Publications

Kashaninejad, N, Yaghoobi, M, Pourhassan‐Moghaddam, M, Bazaz, SR, Jin, D & Warkiani, ME 2020, 'Biological Diagnosis Based on Microfluidics and Nanotechnology' in Nanotechnology for Microfluidics, Wiley, USA, pp. 211-238.
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This chapter discusses the integrations of the nanoparticles with microfluidic platforms for biological diagnosis. It evaluates the applications of two emerging formats of microfluidics, digital microfluidics and paper-based microfluidics, for biological diagnosis. Microfluidics is an enabling technology that can be employed in numerous biological studies because of its high-throughput, precision, sample efficiency, portability, and low-cost production. Many investigations are currently underway concerning the imaging of the biological molecules and cellular components using fluorescent nanomaterials. The main problems associated with fluorescence methods can be addressed by using semiconductor quantum dots (Qdots) possessing unique optical properties. Their surface is capable of being modified with various biomolecules making them selective to different analytes. In the bioanalysis with Qdots, these nanoparticles are conjugated with biomolecules for the detection of analytes. In the case of a disease, the target analytes can be viruses, antigens, and cancer biomarkers, whose concentration is also of interest.

Lawson, J, Zucker, I & Hadgraft, R 2020, 'Students Take over as Curriculum Co-designers and Facilitators: A Case Study from Engineering' in Applied Degree Education and the Future of Work, Springer Singapore, Singapore, pp. 181-194.
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© 2020, Springer Nature Singapore Pte Ltd. The Faculty of Engineering and Information Technology (FEIT) at the University of Technology Sydney is taking courageous and creative steps in its teaching and learning. FEIT is developing landmark innovations to transform the curriculum to better engage with students and respond to the demands of a rapidly changing future workforce. For example, drawing inspiration from design studios, many programs now contain engineering studios to engage students in authentic and complex problems drawn from professional practice. This chapter reports on the first iteration of ‘Summer Studios’, an innovative subject that involved senior undergraduate students designing and facilitating studios for fellow students.

Tekmen-Araci, Y, Francis, B, Hadgraft, R, Zucker, I, Lawson, J & Jarman, R 2020, 'Changing the Mindset of Engineering Educators to Teach Design Studios' in Applied Degree Education and the Future of Work, Springer Singapore, pp. 169-179.
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The Faculty of Engineering and Information Technology at the University of Technology Sydney recruited and established a ‘Learning and Teaching Design’ team. One of the primary aims of this team was to change the mindset of engineering academics to deliver a curriculum that produced More Innovative Design-Abled Students and Staff (MIDAS). To model what an inspiring pedagogy might look like, a set of short, intensive, summer school offerings were designed and delivered. These ‘MIDAS Summer Studios’ aimed to strategically shift the culture of education and to revolutionise how students learn engineering and information technology. In order to confirm that each of the MIDAS Summer Studios and their studio leaders delivered a calibrated student learning experience, a series of training workshops were delivered to ensure the language used by studio facilitators remained consistent. During these workshops, the participants were encouraged to adopt some values and principles. This study reports how these values have been effective in transforming engineering education in one Australian university.

Tran, PA, Sarker, A, Tran, N, Jeffery, C, Rifai, A & Fox, K 2020, 'Coatings on metallic implants for biomedical applications' in Metallic Biomaterials Processing and Medical Device Manufacturing, Elsevier, pp. 359-385.
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Aboulkheyr Es, H, Zhand, S, Thiery, JP & Warkiani, ME 2020, 'Pirfenidone reduces immune-suppressive capacity of cancer-associated fibroblasts through targeting CCL17 and TNF-beta', Integrative Biology, vol. 12, no. 7, pp. 188-197.
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Abstract Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in carcinoma cells. The cancer-associated fibroblasts (CAFs) play a crucial role in regulating and rewiring TME to enhance their immune suppressive function and to favor the invasion of the malignant cells. Tumor progression may be retarded by targeting CAFs in the TME. Various studies highlighted the ability of targeting CAF with pirfenidone (PFD), leading to increased efficacy of chemotherapy. However, its potential for the reduction of immune-suppression capacity of CAFs remains to be elusive. Here, we assessed the effect of PFD on the expression of PD-L1 on CAF cells. Besides migration inhibitory effects of PFD on CAFs, the expression level of PD-L1 reduced in CAFs after treatment with PFD. The downstream analysis of released cytokines from CAFs showed that PFD significantly dropped the secretion of CCL17 and TNF-β, where a positive association between PFD-targeted proteins and PD-L1 was observed. These data suggest that the treatment of CAF within TME through the PFD may reduce the acquisition of CAF-mediated invasive and immune-suppressive capacity of breast carcinoma cells.

Aksoy, YA, Deng, W, Stoddart, J, Chung, R, Guillemin, G, Cole, NJ, Neely, GG & Hesselson, D 2020, '“STRESSED OUT”: The role of FUS and TDP-43 in amyotrophic lateral sclerosis', The International Journal of Biochemistry & Cell Biology, vol. 126, pp. 105821-105821.
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Aksoy, YA, Yang, B, Chen, W, Hung, T, Kuchel, RP, Zammit, NW, Grey, ST, Goldys, EM & Deng, W 2020, 'Spatial and Temporal Control of CRISPR-Cas9-Mediated Gene Editing Delivered via a Light-Triggered Liposome System', ACS Applied Materials & Interfaces, vol. 12, no. 47, pp. 52433-52444.
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Alajlouni, D, Bliuc, D, Tran, T, Eisman, JA, Nguyen, TV & Center, JR 2020, 'Decline in Muscle Strength and Performance Predicts Fracture Risk in Elderly Women and Men', The Journal of Clinical Endocrinology & Metabolism, vol. 105, no. 9, pp. e3363-e3373.
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Abstract Context Muscle strength and performance are associated with fractures. However, the contribution of their rate of decline is unclear. Objective To assess the independent contribution of the rate of decline in muscle strength and performance to fracture risk. Design, Setting, and Participants Community-dwelling women (n = 811) and men (n = 440) aged 60 years or older from the prospective Dubbo Osteoporosis Epidemiology Study followed from 2000 to 2018 for incident fracture. Clinical data, appendicular lean mass/height2 (ht)2, bone mineral density, quadricep strength/ht (QS), timed get-up-and-go (TGUG), 5 times repeated sit-to-stand (5xSTS), and gait speed (GS) measured biennially. Rates of decline in muscle parameters were calculated using ordinary least squares regression and fracture risk was assessed using Cox’s models. Main Outcome Incident low-trauma fracture ascertained by x-ray report. Results Apart from lean mass in women, all muscle parameters declined over time. Greater rates of decline in physical performance were associated with increased fracture risk in women (Hazard ratios [HRs] ranging from 2.1 (95% CI: 1.5–2.9) for GS to 2.7 (95% CI: 1.9–3.6) for 5xSTS, while in men only the decline in GS was associated with fracture risk (HR: 3.4 [95% CI: 1.8–6.3]). Baseline performance and strength were also ass...

Alajlouni, D, Tran, T, Bliuc, D, Blank, RD, Cawthon, PM, Orwoll, ES & Center, JR 2020, 'Muscle Strength and Physical Performance Improve Fracture Risk Prediction Beyond Garvan and FRAX: The Osteoporotic Fractures in Men (MrOS) Study', Journal of Bone and Mineral Research, vol. 37, no. 3, pp. 411-419.
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ABSTRACT Muscle strength and physical performance are associated with fracture risk in men. However, it is not known whether these measurements enhance fracture prediction beyond Garvan and FRAX tools. A total of 5665 community-dwelling men, aged ≥65 years, from the Osteoporotic Fractures in Men (MrOS) Study, who had data on muscle strength (grip strength) and physical performance (gait speed and chair stand tests), were followed from 2000 to 2019 for any fracture, major osteoporotic fracture (MOF), initial hip, and any hip fracture. The contributions to different fracture outcomes were assessed using Cox's proportional hazard models. Tool-specific analysis approaches and outcome definitions were used. The added predictive values of muscle strength and physical performance beyond Garvan and FRAX were assessed using categorical net reclassification improvement (NRI) and relative importance analyses. During a median follow-up of 13 (interquartile range 7–17) years, there were 1014 fractures, 536 MOFs, 215 initial hip, and 274 any hip fractures. Grip strength and chair stand improved prediction of any fracture (NRI for grip strength 3.9% and for chair stand 3.2%) and MOF (5.2% and 6.1%). Gait speed improved prediction of initial hip (5.7%) and any hip (7.0%) fracture. Combining grip strength and the relevant performance test further improved the models (5.7%, 8.9%, 9.4%, and 7.0% for any, MOF, initial, and any hip fractures, respectively). The improvements were predominantly driven by reclassification of those with fracture to higher risk categories. Apart from age and femoral neck bone mineral density, muscle strength and performance were ranked equal to or better than the other risk factors included in fracture models, including prior fractures, falls, smoking, alcohol, and glucocorticoid use. Muscle strength and performance measurements improved fracture risk prediction in men beyond Garvan and FRAX. They ...

Alajlouni, DA, Bliuc, D, Tran, TS, Blank, RD, Cawthon, PM, Ensrud, KE, Lane, NE, Orwoll, ES, Cauley, JA & Center, JR 2020, 'Muscle Strength and Physical Performance Are Associated With Risk of Postfracture Mortality But Not Subsequent Fracture in Men', Journal of Bone and Mineral Research, vol. 37, no. 8, pp. 1571-1579.
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ABSTRACT Muscle strength and physical performance are associated with incident fractures and mortality. However, their role in the risk of subsequent fracture and postfracture mortality is not clear. We assessed the association between muscle strength (grip strength) and performance (gait speed and chair stands time) and the risk of subsequent fracture and mortality in 830 men with low-trauma index fracture, who participated in the Osteoporotic Fractures in Men (MrOS) USA Study and had their index measurements assessed within 5 years prior to the index fracture. The annual decline in muscle strength and performance following index fracture, estimated using linear mixed-effects regression, was also examined in relation to mortality. The associations were assessed using Cox proportional hazards models adjusted for age, femoral neck bone mineral density (FN BMD), prior fractures, falls, body mass index (BMI), index fracture site, lifestyle factors, and comorbidities. Over a median follow-up of 3.7 (interquartile range [IQR], 1.3–8.1) years from index fracture to subsequent fracture, 201 (24%) men had a subsequent fracture and over 5.1 (IQR, 1.8–9.6) years to death, and 536 (65%) men died. Index measurements were not associated with subsequent fracture (hazard ratios [HRs] ranging from 0.97 to 1.07). However, they were associated with postfracture mortality. HR (95% confidence interval [CI]) per 1 standard deviation (1-SD) decrement in grip strength: HR 1.12 (95% CI, 1.01–1.25) and gait speed: HR 1.14 (95% CI, 1.02–1.27), and 1-SD increment in chair stands time: HR 1.08 (95% CI, 0.97–1.21). Greater annual declines in these measurements were associated with higher mortality risk, independent of the index values and other covariates. HR (95% CI) per 1-SD annual decrement in change in grip strength: HR 1.15 (95% CI, 1.01–1.33) and in gait speed: HR 1.38 (95% CI, 1.13–1.68), and 1-SD annual increment in chair stan...

