.0001). Using error grid analysis, 93% of the estimated values were clinically acceptable.

Nguyen, TV, Tran, TS, Center, JR & Eisman, JA 1970, 'Small individual-level increase in bone mineral density translated into substantial population-level decrease in fracture incidence: revisiting Goeffrey Rose's axiom', JOURNAL OF BONE AND MINERAL RESEARCH, Annual Meeting of the American-Society-for-Bone-and Mineral Research, WILEY, Orlando, FL, pp. 250-250.

Si, L, Eisman, JA, Winzenberg, T, Sanders, KM, Center, JR, Nguyen, TV, Chen, M & Palmer, AJ 1970, 'RESIDUAL LIFETIME FRACTURE RISKS AND YEARS OF LIFE LOSS DUE TO OSTEOPOROSIS IN THE AUSTRALIAN POPULATION: AN APPLICATION OF AN OS'T'EOPOROSIS HEALTH ECONOMIC MODEL', OSTEOPOROSIS INTERNATIONAL, World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO), SPRINGER LONDON LTD, Paris, FRANCE, pp. S306-S307.

Tran, TS, Bliuc, D, Hansen, L, Abrahamsen, B, van den Bergh, J, Eisman, JA, van Geel, T, Geusens, P, Vestergaard, P, Nguyen, TV & Center, JR 1970, 'Multimorbidity and long-term mortality following a specific fragility fracture: Latent class analysis of a nationwide population-based cohort', JOURNAL OF BONE AND MINERAL RESEARCH, Annual Meeting of the American-Society-for-Bone-and Mineral Research, WILEY, Orlando, FL, pp. 385-386.

Tran, TS, Bliuc, D, O'Donoghue, S, Hansen, L, Abrahamsen, B, van den Bergh, J, van Geel, T, Geusens, P, Vestergaard, P, Nguyen, TV & Center, JR 1970, 'Trajectories to subsequent admissions and mortality following a specific fragility fracture: A nationwide population-based follow-up study', JOURNAL OF BONE AND MINERAL RESEARCH, Annual Meeting of the American-Society-for-Bone-and Mineral Research, WILEY, Orlando, FL, pp. 386-386.

Vranken, L, Wyers, CE, Van der Velde, RY, De Bruin, IJA, Van den Bergh, JPW, Janzing, HMJ, Kaarsemakers, S, Eisman, JA, Center, JR, Nguyen, TV, Bliuc, D, Tran, T & Geusens, PPMM 1970, 'The imminent subsequent fracture risk in patients with a recent fracture at the FLS is mainly associated with falls - a 3 year prospective cohort study.', JOURNAL OF BONE AND MINERAL RESEARCH, Annual Meeting of the American-Society-for-Bone-and Mineral Research, WILEY, Orlando, FL, pp. 181-182.

Wahlroos, S, Wilkinson, A, Gallego-Ortega, D, Febbraio, M & Lim, E 1970, 'Abstract P6-21-05: Concurrent exercise and chemotherapy in preclinical breast cancer models', Cancer Research, Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas, American Association for Cancer Research (AACR), San Antonio, TX.
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Abstract The benefits of exercise following a cancer diagnosis is increasingly recognized. Increased physical activity is associated with reduced breast cancer recurrence and breast cancer specific mortality. However, the mechanisms underpinning this effect are still under investigation. The role of exercise as an adjunct to systemic therapy for breast cancer remains unclear. We hypothesize that exercise may exert an anti-tumor effect and a change in tumor immune cell infiltration. Methods We evaluated the effect of exercise alone and in combination with chemotherapy in preclinical patient-derived TNBC xenografts (PDX) established in Nude mice and PyMT mouse tumor models. Mice were individually housed in boxes equipped with running wheels and randomized to 1) clamped wheels (sedentary controls), 2) doxorubicin (Dox, 2mg/kg/week), 3) exercise (Ex) and 4) Ex + Dox. Daily distance run was measured. One week after randomization (acclimatization period), the intervention was commenced. Body composition was measured at randomization and at end point. Tumors were harvested after 5 weeks of intervention or at ethical endpoint. Tumor immune infiltrates were analyzed, and transcriptomic analysis performed. Results In the TNBC PDX model, there was no difference in tumor volume at randomization (p=0.96), or cumulative distance run after 1 week of acclimatization to the running wheel (p=0.47). At 5 weeks, Ex alone significantly reduced tumor growth rate compared with controls (relative reduction 10%, p=0.025). There was no difference between the other interventions. Mice randomized to Ex + Dox ran a shorter cumulative distance over 5 weeks compared with Ex alone (103.6 ± 16.2km vs 168.8 ±23km, p=0.028). There was no correlation between distance run and tumor volume in either of the treatment c...

Warkiani, ME 1970, 'Label-free Cell Sorting Using Inertial Microfluidics', 2019 13TH IEEE INTERNATIONAL CONFERENCE ON NANO/MOLECULAR MEDICINE & ENGINEERING (IEEE-NANOMED 2019), 13th IEEE International Conference on Nano/Molecular Medicine and Engineering (IEEE NANOMED), IEEE, SOUTH KOREA, Gwangju, pp. 52-53.

Warkiani, ME, Moloudi, R, Oh, S & Naing, MW 1970, 'Inertial-based Microcarrier-cell retention in bioprocessing', Cytotherapy, Elsevier BV, Australia, pp. e4-e5.
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Aksoy, YA, Chen, W, Goldys, EM & Deng, W 2019, 'Spatial and temporal control of CRISPR/Cas9-mediated gene editing delivered via a light-triggered liposome system', Cold Spring Harbor Laboratory.
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Casares-Arias, J, Gonzalez, MU, San Paulo, A, Ventimiglia, LN, Sadler, JBA, Miguez, DG, Labat-de-Hoz, L, Rubio-Ramos, A, Rangel, L, Bernabé-Rubio, M, Fernández-Barrera, J, Correas, I, Martín-Serrano, J & Alonso, MA 2019, 'Midbody remnant inheritance is regulated by the ESCRT subunit CHMP4C', Cold Spring Harbor Laboratory.
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Du, Z, Gupta, A, Clarke, C, Cappadana, M, Clases, D, Liu, D, Yang, Z, Doble, P, Price, B & Xu, X 2019, 'Porous upconversion nanostructures as bimodal biomedical imaging contrast agents', Cold Spring Harbor Laboratory.
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Su, QP, Zhao, ZW, Meng, L, Ding, M, Zhang, W, Li, Y, Liu, M, Li, R, Gao, Y-Q, Xie, XS & Sun, Y 2019, 'CTCF-mediated Chromatin Structures Dictate the Spatio-temporal Propagation of Replication Foci', Cold Spring Harbor Laboratory.
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