Alarkawi, D, Bliuc, D, Tran, T, Ahmed, LA, Emaus, N, Bjørnerem, A, Jørgensen, L, Christoffersen, T, Eisman, JA & Center, JR 2020, 'Impact of osteoporotic fracture type and subsequent fracture on mortality: the Tromsø Study', Osteoporosis International, vol. 31, no. 1, pp. 119-130.
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UNLABELLED: Less is known about the impact of non-hip non-vertebral fractures (NHNV) on early death. This study demonstrated increased risk of dying following hip and NHNV fractures which was further increased by a subsequent fracture. This highlights the importance of early intervention to prevent both initial and subsequent fractures and improve survival. INTRODUCTION: Osteoporotic fractures are a major health concern. Limited evidence exists on their impact on mortality in ageing populations. This study examined the contribution of initial fracture type and subsequent fracture on mortality in a Norwegian population that has one of the highest rates of fractures. METHODS: The Tromsø Study is a prospective population-based cohort in Norway. Women and men aged 50+ years were followed from 1994 to 2010. All incident hip and non-hip non-vertebral (NHNV) fractures were registered. NHNV fractures were classified as either proximal or distal. Information on self-reported co-morbidities, lifestyle factors, general health and education level was collected. Multivariable Cox models were used to quantify mortality risk with incident and subsequent fractures analysed as time-dependent variables. RESULTS: Of 5214 women and 4620 men, 1549 (30%) and 504 (11%) sustained a fracture, followed by 589 (38%) and 254 (51%) deaths over 10,523 and 2821 person-years, respectively. There were 403 (26%) subsequent fractures in women and 68 (13%) in men. Hip fracture was associated with a two-fold increase in mortality risk (HR 2.05, 95% CI 1.73-2.42 in women and 2.49, 95% CI 2.00-3.11 in men). Proximal NHNV fractures were associated with 49% and 81% increased mortality risk in women and men (HR 1.49, 95% CI 1.21-1.84 and 1.81, 95% CI 1.37-2.41), respectively. Distal NHNV fractures were not associated with mortality. Subsequent fracture was associated with 89% and 77% increased mortality risk in women and men (HR 1.89, 95% CI 1.52-2.35 and 1.77, 95% CI 1.16-2.71), respectively. ...

Ali, A, Syed, SM, Jamaluddin, MFB, Colino-Sanguino, Y, Gallego-Ortega, D & Tanwar, PS 2020, 'Cell Lineage Tracing Identifies Hormone-Regulated and Wnt-Responsive Vaginal Epithelial Stem Cells', Cell Reports, vol. 30, no. 5, pp. 1463-1477.e7.
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Al-Karagoly, MKU, Ayani, M-B, Mamourian, M & Razavi Bazaz, S 2020, 'Experimental parametric study of a deep groove within a pin fin arrays regarding fin thermal resistance', International Communications in Heat and Mass Transfer, vol. 115, pp. 104615-104615.
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Amin, DB, Tavakoli, J, Freeman, BJC & Costi, JJ 2020, 'Mechanisms of Failure Following Simulated Repetitive Lifting', Spine, vol. 45, no. 6, pp. 357-367.
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Study Design. A biomechanical analysis correlating internal disc strains and tissue damage during simulated repetitive lifting. Objective. To understand the failure modes during simulated safe and unsafe repetitive lifting. Summary of Background Data. Repetitive lifting has been shown to lead to lumbar disc herniation (LDH). In vitro studies have developed a qualitative understanding of the effect of repetitive loading on LDH. However, no studies have measured internal disc strains and subsequently correlated these with disc damage. Methods. Thirty human cadaver lumbar functional spinal units were subjected to an equivalent of 1 year of simulated repetitive lifting under safe and unsafe levels of compression, in combination with flexion (13–15°), and right axial rotation (2°) for 20,000 cycles or until failure. Safe or unsafe lifting were applied as a compressive load to mimic holding a 20 kg weight either close to, or at arm's length, from the body, respectively. Maximum shear strains (MSS) were measured, and disc damage scores were determined in nine regions from axial post-test magnetic resonance imaging (MRI) and macroscopic images. Results. Twenty percent of specimens in the safe lifting group failed before 20,000 cycles due to endplate failure, compared with 67% in the unsafe group. Over half of the specimens in the safe lifting group failed via either disc protrusion or LDH, compared with only 20% via protrusion ...

Asadian, S, Mirzaei, H, Kalantari, BA, Davarpanah, MR, Mohamadi, M, Shpichka, A, Nasehi, L, Es, HA, Timashev, P, Najimi, M, Gheibi, N, Hassan, M & Vosough, M 2020, 'β-radiating radionuclides in cancer treatment, novel insight into promising approach', Pharmacological Research, vol. 160, pp. 105070-105070.
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Asadniaye Fardjahromi, M, Razmjou, A, Vesey, G, Ejeian, F, Banerjee, B, Chandra Mukhopadhyay, S & Ebrahimi Warkiani, M 2020, 'Mussel inspired ZIF8 microcarriers: a new approach for large-scale production of stem cells', RSC Advances, vol. 10, no. 34, pp. 20118-20128.
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Mussel inspired ZIF8 microcarriers with high surface area, biocompatibility, and nanoscale surface roughness are applied to enhance mesenchymal stem cell attachment and proliferation in 3D cell culture.

Azadi, S, Aboulkheyr Es, H, Kulasinghe, A, Bordhan, P & Ebrahimi Warkiani, M 2020, 'Application of microfluidic technology in cancer research and therapy', Advances in Clinical Chemistry, vol. 99, pp. 193-235.
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Cancer is a heterogeneous disease that requires a multimodal approach to diagnose, manage and treat. A better understanding of the disease biology can lead to identification of novel diagnostic/prognostic biomarkers and the discovery of the novel therapeutics with the goal of improving patient outcomes. Employing advanced technologies can facilitate this, enabling better diagnostic and treatment for cancer patients. In this regard, microfluidic technology has emerged as a promising tool in the studies of cancer, including single cancer cell analysis, modeling angiogenesis and metastasis, drug screening and liquid biopsy. Microfluidic technologies have opened new ways to study tumors in the preclinical and clinical settings. In this chapter, we highlight novel application of this technology in area of fundamental, translational and clinical cancer research.

Bajan, S & Hutvagner, G 2020, 'RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs', Cells, vol. 9, no. 1, pp. 137-137.
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The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based oligonucleotide was United States Food and Drug Administration (FDA) approved. This promises to be a rapidly expanding market, as many emerging biopharmaceutical companies are developing RNA interference (RNAi)-based, and RNA-based antisense oligonucleotide therapies. However, miRNA therapeutics are noticeably absent. miRNAs are regulatory RNAs that regulate gene expression. In disease states, the expression of many miRNAs is measurably altered. The potential of miRNAs as therapies and therapeutic targets has long been discussed and in the context of a wide variety of infections and diseases. Despite the great number of studies identifying miRNAs as potential therapeutic targets, only a handful of miRNA-targeting drugs (mimics or inhibitors) have entered clinical trials. In this review, we will discuss whether the investment in finding potential miRNA therapeutic targets has yielded feasible and practicable results, the benefits and obstacles of miRNAs as therapeutic targets, and the potential future of the field.

Blazevski, A, Scheltema, MJ, Yuen, B, Masand, N, Nguyen, TV, Delprado, W, Shnier, R, Haynes, A-M, Cusick, T, Thompson, J & Stricker, P 2020, 'Oncological and Quality-of-life Outcomes Following Focal Irreversible Electroporation as Primary Treatment for Localised Prostate Cancer: A Biopsy-monitored Prospective Cohort', European Urology Oncology, vol. 3, no. 3, pp. 283-290.
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BACKGROUND:Focal irreversible electroporation (IRE) can be used to treat men with localised prostate cancer (PCa) with reduced impact on quality of life (QoL). OBJECTIVE:To assess oncological and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS:To report on a prospective database of patients undergoing primary IRE between February 2013 and August 2018. A minimum of 12-mo follow-up was available for 123 patients. Median follow-up was 36 mo (interquartile range [IQR] 24-52 mo). A total of 112 (91%) patients had National Comprehensive Cancer Network intermediate risk and 11 (9%) had low risk. A total of 12 (9.8%) had International Society of Urological Pathology (ISUP) grade 1, 88 (71.5%) had ISUP 2, and 23 (18.7%) had ISUP 3. INTERVENTION:Focal IRE ablation of PCa lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Follow-up involved serial prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI), and transperineal template mapping biopsy (TTMB) at 12 mo. Failure-free survival (FFS) was defined as progression to whole-gland or systemic treatment or metastasis/death. Functional outcomes were assessed. RESULTS AND LIMITATIONS:Median age was 68yr (IQR 62-73yr). Median preoperative PSA was 5.7ng/ml (IQR 3.8-8.0ng/ml). On post-treatment TTMB, in-field recurrence was present in 2.7-9.8% of patients. FFS at 3yr was 96.75%, metastasis-free survival 99%, and overall survival 100%. A total of 18 patients required salvage treatment (12 had repeat IRE; six had whole-gland treatment). The negative predictive value of mpMRI was 94% and sensitivity 40% for detecting in-field residual disease 6 mo after treatment. Among patients who returned questionnaires, 80/81 (98.8%) remained pad free and 40/53 (76%) had no change in erectile function. CONCLUSIONS:Focal IRE in select patients with localised clinically significant PCa has satisfactory short-term oncological outcomes with a minimal impact on patient QoL. PATIENT SUMMARY:In this study...

Bliuc, D, Tran, T, Adachi, JD, Atkins, GJ, Berger, C, van den Bergh, J, Cappai, R, Eisman, JA, van Geel, T, Geusens, P, Goltzman, D, Hanley, DA, Josse, R, Kaiser, S, Kovacs, CS, Langsetmo, L, Prior, JC, Nguyen, TV, Solomon, LB, Stapledon, C & Center, JR 2020, 'Reply to: The Association Between Cognitive Decline and Bone Loss and Fracture Risk Is Not Affected by Medication With Anticholinergic Effect', Journal of Bone and Mineral Research, vol. 37, no. 5, pp. 1075-1076.
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Carmichael, CL, Wang, J, Nguyen, T, Kolawole, O, Benyoucef, A, De Mazière, C, Milne, AR, Samuel, S, Gillinder, K, Hediyeh-zadeh, S, Vo, ANQ, Huang, Y, Knezevic, K, McInnes, WRL, Shields, BJ, Mitchell, H, Ritchie, ME, Lammens, T, Lintermans, B, Van Vlierberghe, P, Wong, NC, Haigh, K, Thoms, JAI, Toulmin, E, Curtis, DJ, Oxley, EP, Dickins, RA, Beck, D, Perkins, A, McCormack, MP, Davis, MJ, Berx, G, Zuber, J, Pimanda, JE, Kile, BT, Goossens, S & Haigh, JJ 2020, 'The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1', Blood, vol. 136, no. 8, pp. 957-973.
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Abstract Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML.

Casares-Arias, J, González, 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 2020, 'Midbody Remnant Inheritance Is Regulated by the ESCRT Subunit CHMP4C', iScience, vol. 23, no. 6, pp. 101244-101244.
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Castillo, L, Young, AIJ, Mawson, A, Schafranek, P, Steinmann, AM, Nessem, D, Parkin, A, Johns, A, Chou, A, Law, AMK, Lucas, MC, Murphy, KJ, Deng, N, Gallego-Ortega, D, Caldon, CE, Timpson, P, Pajic, M, Ormandy, CJ & Oakes, SR 2020, 'MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma', Oncogene, vol. 39, no. 8, pp. 1821-1829.
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AbstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC.

Chamoli, U, Umali, J, Kleuskens, MWA, Chepurin, D & Diwan, AD 2020, 'Morphological characteristics of the kangaroo lumbar intervertebral discs and comparison with other animal models used in spine research', European Spine Journal, vol. 29, no. 4, pp. 652-662.
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PURPOSE:Animal models are frequently used to elucidate pathomechanism and pathophysiology of various disorders of the human intervertebral disc (IVD) and also to develop therapeutic approaches. Here we report morphological characteristics of the kangaroo lumbar IVDs and compare them with other animal models used in spine research. METHODS:Twenty-five fresh-frozen cadaveric lumbar spines (T12-S1) derived from kangaroo carcases (Macropus giganteus) of undetermined age were first scanned in a C-Arm X-ray machine. A photograph of the axial section of the disc including a calibrated metric scale was also acquired. The digital radiographs and photographs were processed in ImageJ to determine the axial and sagittal plane dimensions for the whole disc (WD) and the nucleus pulposus (NP) and the mid-sagittal disc height for all the lumbar levels. RESULTS:Our results suggest that the L6-S1 IVD in kangaroos is distinctly large compared with the upper lumbar IVDs. Based on previously published data, human lumbar IVDs are the largest of all the animal IVDs used in spine research, with camelid cervical IVDs being the closest relative in absolute dimensions (llamas: 78% in disc height, 40% in WD volume, and 38% in NP volume). Kangaroo L6-S1 IVD was approximately 51% in height, 20% in WD volume, and 20% in NP volume of the human lumbar IVD. CONCLUSIONS:We conclude that morphological similarities exist between a kangaroo and human lumbar IVD, especially with the lima bean shape in the axial plane, wedge shape in the sagittal plane, convexity at the cephalad endplates, and percentage volume occupied by the NP in the IVD. These slides can be retrieved under Electronic Supplementary Material.

Chandran, M, Bhadada, SK, Ebeling, PR, Gilchrist, NL, Khan, AH, Halbout, P, Lekamwasam, S, Lyubomirsky, G, Mitchell, PJ, Nguyen, TV & Tiu, KL 2020, 'IQ driving QI: the Asia Pacific Consortium on Osteoporosis (APCO): an innovative and collaborative initiative to improve osteoporosis care in the Asia Pacific', Osteoporosis International, vol. 31, no. 11, pp. 2077-2081.
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Asia Pacific Consortium on Osteoporosis (APCO) comprises of clinical experts from across the Asia Pacific region, uniting to develop solutions to problems facing osteoporosis management and care. The vision of APCO is to reduce the burden of osteoporosis and fragility fractures in the Asia Pacific region.

Introduction

The Asia Pacific (AP) region comprises 71 countries with vastly different healthcare systems. It is predicted that by 2050, more than half the world's hip fractures will occur in this region. The Asia Pacific Consortium on Osteoporosis (APCO) was set up in May 2019 with the vision of reducing the burden of osteoporosis and fragility fractures in the AP region.

Methods

APCO has so far brought together 39 clinical experts from countries and regions across the AP to develop solutions to challenges facing osteoporosis management and fracture prevention in this highly populous region of the world. APCO aims to achieve its vision by engaging with relevant stakeholders including healthcare providers, policy makers and the public. The initial APCO project is to develop and implement a Framework of pan-AP minimum clinical standards for the screening, diagnosis and management of osteoporosis.

Results and conclusions

The Framework will serve as a platform upon which new national clinical guidelines can be developed or existing guidelines be revised, in a standardised fashion. The Framework will also facilitate benchmarking for provision of quality of care. It is hoped that the principles underlying the formation and functioning of APCO can be adopted by other regions and that every health care facility and progressively every country in the world can follow our aspirational path and progress towards best practice.

Chandran, M, Ebeling, PR, Mitchell, PJ & Nguyen, TV 2020, 'Harmonization of Osteoporosis Guidelines: Paving the Way for Disrupting the Status Quo in Osteoporosis Management in the Asia Pacific', Journal of Bone and Mineral Research, vol. 37, no. 4, pp. 608-615.
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ABSTRACT In the Asia Pacific (AP) region, osteoporosis and its consequence of fragility fractures are not widely recognized as a major public health problem. Several challenges including underdiagnosis and undertreatment exist. The Asia Pacific Consortium on Osteoporosis (APCO) is a nonpartisan and apolitical organization comprising musculoskeletal experts and stakeholders from both private and public sectors who have united to develop tangible solutions for these substantive challenges. APCO's vision is to reduce the burden of osteoporosis and fragility fractures in the AP region. Heterogeneity in both scope and recommendations among the available clinical practice guidelines (CPGs) contribute to the large osteoporosis treatment gap in the Asia Pacific. APCO has therefore developed a pan Asia-Oceania harmonized set of standards of care (The Framework), for the screening, diagnosis, and management of osteoporosis. First, a structured analysis of the 18 extant AP CPGs was completed. Subsequently, a prioritization of themes and agreement on fundamental principles in osteoporosis management were made through a Delphi process of consensus building. This approach, ensuring the opinions of all participating members were equally considered, was especially useful for a geographically diverse group such as APCO. It is hoped that the Framework will serve as a platform upon which new AP national CPGs can be developed and existing ones be revised. APCO is currently embarking on country-specific engagement plans to embed the Framework in clinical practice in the AP region. This is through partnering with regulatory bodies and national guidelines development authorities, through peer-to-peer health care professional education and by conducting path finder audits to benchmark current osteoporosis services against the Framework standards. The principles underpinning the harmonization of guidelines in the AP region can als...

Changani, Z, Razmjou, A, Taheri-Kafrani, A, Warkiani, ME & Asadnia, M 2020, 'Surface modification of polypropylene membrane for the removal of iodine using polydopamine chemistry', Chemosphere, vol. 249, pp. 126079-126079.
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The development of stable and effective iodine removal systems would be highly desirable in addressing environmental issues relevant to water contamination. In the present research, a novel iodine adsorbent was synthesized by self-polymerization of dopamine (PDA) onto inert polypropylene (PP) membrane. This PP/PDA membrane was thoroughly characterized and its susrface propeties was analyzed by various analytical techniques indcluding field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH), contact angle, and surface free energy measurement. The PP/PDA membranes were subsequently used for batchwise removal of iodine at different temperatures (25-70 °C), pH (2-7), and surface areas (1-10 cm2) to understand the underlying adsorption phenomena and to estimate the membrane capacity for iodine uptake. The increase in temperature and pH both led to higher adsorption of iodine. The present approach showed a removal efficiency of over 75% for iodine using 10 cm2 PP/PDA membrane (18.87 m2 g-1) within 2 h at moderate temperatures (∼50 °C) and pH > 4, about 15 fold compared to the PP control membrane. The adsorption kinetics and isotherms were well fitted to the pseudo-second-order kinetic and Langmuir isotherm models (R2 > 0.99). This adsorbent can be recycled and reused at least six times with stable iodine adsorption. These findings were attributed to the homogenous monolayer adsorption of the iodide on the surface due to the presence of catechol and amine groups in the PP/PDA membrane. This study proposes an efficient adsorbent for iodine removal.

Chehade, M, Bullock, M, Glover, A, Hutvagner, G & Sidhu, S 2020, 'Key MicroRNA’s and Their Targetome in Adrenocortical Cancer', Cancers, vol. 12, no. 8, pp. 2198-2198.
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Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics.

Chen, W, Goldys, EM & Deng, W 2020, 'Light-induced liposomes for cancer therapeutics', Progress in Lipid Research, vol. 79, pp. 101052-101052.
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Chen, X, Chamoli, U, Vargas Castillo, J, Ramakrishna, VAS & Diwan, AD 2020, 'Complication rates of different discectomy techniques for symptomatic lumbar disc herniation: a systematic review and meta-analysis', European Spine Journal, vol. 29, no. 7, pp. 1752-1770.
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Clement, S, Campbell, JM, Deng, W, Guller, A, Nisar, S, Liu, G, Wilson, BC & Goldys, EM 2020, 'Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer', Advanced Science, vol. 7, no. 24, pp. 2003584-2003584.
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AbstractEngineered nanomaterials that produce reactive oxygen species on exposure to X‐ and gamma‐rays used in radiation therapy offer promise of novel cancer treatment strategies. Similar to photodynamic therapy but suitable for large and deep tumors, this new approach where nanomaterials acting as sensitizing agents are combined with clinical radiation can be effective at well‐tolerated low radiation doses. Suitably engineered nanomaterials can enhance cancer radiotherapy by increasing the tumor selectivity and decreasing side effects. Additionally, the nanomaterial platform offers therapeutically valuable functionalities, including molecular targeting, drug/gene delivery, and adaptive responses to trigger drug release. The potential of such nanomaterials to be combined with radiotherapy is widely recognized. In order for further breakthroughs to be made, and to facilitate clinical translation, the applicable principles and fundamentals should be articulated. This review focuses on mechanisms underpinning rational nanomaterial design to enhance radiation therapy, the understanding of which will enable novel ways to optimize its therapeutic efficacy. A roadmap for designing nanomaterials with optimized anticancer performance is also shown and the potential clinical significance and future translation are discussed.

Deng, ZX, Tao, JW, Zhao, LJ, Zhang, W, Wang, YB, Mu, HJ, Wu, HJ, Xu, XX & Zheng, W 2020, 'Effect of protein adsorption on bioelectrochemistry of electrospun core-shell MWCNTs/gelatin-Hb nanobelts on electrode surface', Process Biochemistry, vol. 96, pp. 73-79.
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© 2020 Elsevier Ltd Implantable electrochemical biosensor is one powerful tool for the accurate and reliable measurements of small molecules in vivo. However, the electrode is inevitably subjected to the protein adsorption when implanted into the living animals, affecting the sensitivity and stability of biosensor. Herein, we designed the multi-walled carbon nanotubes/gelatin-hemoglobin (MWCNTs/gelatin-Hb) core-shell nanobelts constructed on glassy carbon electrode (GC) using the one-step electrospinning technique for studying the effect of protein adsorption on the electrode surface properties. The results of the water contact angle and the scanning electron microscopy (SEM) showed that the electrospun core-shell MWCNTs/gelatin-Hb nanobelts present hydrophilic and certain anti-protein adsorption properties. Direct electron transfer between the Hb molecules in the electrospun core-shell nanobelts and electrode and catalysis of hydrogen peroxide (H2O2) can be still achieved after the electrospun core-shell MWCNTs/gelatin-Hb nanobelts adsorbed protein. Moreover, compared with before protein adsorption (Kmapp =0.0155 mmol/L), the electrospun core-shell MWCNTs/gelatin-Hb nanobelts after protein adsorption still displayed high biological affinity to H2O2 (Kmapp =0.0382 mmol/L). The constructed H2O2 biosensor by using the electrospun core-shell MWCNTs/gelatin-Hb nanobelts showed high sensitivity, great reproducibility and stability after protein adsorption. This study provides a novel design and an effective platform for the development of implantable electrochemical biosensors.

Di, X, Wang, D, Zhou, J, Zhang, L, Stenzel, M, Su, QP & Jin, D 2020, 'Quantitatively Monitoringin situMitochondrial Thermal Dynamics by Upconversion Nanoparticles', p. 2020.11.29.402818.
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AbstractTemperature dynamics reflect the physiological conditions of cells and organisms. Mitochondria regulates temperature dynamics in living cells, as they oxidize the respiratory substrates and synthesize ATP, with heat being released as a by-product of active metabolism. Here, we report an upconversion nanoparticles based thermometer that allowsin situthermal dynamics monitoring of mitochondria in living cells. We demonstrate that the upconversion nanothermometers can efficiently target mitochondria and the temperature responsive feature is independent of probe concentration and medium conditions. The relative sensing sensitivity of 3.2% K−1in HeLa cells allows us to measure the mitochondrial temperature difference through the stimulations of high glucose, lipid, Ca2+shock and the inhibitor of oxidative phosphorylation. Moreover, cells display distinct response time and thermal dynamic profiles under different stimulations, which highlights the potential applications of this thermometer to studyin situvital processes related to mitochondrial metabolism pathways and interactions between organelles.

Du, Z, Gupta, A, Clarke, C, Cappadona, M, Clases, D, Liu, D, Yang, Z, Karan, S, Price, WS & Xu, X 2020, 'Porous Upconversion Nanostructures as Bimodal Biomedical Imaging Contrast Agents', The Journal of Physical Chemistry C, vol. 124, no. 22, pp. 12168-12174.
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Copyright © 2020 American Chemical Society. Lanthanide ion doped upconversion nanoparticles (UCNPs) hold great promise as multimodal contrast agents for a range of medical imaging techniques, including optical bioimaging (OBI), magnetic resonance imaging (MRI), and computed tomography (CT). However, it is challenging to obtain UCNPs with both maximal contrast enhancement effects for both OBI and MRI simultaneously owing to the dilemma in the size of UCNPs. UCNPs in large dimensions contain more photonic Ln ions and less surface defects, which is favored for high luminescent emissions, while small UCNPs with high specific surface areas allow a higher proportion of paramagnetic Ln ions to be more accessible to water molecules, which offers enhanced contrast in MRI. In this work, we report the novel design of core-porous shell UCNPs with both high luminescent emissions and magnetic relaxivities as potential dual-modal contrast agents. The core-porous shell UCNPs were fabricated via the selective etching of the inert shell of NaYF4: 30%Gd at the active core of NaYF4: 20%Yb, 1%Er. Their morphology and composition were carefully characterized using transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy, X-ray diffraction, and high resolution TEM. Their photoluminescent and magnetic resonance properties were experimentally determined and compared for the core, core-dense shell, and core-porous shell UCNPs. Core-porous shell UCNPs were found to display bright luminescence and superior MRI contrast enhancement, thus showing great potential as bimodal OBI and MRI contrast agents.

Dun, MD, Mannan, A, Rigby, CJ, Butler, S, Toop, HD, Beck, D, Connerty, P, Sillar, J, Kahl, RGS, Duchatel, RJ, Germon, Z, Faulkner, S, Chi, M, Skerrett-Byrne, D, Murray, HC, Flanagan, H, Almazi, JG, Hondermarck, H, Nixon, B, De Iuliis, G, Chamberlain, J, Alvaro, F, de Bock, CE, Morris, JC, Enjeti, AK & Verrills, NM 2020, 'Shwachman–Bodian–Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia', Leukemia, vol. 34, no. 12, pp. 3393-3397.
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Ejeian, F, Razmjou, A, Nasr-Esfahani, MH, Mohammad, M, Karamali, F, Ebrahimi Warkiani, M, Asadnia, M & Chen, V 2020, '<p>ZIF-8 Modified Polypropylene Membrane: A Biomimetic Cell Culture Platform with a View to the Improvement of Guided Bone Regeneration</p>', International Journal of Nanomedicine, vol. Volume 15, pp. 10029-10043.
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Purpose

Despite the significant advances in modeling of biomechanical aspects of cell microenvironment, it remains a major challenge to precisely mimic the physiological condition of the particular cell niche. Here, the metal-organic frameworks (MOFs) have been introduced as a feasible platform for multifactorial control of cell-substrate interaction, given the wide range of physical and mechanical properties of MOF materials and their structural flexibility.

Results

In situ crystallization of zeolitic imidazolate framework-8 (ZIF-8) on the polydopamine (PDA)-modified membrane significantly raised surface energy, wettability, roughness, and stiffness of the substrate. This modulation led to an almost twofold increment in the primary attachment of dental pulp stem cells (DPSCs) compare to conventional plastic culture dishes. The findings indicate that polypropylene (PP) membrane modified by PDA/ZIF-8 coating effectively supports the growth and proliferation of DPSCs at a substantial rate. Further analysis also displayed the exaggerated multilineage differentiation of DPSCs with amplified level of autocrine cell fate determination signals, like BSP1, BMP2, PPARG, FABP4, ACAN, and COL2A. Notably, osteogenic markers were dramatically overexpressed (more than 100-folds rather than tissue culture plate) in response to biomechanical characteristics of the ZIF-8 layer.

Conclusion

Hence, surface modification of cell culture platforms with MOF nanostructures proposed as a powerful nanomedical approach for selectively guiding stem cells for tissue regeneration. In particular, PP/PDA/ZIF-8 membrane presented ideal characteristics for using as a barrier membrane for guided bone regeneration (GBR) in periodontal tissue engineering.

Entezari, A, Liu, NC, Roohani, I, Zhang, Z, Chen, J, Sarrafpour, B, Zoellner, H, Behi, M, Zreiqat, H & Li, Q 2020, 'On design for additive manufacturing (DAM) parameter and its effects on biomechanical properties of 3D printed ceramic scaffolds', Materials Today Communications, vol. 23, pp. 101065-101065.
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Entezari, A, Swain, MV, Gooding, JJ, Roohani, I & Li, Q 2020, 'A modular design strategy to integrate mechanotransduction concepts in scaffold-based bone tissue engineering', Acta Biomaterialia, vol. 118, pp. 100-112.
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Fathollahipour, S, Koosha, M, Tavakoli, J, Maziarfar, S & Fallah Mehrabadi, J 2020, 'Erythromycin Releasing PVA/sucrose and PVA/honey Hydrogels as Wound Dressings with Antibacterial Activity and Enhanced Bio-adhesion.', Iran J Pharm Res, vol. 19, no. 1, pp. 448-464.
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The present study deals with preparation and characterization of thermally crosslinked PVA-based hydrogels containing honey and sucrose for the purpose of erythromycin delivery. The hydrogels have been characterized and compared by scanning electron microscopy, Fourier transform infrared spectroscopy, and bio-adhesion tests. Swelling measurements showed that addition of sucrose and honey decreased the equilibrium swelling of the hydrogels. Results of release studies showed that the amount of erythromycin, released at the early hours was higher for PVA/sucrose and PVA/honey hydrogels compared to PVA hydrogel while the drug released at later times was highly reduced for PVA/honey hydrogel. Both Peppas-Sahlin and Korsmeyer-Peppas models fitted well to the release data. Fitting Peppas-Sahlin model to the release data showed that at the initial times, release of drug from the hydrogel network was mainly governed by Fickian mechanism; however, at later times the drug is dominantly released by relaxational mechanism due to swelling of the network,. Addition of honey improved the bio-adhesion of PVA/honey hydrogel as compared to PVA/sucrose and pure PVA hydrogel. Results of antibacterial tests showed growth inhibitory action of erythromycin-loaded PVA hydrogels against Pseudomonas aeruginosa and Staphylococcus aureus bacteria. This study indicates that these hybrid hydrogels are capable of being used as functional wound dressings aiming to control the rate of antibiotic delivery to the wound site and prevent the wounds from infection.

Fox, K, Mani, N, Rifai, A, Reineck, P, Jones, A, Tran, PA, Ramezannejad, A, Brandt, M, Gibson, BC, Greentree, AD & Tran, N 2020, '3D-Printed Diamond–Titanium Composite: A Hybrid Material for Implant Engineering', ACS Applied Bio Materials, vol. 3, no. 1, pp. 29-36.
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Fröch, JE, Kim, S, Stewart, C, Xu, X, Du, Z, Lockrey, M, Toth, M & Aharonovich, I 2020, 'Photonic Nanobeam Cavities with Nanopockets for Efficient Integration of Fluorescent Nanoparticles', Nano Letters, vol. 20, no. 4, pp. 2784-2790.
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Integrating fluorescent nanoparticles with high-Q, small mode volume cavities is indispensable for nanophotonics and quantum technologies. To date, nanoparticles have largely been coupled to evanescent fields of cavity modes, which limits the strength of the interaction. Here, we developed both a cavity design and a fabrication method that enable efficient coupling between a fluorescent nanoparticle and a cavity optical mode. The design consists of a fishbone-shaped, one-dimensional photonic crystal cavity with a nanopocket located at the electric field maximum of the fundamental optical mode. Furthermore, the presence of a nanoparticle inside the pocket reduces the mode volume substantially and induces subwavelength light confinement. Our approach opens exciting pathways to achieve tight light confinement around fluorescent nanoparticles for applications in energy, sensing, lasing, and quantum technologies.

Frost, SA, Kelly, A, Gaudin, J, Evoy, LM, Wilson, C, Marov, L, El Haddad, C, Center, J, Eisman, JA, Nguyen, TV & Hassett, G 2020, 'Establishing baseline absolute risk of subsequent fracture among adults presenting to hospital with a minimal-trauma-fracture', BMC Musculoskeletal Disorders, vol. 21, no. 1.
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AbstractBackgroundOne in three women and one in five men are expected to experience a minimal-trauma-fracture after the age of 50-years, which increases the risk of subsequent fracture. Importantly, timely diagnosis and optimal treatment in the form of a fracture liaison service (FLS), has been shown to reduce this risk of a subsequent fracture. However, baseline risk of subsequent fracture among this group of FLS patients has not been well described. Therefore, this study aims to estimate absolute risk of subsequent fracture, among women and men aged 50-years or more, presenting to hospital with a minimal-trauma-fracture.MethodsWomen and men aged 50-years or more with a minimal-trauma-fracture, presenting to hospitals across the South Western Sydney Local Health District between January 2003 and December 2017 were followed to identify subsequent fracture presentations to hospital. Absolute risk of subsequent fracture was estimated, by taking into account the competing risk of death.ResultsBetween January 2003 and December 2017–15,088 patients presented to the emergency departments of the five hospitals in the SWSLHD (11,149, women [74%]), with minimal-trauma-fractures. Subsequent fractures identified during the follow-up period (median = 4.5 years [IQR, 1.6–8.2]), occurred in 2024 (13%) patients. Death during the initial hospital stay, or during a subsequent hospital visit was recorded among 1646 patients (11%). Women were observed to have 7.1% risk of subsequent fracture after 1-year, following an initial fracture; and, the risk of subsequent fracture after 1-year was 6.2% for men. After 5-years the rate among women was 13.7, and 11.3% for men, respectively. Cumulative risk of subsequent fracture when initial fractures were classified as being at proxim...

Gao, L, Shan, X, Xu, X, Liu, Y, Liu, B, Li, S, Wen, S, Ma, C, Jin, D & Wang, F 2020, 'Correction: Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles', Nanoscale, vol. 12, no. 36, pp. 18987-18987.
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Correction for ‘Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles’ by Laixu Gao et al., Nanoscale, 2020, DOI: 10.1039/d0nr03076g.

Gao, L, Shan, X, Xu, X, Liu, Y, Liu, B, Li, S, Wen, S, Ma, C, Jin, D & Wang, F 2020, 'Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles', Nanoscale, vol. 12, no. 36, pp. 18595-18599.
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A method for video-rate display with optimized single UCNP brightness by integrating the full emission intensity over excitation time and lifetime.

Ghorbani, F, Fathi, F, Aghebati-Maleki, L, Abolhasan, R, Rikhtegar, R, Dolatabadi, JEN, Babaloo, Z, Khalilzadeh, B, Ebrahimi-Warkiani, M, Sharifzadeh, Z, Rashidi, M-R & Yousefi, M 2020, 'Kinetic and thermodynamic study of c-Met interaction with single chain fragment variable (scFv) antibodies using phage based surface plasmon resonance', European Journal of Pharmaceutical Sciences, vol. 150, pp. 105362-105362.
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Mesenchymal epithelial transition factor (c-Met) has been recently regarded as an attractive target for the treatment of cancer. Our previous study showed that c-Met-specific single chain fragment variables (scFvs) can be considered as a promising therapy for cancer, however, their molecular interaction with c-Met protein have not been assessed. Accordingly, in the current study we aim to evaluate the kinetic and thermodynamic properties of c-Met interaction with these scFvs as anticancer agents by means of surface plasmon resonance (SPR) technique. Phage-scFvs were immobilized on the 11-mercaptoundecanoic acid gold chips after carboxylic groups activation by N-ethyl-N-(3-diethylaminopropyl) carbodiimide/N-hydroxysuccinimide and, then the c-Met binding to each scFvs (ES1, ES2, and ES3) at different concentrations (ranging from 20 to 665 μM) was explored. Kinetic studies revealed that ES1 has the highest affinity (KD = 3.36 × 10-8) toward its target at 25°C. Calculation of thermodynamic parameters also showed positive values for enthalpy and entropy changes, which was representative of hydrophobic forces between c-Met and ES1. Furthermore, the positive value of Gibbs free energy indicated that c-Met binding to ES1 was enthalpy-driven. Taken together, we concluded that produced ES1 can be applied as promising scFv-based therapy for diagnosis or targeting of c-Met in various cancers.

Gu, X, Shen, C, Li, H, Goldys, EM & Deng, W 2020, 'X-ray induced photodynamic therapy (PDT) with a mitochondria-targeted liposome delivery system', Journal of Nanobiotechnology, vol. 18, no. 1, p. 87.
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AbstractIn this study, we constructed multifunctional liposomes with preferentially mitochondria-targeted feature and gold nanoparticles-assisted synergistic photodynamic therapy. We systemically investigated the in vitro X-ray triggered PDT effect of these liposomes on HCT 116 cells including the levels of singlet oxygen, mitochondrial membrane potential, cell apoptosis/necrosis and the expression of apoptosis-related proteins. The results corroborated that synchronous action of PDT and X-ray radiation enhance the generation of cytotoxic reactive oxygen species produced from the engineered liposomes, causing mitochondrial dysfunction and increasing the levels of apoptosis.

Guo, A, Wang, B, Lyu, C, Li, W, Wu, Y, Zhu, L, Bi, R, Huang, C, Li, JJ & Du, Y 2020, 'Consistent apparent Young’s modulus of human embryonic stem cells and derived cell types stabilized by substrate stiffness regulation promotes lineage specificity maintenance', Cell Regeneration, vol. 9, no. 1, p. 15.
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Abstract Background Apparent Young’s modulus (AYM), which reflects the fundamental mechanical property of live cells measured by atomic force microscopy and is determined by substrate stiffness regulated cytoskeletal organization, has been investigated as potential indicators of cell fate in specific cell types. However, applying biophysical cues, such as modulating the substrate stiffness, to regulate AYM and thereby reflect and/or control stem cell lineage specificity for downstream applications, remains a primary challenge during in vitro stem cell expansion. Moreover, substrate stiffness could modulate cell heterogeneity in the single-cell stage and contribute to cell fate regulation, yet the indicative link between AYM and cell fate determination during in vitro dynamic cell expansion (from single-cell stage to multi-cell stage) has not been established. Results Here, we show that the AYM of cells changed dynamically during passaging and proliferation on substrates with different stiffness. Moreover, the same change in substrate stiffness caused different patterns of AYM change in epithelial and mesenchymal cell types. Embryonic stem cells and their derived progenitor cells exhibited distinguishing AYM changes in response to different substrate stiffness that had significant effects on their maintenance of pluripotency and/or lineage-specific characteristics. On substrates that were too rigid or too soft, fluctuations in AYM occurred during cell passaging and proliferation that led to a loss in lineage specificity. On a substrate with ‘optimal’ stiffness (i.e., 3.5 kPa), the AYM was maintained at a constant level that was consistent with the parental cells during passaging and proliferation and led to preservation of lineage specificity. The ...

Hagihghi, R, Razmjou, A, Orooji, Y, Warkiani, ME & Asadnia, M 2020, 'A miniaturized piezoresistive flow sensor for real‐time monitoring of intravenous infusion', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 108, no. 2, pp. 568-576.
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AbstractDrug overdose (DO) is considered one of the current issues of intravenous (IV) infusion particularly resulting in serious injuries and deaths. Malfunction of infusion pumps is reported as the main cause of the drug overdose. Live monitoring and flow rate calculation by health professionals have been practicing to avoid DO. However, human errors and miscalculations are inevitable. A secondary measurement tool is required to avoid the risk of OD when infusion pump malfunctions cannot be detected immediately. Here, inspired by nature, we developed a real‐time monitoring device through which an administrator can review, evaluate, and modify the IV infusion process. Our flow sensor possesses an erected polymer hair cell on a multi‐layered silicon base forming from a patterned gold strained gauge layer on a piezoresistive liquid crystal polymer (LCP) membrane. Gold strain gauges on an LCP membrane have been used instead of a piezoresistive silicon membrane as the sensing element. The combination of gold strain gauges and LCP membrane provides better sensitivity than a piezoresistive silicon membrane of the same dimensions and thickness. We also miniaturized our biocompatible sensor such that it can be possible to install it inside the IV tube in contact with the liquid providing an in‐suite online flow monitoring. The proposed LCP membrane sensor is compared with two commercially available IV sensors to validate its flow sensing ability. The experimental results demonstrate that the proposed sensor provides a low threshold detection limit of 5 mL/hr, which betters the performance of other commercial sensors at low flow rates.

Hao, D, Liu, C, Xu, X, Kianinia, M, Aharonovich, I, Bai, X, Liu, X, Chen, Z, Wei, W, Jia, G & Ni, B-J 2020, 'Surface defect-abundant one-dimensional graphitic carbon nitride nanorods boost photocatalytic nitrogen fixation', New Journal of Chemistry, vol. 44, no. 47, pp. 20651-20658.
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Defective g-C₃N₄ nanorods enable to boots the adsorption and cleavage of N₂ molecules to achieve higher photocatalytic nitrogen fixation performance.

Hao, H, Niu, J, Xue, B, Su, QP, Liu, M, Yang, J, Qin, J, Zhao, S, Wu, C & Sun, Y 2020, 'Golgi‐associated microtubules are fast cargo tracks and required for persistent cell migration', EMBO reports, vol. 21, no. 3.
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Microtubules derived from the Golgi (Golgi MTs) have been implicated to play critical roles in persistent cell migration, but the underlying mechanisms remain elusive, partially due to the lack of direct observation of Golgi MT-dependent vesicular trafficking. Here, using super-resolution stochastic optical reconstruction microscopy (STORM), we discovered that post-Golgi cargos are more enriched on Golgi MTs and also surprisingly move much faster than on non-Golgi MTs. We found that, compared to non-Golgi MTs, Golgi MTs are morphologically more polarized toward the cell leading edge with significantly fewer inter-MT intersections. In addition, Golgi MTs are more stable and contain fewer lattice repair sites than non-Golgi MTs. Our STORM/live-cell imaging demonstrates that cargos frequently pause at the sites of both MT intersections and MT defects. Furthermore, by optogenetic maneuvering of cell direction, we demonstrate that Golgi MTs are essential for persistent cell migration but not for cells to change direction. Together, our study unveils the role of Golgi MTs in serving as a group of 'fast tracks' for anterograde trafficking of post-Golgi cargos.

Hassanzadeh-Barforoushi, A, Warkiani, ME, Gallego-Ortega, D, Liu, G & Barber, T 2020, 'Capillary-assisted microfluidic biosensing platform captures single cell secretion dynamics in nanoliter compartments', Biosensors and Bioelectronics, vol. 155, pp. 112113-112113.
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Cancer cells continuously secrete inflammatory biomolecules which play significant roles in disease progression and tumor metastasis toward secondary sites. Despite recent efforts to capture cancer cells' intercellular secretion heterogeneity using microfluidics, the challenges in operation of these systems as well as the complexity of designing a biosensing assay for long-term and real-time measurement of single cell secretions have become grand research barriers. Here, we present a new capillary-based microfluidic biosensing approach to easily and reliably capture ~500 single cells inside isolated dead-end nanoliter compartments using simple pipette injection, and quantify their individual secretion dynamics at the single cell resolution over a long period of culture (~16 h). We first present a detailed investigation of the fluid mechanics underlying the formation of nanoliter compartments in the microfluidic system. Based on the measurement of single cell capture efficiency, we employ a one-step FRET-based biosensor which monitors the single cancer cells' protease activity. The sensor reports the fluorescent signal as a product of amino acid chain cleavage and reduction in its quenching capability. Using the single cell protease secretion data, we identified modes of cell secretion dynamics in our cell sample. While most of the cells had low secretion levels, two other smaller and more aggressive secretion dynamics were cells with secretion modes that include sharp spikes or slow but progressive trend. The method presented here overcomes the difficulties associated with performing single cell secretion assays, enabling a feasible and reliable technique for high throughput measurement of metabolic activities in cancer cells.

Hejazi, MA, Tong, W, Stacey, A, Soto-Breceda, A, Ibbotson, MR, Yunzab, M, Maturana, MI, Almasi, A, Jung, YJ, Sun, S, Meffin, H, Fang, J, Stamp, MEM, Ganesan, K, Fox, K, Rifai, A, Nadarajah, A, Falahatdoost, S, Prawer, S, Apollo, NV & Garrett, DJ 2020, 'Hybrid diamond/ carbon fiber microelectrodes enable multimodal electrical/chemical neural interfacing', Biomaterials, vol. 230, pp. 119648-119648.
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Herath, S, Razavi Bazaz, S, Monkman, J, Ebrahimi Warkiani, M, Richard, D, O’Byrne, K & Kulasinghe, A 2020, 'Circulating tumor cell clusters: Insights into tumour dissemination and metastasis', Expert Review of Molecular Diagnostics, vol. 20, no. 11, pp. 1139-1147.
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INTRODUCTION:Metastasis results in more than 90% of cancer related deaths globally. The process is thought to be facilitated by metastatic precursor cells, commonly termed circulating tumour cells (CTCs). CTCs can exist as single cells or cell clusters and travel through the lymphovasculature to distant organs where they can form overt metastasis. Areas covered: Studies have highlighted that CTC clusters, which may be homotypic or heterotypic in composition, have a higher metastatic potential compared to single CTCs. The characterisation of CTC clusters is becoming important as heterotypic clusters can provide a mechanism for immune evasion. This review summarises the latest advances in CTC cluster mediated metastasis and clinical significance. Expert Opinion: Comprehensive characterisation of CTC clusters is needed to understand the cell types and interactions within clusters, in order to identify ways in which to reduce CTC cluster mediated metastasis. The role of CTC clusters in prognosticating disease progression needs to be determined by documenting CTC clusters from the time of diagnosis over the course of therapy.

Hill, M, Sais, D, Monteiro Marques, T, Gama Carvalho, M & Tran, N 2020, 'Developing a virus-microRNA interactome using cytoscape', MethodsX, vol. 7, pp. 100700-100700.
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© 2019 It is currently difficult to determine the effect of oncogenic viruses on the global function and regulation of pathways within mammalian cells. A thorough understanding of the molecular pathways and individual genes altered by oncogenic viruses is needed for the identification of targets that can be utilised for early diagnosis, prevention, and treatment methods. We detail a logical step-by-step guide to uncover viral-protein-miRNA interactions using publically available datasets and the network building program, Cytoscape. This method may be applied to identify specific pathways that are altered in viral infection, and contribute to the oncogenic transformation of cells. To demonstrate this, we constructed a gene regulatory interactome encompassing Human Papillomavirus Type 16 (HPV16) and its control of specific miRNAs. This approach can be broadly applied to understand and map the regulatory functions of other oncogenic viruses, and determine their role in altering the cellular environment in cancer. Availability and Implementation Cytoscape (Shannon et al. (2003), Smoot et al. (2010)) is freely available at https://cytoscape.org/. • This method allows for the analysis and visualization of large datasets to generate an interactome that integrates key players of molecular biology • This approach may be applied to any oncogenic virus to map its regulatory functions, and its secondary impact on gene regulation via microRNAs.

Ho-Le, TP & Nguyen, TV 2020, 'Hip Fracture and Mortality: A Loss of Life Expectancy Interpretation', Journal of Bone and Mineral Research, vol. 36, no. 12, pp. 2457-2458.
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Ho-Pham, LT, Doan, MC, Van, LH & Nguyen, TV 2020, 'Development of a model for identification of individuals with high risk of osteoporosis', Archives of Osteoporosis, vol. 15, no. 1, p. 111.
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Many developing countries, including Vietnam, lack DXA resources for the diagnosis of osteoporosis, which poses difficulties in the treatment and prevention of osteoporosis at the individual level. We have developed and validated a prediction model for individualized assessment of osteoporosis based on age and body weight for men and women. PURPOSE:To estimate the prevalence of osteoporosis and to develop and validate a prediction model for estimating the absolute risk of osteoporosis in the Vietnamese population. METHODS:The study involved 1477 women and 669 men aged 50 years and older, who were recruited from the general population in Ho Chi Minh City (Vietnam). Bone mineral density (BMD) at the femoral neck, total hip, and lumbar spine was measured by DXA (Hologic Horizon). The diagnosis of osteoporosis was based on BMD T-score (T-score ≤ - 2.5) at the femoral neck or lumbar spine which was derived from a published reference range for the Vietnamese population. The logistic regression model was used to develop the prediction model for men and women separately. The bootstrap method was used to evaluate the model performance using 3 indices: the area under the receiver's operating characteristic curve (AUC), Brier score, and R-squared values. RESULTS:The prevalence of osteoporosis at any site was 28.3% in women and 15.5% in men. The best predictors of osteoporosis risk were age and body weight. Using these indices, a cut-off of 0.195 for women yielded an AUC of 0.825, Brier score = 0.112, and it explained 33.8% of total variance in risk of osteoporosis between individuals. Similarly, in men, the internal validation with a cut-off of 0.09 yielded good accuracy, with AUC = 0.858, Brier score = 0.040, and R-squared = 30.3%. CONCLUSION:We have developed and validated a prediction model for individualized assessment of osteoporosis. In settings without DXA, this model can serve as a useful screening tool to identify high-risk individuals for DXA scan.

Houshyar, S, Sarker, A, Jadhav, A, Kumar, GS, Bhattacharyya, A, Nayak, R, Shanks, RA, Saha, T, Rifai, A, Padhye, R & Fox, K 2020, 'Polypropylene-nanodiamond composite for hernia mesh', Materials Science and Engineering: C, vol. 111, pp. 110780-110780.
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Huang, G, Lin, G, Zhu, Y, Duan, W & Jin, D 2020, 'Emerging technologies for profiling extracellular vesicle heterogeneity', Lab on a Chip, vol. 20, no. 14, pp. 2423-2437.
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Approaches, challenges and promising opportunities towards decoding the complexity of extracellular vesicle heterogeneity are discussed.

Kapeleris, J, Kulasinghe, A, Warkiani, ME, Oleary, C, Vela, I, Leo, P, Sternes, P, O’Byrne, K & Punyadeera, C 2020, 'Ex vivo culture of circulating tumour cells derived from non-small cell lung cancer', Translational Lung Cancer Research, vol. 9, no. 5, pp. 1795-1809.
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Background

Tumour tissue-based information is limited. Liquid biopsy can provide valuable real-time information through circulating tumour cells (CTCs). Profiling and expanding CTCs may provide avenues to study transient metastatic disease.

Methods

Seventy non-small cell lung cancer (NSCLC) patients were recruited. CTCs were enriched using the spiral microfluidic chip and a RosetteSep™ using bloods from NSCLC patients. CTC cultures were carried out using the Clevers media under hypoxic conditions. CTCs were characterized using immunofluorescence and mutation-specific antibodies for samples with known mutation profiles. Exome sequencing was used to characterized CTC cultures.

Results

CTCs (>2 cells) were detected in 38/70 (54.3%) of patients ranging from 0 to 385 CTCs per 7.5 mL blood. In 4/5 patients where primary tumours harboured an EGFR exon 19 deletion, this EGFR mutation was also captured in CTCs. ALK translocation was confirmed on CTCs from a patient harbouring an ALK-rearrangement in the primary tumour. Short term CTC cultures were successfully generated in 9/70 NSCLC patients. Whole exome sequencing (WES) confirmed the presence of somatic mutations in the CTC cultures with mutational signatures consistent with NSCLC.

Conclusions

We were able to detect CTCs in >50% of NSCLC patients. NSCLC patients with >2 CTCs had a poor prognosis. The short-term CTC culture success rate was 12.9%. Further optimization of this culture methodology may provide a means by which to expand CTCs derived from NSCLC patient's bloods. CTC cultures allow for expansion of cells to a critical mass, allowing for functional characterization of CTCs with the goal of drug sensitivity testing and the creation of CTC cell lines.

Khan, MA, Zhu, Y, Yao, Y, Zhang, P, Agrawal, A & Reece, PJ 2020, 'Impact of metal crystallinity-related morphologies on the sensing performance of plasmonic nanohole arrays', Nanoscale, vol. 12, no. 14, pp. 7577-7585.
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Low surface roughness and large metal grain sizes improve the sensitivity of a plasmonic nanohole array sensor.

Khorsand, M, Tavakoli, J, Guan, H & Tang, Y 2020, 'Artificial intelligence enhanced mathematical modeling on rotary triboelectric nanogenerators under various kinematic and geometric conditions', Nano Energy, vol. 75, pp. 104993-104993.
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© 2020 Elsevier Ltd The triboelectric nanogenerator (TENG) has been introduced as a revolutionary technology in the renewable electrical energy generation at micro/nanoscale. In the current study, experimental and theoretical models for augmented rotary TENGs are presented. The power generated by TENGs is found to be a function of the number of segments, rotational speed, and tribo-surface spacing. Mathematical modeling combined with artificial intelligence is applied to characterize the TENG output under various kinematics and geometric conditions. Sensitivity analysis reveals that the generated energy and the matched resistance depend highly on segmentation and angular velocity rate. It is shown that the optimized harvested energy reaches 0.369 mJ at each cycle. The TENG dynamic outputs for various structural parameters are found and described. This study enhances understanding of rotation-induced periodic TENGs and reveals optimized characteristics for disk-shaped TENG energy harvesters.

Kulasinghe, A, Lim, Y, Kapeleris, J, Warkiani, M, O’Byrne, K & Punyadeera, C 2020, 'The Use of Three-Dimensional DNA Fluorescent In Situ Hybridization (3D DNA FISH) for the Detection of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer (NSCLC) Circulating Tumor Cells', Cells, vol. 9, no. 6, pp. 1465-1465.
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Tumor tissue biopsy is often limited for non-small cell lung cancer (NSCLC) patients and alternative sources of tumoral information are desirable to determine molecular alterations such as anaplastic lymphoma kinase (ALK) rearrangements. Circulating tumor cells (CTCs) are an appealing component of liquid biopsies, which can be sampled serially over the course of treatment. In this study, we enrolled a cohort of ALK-positive (n = 8) and ALK-negative (n = 12) NSCLC patients, enriched for CTCs using spiral microfluidic technology and performed DNA fluorescent in situ hybridization (FISH) for ALK. CTCs were identified in 12/20 NSCLC patients ranging from 1 to 26 CTCs/7.5 mL blood. Our study revealed that 3D imaging of CTCs for ALK translocations captured a well-defined separation of 3′ and 5′ signals indicative of ALK translocations and overlapping 3′/5′ signal was easily resolved by imaging through the nuclear volume. This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC.

Law, AMK, Valdes-Mora, F & Gallego-Ortega, D 2020, 'Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer', Cells, vol. 9, no. 3, pp. 561-561.
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The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

Lee, H, Phillips, JB, Hall, RM & Tipper, JL 2020, 'Neural cell responses to wear debris from metal-on-metal total disc replacements', European Spine Journal, vol. 29, no. 11, pp. 2701-2712.
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PurposeAbstractTotal disc replacements, comprising all-metal articulations, are compromised by wear and particle production. Metallic wear debris and ions trigger a range of biological responses including inflammation, genotoxicity, cytotoxicity, hypersensitivity and pseudotumour formation, therefore we hypothesise that, due to proximity to the spinal cord, glial cells may be adversely affected.MethodsClinically relevant cobalt chrome (CoCr) and stainless steel (SS) wear particles were generated using a six-station pin-on-plate wear simulator. The effects of metallic particles (0.5–50 μm3 debris per cell) and metal ions on glial cell viability, cellular activity (glial fibrillary acidic protein (GFAP) expression) and DNA integrity were investigated in 2D and 3D culture using live/dead, immunocytochemistry and a comet assay, respectively.ResultsCoCr wear particles and ions caused significant reductions in glial cell viability in both 2D and 3D culture systems. Stainless steel particles did not affect glial cell viability or astrocyte activation. In contrast, ions released from SS caused significant reductions in glial cell viability, an effect that was especially noticeable when astrocytes were cultured in isolation without microglia. DNA damage was observed in both cell types and with both biomaterials tested. CoCr wear particles had a dose-dependent effect on astrocyte activation, measured through expression of GFAP.ConclusionsThe results from this study suggest that microglia influence the effects that metal particles have on astrocytes, that SS ions and particles play a role in the adverse effects observed and that SS is a less toxic biomaterial than CoCr alloy f...

Li, D, Li, JJ, Zhu, Y, Hou, F, Li, Y, Zhao, B & Wang, B 2020, 'Large autologous ilium with periosteum for tibiotalar joint reconstruction in Rüedi-Allgöwer III or AO/OTA type C3 pilon fractures: a pilot study', BMC Musculoskeletal Disorders, vol. 21, no. 1, p. 632.
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Abstract Background Management of Rüedi-Allgöwer III or AO/OTA type C3 pilon fracture presents numerous challenges to the orthopaedic surgeon. A joint preservation technique using a large autologous ilium with periosteum in combination with internal implant fixation was reported to improve the outcome of reconstruction. Methods Twenty-five patients according to Tscherne/Oestern FxCO-I closed fracture and FxOI open fractures classification after Rüedi-Allgöwer III or AO/OTA type C3 pilon fracture received a large autologous ilium with periosteum for tibiotalar joint reconstruction and open reduction and internal fixation (ORIF), between March 2015 and September 2018. The visual analog scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS) score, and Burwell and Charnley criteria were used for outcome analysis. Results Twenty patients with an average age of 45.2 years were followed for an average of 18.3 months. The VAS and AOFAS scores, and Burwell and Charnley ratings were recorded at the last follow-up after reconstructive surgery. Two patients developed redness and swelling at the wound site, but recovered after local care and dressing changes. No patient displayed deep surgical site infection, donor site complication, non-union or local complication during the final follow-up. The average bone union time was 18.3 months (range 3–36). Conclusions Large autologous ilium with periosteum in combination with ORIF can be performed for tibiotalar joint reconstruction. This experimental procedure reduc...

Ling, T, Li, JJ, Xu, R-J, Wang, B & Ge, W-H 2020, 'Topical Diclofenac Solution for Osteoarthritis of the Knee: An Updated Meta-Analysis of Randomized Controlled Trials', BioMed Research International, vol. 2020, pp. 1-11.
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This study was performed to assess the efficacy and safety of a topical diclofenac solution in patients with knee osteoarthritis (OA). PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases were searched for randomized controlled trials until June 2020. The WOMAC pain, stiffness, physical function subscales, pain on walking, and the occurrence of adverse events were pooled to comprehensively analyse the efficacy and safety of topical diclofenac solution. All statistical analyses were conducted using Review Manager 5.3 software. Five RCTs were included, which provided high-quality evidence. In comparison to the vehicle control, the mean differences for WOMAC pain, stiffness, and physical function subscales, as well as pain on walking, were all statistically significant in favor of topical diclofenac solution. The safety of topical diclofenac solution was similar to the vehicle control, apart from adverse events involving application-site skin reactions. Topical diclofenac solution is effective and safe for use in patients with knee OA, but may cause minor skin reactions.

Liu, B, Chen, C, Di, X, Liao, J, Wen, S, Su, QP, Shan, X, Xu, Z-Q, Ju, LA, Mi, C, Wang, F & Jin, D 2020, 'Upconversion Nonlinear Structured Illumination Microscopy', Nano Letters, vol. 20, no. 7, pp. 4775-4781.
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Video-rate super-resolution imaging through biological tissue can visualize and track biomolecule interplays and transportations inside cellular organisms. Structured illumination microscopy allows for wide-field super resolution observation of biological samples but is limited by the strong extinction of light by biological tissues, which restricts the imaging depth and degrades its imaging resolution. Here we report a photon upconversion scheme using lanthanide-doped nanoparticles for wide-field super-resolution imaging through the biological transparent window, featured by near-infrared and low-irradiance nonlinear structured illumination. We demonstrate that the 976 nm excitation and 800 nm upconverted emission can mitigate the aberration. We found that the nonlinear response of upconversion emissions from single nanoparticles can effectively generate the required high spatial frequency components in the Fourier domain. These strategies lead to a new modality in microscopy with a resolution below 131 nm, 1/7th of the excitation wavelength, and an imaging rate of 1 Hz.

Liu, Y, Wang, F, Lu, H, Fang, G, Wen, S, Chen, C, Shan, X, Xu, X, Zhang, L, Stenzel, M & Jin, D 2020, 'Cancer Spheroids: Super‐Resolution Mapping of Single Nanoparticles inside Tumor Spheroids (Small 6/2020)', Small, vol. 16, no. 6, pp. 2070030-2070030.
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Liu, Y, Wang, F, Lu, H, Fang, G, Wen, S, Chen, C, Shan, X, Xu, X, Zhang, L, Stenzel, M & Jin, D 2020, 'Super‐Resolution Mapping of Single Nanoparticles inside Tumor Spheroids', Small, vol. 16, no. 6, pp. 1905572-1905572.
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AbstractCancer spheroids have structural, functional, and physiological similarities to the tumor, and have become a low‐cost in vitro model to study the physiological responses of single cells and therapeutic efficacy of drugs. However, the tiny spheroid, made of a cluster of high‐density cells, is highly scattering and absorptive, which prevents light microscopy techniques to reach the depth inside spheroids with high resolution. Here, a method is reported for super‐resolution mapping of single nanoparticles inside a spheroid. It first takes advantage of the self‐healing property of a “nondiffractive” doughnut‐shaped Bessel beam from a 980 nm diode laser as the excitation, and further employs the nonlinear response of the 800 nm emission from upconversion nanoparticles, so that both excitation and emission at the near‐infrared can experience minimal loss through the spheroid. These strategies lead to the development of a new nanoscopy modality with a resolution of 37 nm, 1/26th of the excitation wavelength. This method enables mapping of single nanoparticles located 55 µm inside a spheroid, with a resolution of 98 nm. It suggests a solution to track single nanoparticles and monitor their release of drugs in 3D multicellar environments.

Mahmoudi, T, Pirpour Tazehkand, A, Pourhassan-Moghaddam, M, Alizadeh-Ghodsi, M, Ding, L, Baradaran, B, Razavi Bazaz, S, Jin, D & Ebrahimi Warkiani, M 2020, 'PCR-free paper-based nanobiosensing platform for visual detection of telomerase activity via gold enhancement', Microchemical Journal, vol. 154, pp. 104594-104594.
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© 2020 Elsevier B.V. Telomerase activity has been demonstrated in a wide variety of most solid tumors and considered as a well-known cancer biomarker. The commonly utilized method for its detection is polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP). However, the TRAP technique suffers from false-negative results caused by the failure of PCR step. Moreover, it requires advanced equipment with a tedious and time-consuming procedure. Herein, we presented a portable nitrocellulose paper-based nanobiosensing platform for ultrafast and equipment-free detection of telomerase activity based on a simple colorimetric assay that enabled naked-eye visualization of the color change in response to enzyme activity. In this platform, hybridization was initially performed between telomere complementary oligonucleotide immobilized on gold nanoparticles (GNPs) and telomerase elongated biotinylated probe. Thereafter, the assembly was attached on activated paper strip via avidin-biotin interaction. The signal amplification was carried out by enlargement of the attached GNPs on the paper strip, forming tightly compact rod-shaped submicron structures of gold representing a visual color formation. Thanks to significant sensitivity enhancement, the color change was occurred for down to 6 cells, which can be easily observed by the naked eye. Due to the desired aspects of the developed assay including PCR-free, low cost, simple, and high sensitivity, it can be used for evaluation of telomerase activity in cell extracts for future clinical applications. Furthermore, this design has the ability to be easily integrated into lab-on-chip devices for point-of-care telomerase sensing.

Mahmoudi, Z, Mohammadnejad, J, Razavi Bazaz, S, Abouei Mehrizi, A, Saidijam, M, Dinarvand, R, Ebrahimi Warkiani, M & Soleimani, M 2020, 'Promoted chondrogenesis of hMCSs with controlled release of TGF-β3 via microfluidics synthesized alginate nanogels', Carbohydrate Polymers, vol. 229, pp. 115551-115551.
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The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

Mani, N, Rifai, A, Houshyar, S, Booth, MA & Fox, K 2020, 'Diamond in medical devices and sensors: An overview of diamond surfaces', MEDICAL DEVICES & SENSORS, vol. 3, no. 6.
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AbstractSignificant challenges arise when the human body is damaged, diseased and unable to repair itself. Current biomaterials for biomedical devices have limitations to restore function, while materials for implants and sensors often invoke a large foreign body response. Therefore, there is a need to develop suitable biomaterials in the fields of medical devices and sensors. Diamond is emerging due to its many favourable properties including biocompatibility, antimicrobial capability, antifouling properties, electrical conductivity and chemical functionalization capability. Thin film coatings of diamond can be fabricated by chemical vapour deposition, or by particle coatings with nanodiamond materials. Hybrid/composite diamond materials include soft materials such as those processed by electrospinning and melt extrusion, as well as hard materials such as those processed by additive manufacturing. Additive manufacturing is a developing area for diamond biomaterial fabrication and can include both hard and soft materials. The fabrication method used will depend on the properties required of the biomaterial, as well as the application. In this mini‐review, recent progress on using diamond in medical devices and sensors is outlined, with particular emphasis on fabrication methods. We highlight selected applications from recent literature and, in closing, make comments and suggestions to advance the field and direction of diamond application in medical devices and sensors.

Meyer, S, Gonzalez de Vega, R, Xu, X, Du, Z, Doble, PA & Clases, D 2020, 'Characterization of Upconversion Nanoparticles by Single-Particle ICP-MS Employing a Quadrupole Mass Filter with Increased Bandpass', Analytical Chemistry, vol. 92, no. 22, pp. 15007-15016.
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This work introduces new methods to characterize dispersions of small-diameter or low-mass-fraction nanoparticles (NPs) by single-particle inductively coupled plasma-mass spectrometry (SP ICP-MS). The optimization of ion extraction, ion transport, and the operation of the quadrupole with increased mass bandwidth improved the signal-to-noise ratios significantly and decreased the size detection limits for all NP dispersions investigated. As a model system, 10.9 ± 1.0 nm Au NPs were analyzed to demonstrate the effects of increasing ion transmission. Specifically, increasing the mass bandwidth of the quadrupole improved the size detection limit to 4.2 nm and enabled the resolution of NP signals from ionic background and noise. Subsequently, the methods were applied to the characterization of lanthanide-doped upconversion nanoparticles (UCNPs) by SP ICP-MS. Three different types of UCNPs (90 nm NaYF4: 20% Yb, 2% Er; 20 nm NaGdF4: 20% Yb, 1% Er; 15 nm NaYF4: 20% Yb, 2% Er) were investigated. Y showed the best signal-to-noise ratios with optimized ion extraction and transport parameters only, whereas the signal-to-noise ratios of Gd, Er, and Yb were further improved by increasing the mass bandwidth of a quadrupole mass filter. The novel methods were suitable for detailed characterization of diluted UCNP dispersions including particle stoichiometries and size distributions. A Poisson model was further applied to assess particle-particle interactions in the aqueous dispersions. The methods have considerable potential for the characterization of small-diameter and/or low-mass-fraction nanoparticles.

Mihandoust, A, Razavi Bazaz, S, Maleki-Jirsaraei, N, Alizadeh, M, A. Taylor, R & Ebrahimi Warkiani, M 2020, 'High-Throughput Particle Concentration Using Complex Cross-Section Microchannels', Micromachines, vol. 11, no. 4, pp. 440-440.
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High throughput particle/cell concentration is crucial for a wide variety of biomedical, clinical, and environmental applications. In this work, we have proposed a passive spiral microfluidic concentrator with a complex cross-sectional shape, i.e., a combination of rectangle and trapezoid, for high separation efficiency and a confinement ratio less than 0.07. Particle focusing in our microfluidic system was observed in a single, tight focusing line, in which higher particle concentration is possible, as compared with simple rectangular or trapezoidal cross-sections with similar flow area. The sharper focusing stems from the confinement of Dean vortices in the trapezoidal region of the complex cross-section. To quantify this effect, we introduce a new parameter, complex focusing number or CFN, which is indicative of the enhancement of inertial focusing of particles in these channels. Three spiral microchannels with various widths of 400 µm, 500 µm, and 600 µm, with the corresponding CFNs of 4.3, 4.5, and 6, respectively, were used. The device with the total width of 600 µm was shown to have a separation efficiency of ~98%, and by recirculating, the output concentration of the sample was 500 times higher than the initial input. Finally, the investigation of results showed that the magnitude of CFN relies entirely on the microchannel geometry, and it is independent of the overall width of the channel cross-section. We envision that this concept of particle focusing through complex cross-sections will prove useful in paving the way towards more efficient inertial microfluidic devices.

Mirzaaghaian, A, Ramiar, A, Ranjbar, AA & Warkiani, ME 2020, 'Application of level-set method in simulation of normal and cancer cells deformability within a microfluidic device', Journal of Biomechanics, vol. 112, pp. 110066-110066.
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Application of microfluidic systems for the study of cellular behaviors has been a flourishing area of research in the past decade. In the process of probing cell biomechanics the passage of a cell through a narrow microchannel or a small pore has attracted much attention during the recent years. And the study of cellular deformability and transportability using these systems with enhanced resolution and accuracy has opened a new paradigm for high-throughput characterization of both healthy and diseased cell populations.Here we use the level-set method to explore the relationship between the transit time and mechanical properties of normal white blood cells (WBCs) and breast cancer epithelial cells (MCF7) under different microenvironmental parameters (i.e., pressure difference, cell size, effective cell surface tension, constriction size and taper angle) in a 2-D computational domain by considering the cell as a viscous drop. The novel biomechanical relations are obtained for each cell type by the Response Surface Method (RSM), relating microenvironmental parameters to the dimensionless entry time of the normal and cancer cells. Our results revealed that MCF7 cells show asignificantly different behavior (a bifurcating behavior when the pressure difference of inlet/outlet increases) in regards to the dimensionless entry time as a function of microchannel taper angle in comparison with the WBC. These results suggest that the microenvironmental parameters have a significant effect on the transportability of the cells and different cells have different behaviors in response to a specific microenvironmental parameter. Finally, it can be claimed that this method can be also utilized to distinguish between benign and cancerous cells or even to probe tumor heterogeneity toward high throughput cell cytometry.

Monkman, J, Taheri, T, Ebrahimi Warkiani, M, O’Leary, C, Ladwa, R, Richard, D, O’Byrne, K & Kulasinghe, A 2020, 'High-Plex and High-Throughput Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)', Cancers, vol. 12, no. 12, pp. 3551-3551.
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Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.

Nagy, Z, Cheung, BB, Tsang, W, Tan, O, Herath, M, Ciampa, OC, Shadma, F, Carter, DR & Marshall, GM 2020, 'Withaferin A activates TRIM16 for its anti-cancer activity in melanoma', Scientific Reports, vol. 10, no. 1.
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AbstractAlthough selective BRAF inhibitors and novel immunotherapies have improved short-term treatment responses in metastatic melanoma patients, acquired resistance to these therapeutics still represent a major challenge in clinical practice. In this study, we evaluated the efficacy of Withaferin A (WFA), derived from the medicinal plant Withania Somnifera, as a novel therapeutic agent for the treatment of melanoma. WFA showed selective toxicity to melanoma cells compared to non-malignant cells. WFA induced apoptosis, significantly reduced cell proliferation and inhibited migration of melanoma cells. We identified that repression of the tumour suppressor TRIM16 diminished WFA cytotoxicity, suggesting that TRIM16 was in part responsible for the cytotoxic effects of WFA in melanoma cells. Together our data indicates that WFA has potent cytopathic effects on melanoma cells through TRIM16, suggesting a potential therapeutic application of WFA in the disease.

Nguyen, HG & Nguyen, TV 2020, 'An epidemiologic profile of COVID-19 patients in Vietnam'.
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AbstractBackground and AimThere is a paucity of data on the COVID-19 pandemic in Vietnam. In this paper, we sought to provide an epidemiologic description of patients who were infected with SARS-Cov-2 in Vietnam.MethodsData were abstracted from the wikipedia’s COVID-19 information resource and Johns Hopkins University Dashboard. Demographic data and treatment status were obtained for each patient in each day. The coverage period was from 23/1/2020 to 10/4/2020. Descriptive analyses of incident cases were stratified by gender and age group. The estimation of the reproduction ratio was done with a bootstrap method using the R statistical environment.ResultsDuring the coverage period, Vietnam has recorded 257 cases of COVID-19. Approximately 54% of the cases were women. The median age of patients was 30 years (range: 3 months to 88 years), with 78% of patients aged 49 or younger. About 66% (n = 171) of patients were overseas tourists (20%) and Vietnamese students or workers returning from overseas (46%). Approximately 57% (n = 144) of patients have been recovered and discharged from hospitals. There have been no mortality. The reproduction ratio was estimated to range between 0.95 and 1.24.ConclusionThese data indicate that a majority of COVID-19 patients in Vietnam was imported cases in overseas tourists and young students and workers who had returned from overseas.

Nguyen, HG, Pham, MTD, Ho-Pham, LT & Nguyen, TV 2020, 'Lean mass and peak bone mineral density', Osteoporosis and Sarcopenia, vol. 6, no. 4, pp. 212-216.
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Nguyen, PTK, Tran, HT, Tran, TS, Fitzgerald, DA, Graham, SM & Marais, BJ 2020, 'Predictors of Unlikely Bacterial Pneumonia and Adverse Pneumonia Outcome in Children Admitted to a Hospital in Central Vietnam', Clinical Infectious Diseases, vol. 70, no. 8, pp. 1733-1741.
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Abstract Background Pneumonia is the leading cause of antibiotic use and hospitalization in Vietnam. There is a need for better prediction of unlikely bacterial pneumonia and adverse pneumonia outcome in order to guide hospital admission and improve rational antibiotic use. Methods All children under 5 admitted with pneumonia (per clinician assessment) to the Da Nang Hospital for Women and Children were prospectively enrolled. Children were classified as having likely or unlikely bacterial pneumonia and followed for outcome assessment. A Bayesian model averaging approach was used to identify predictors of unlikely bacterial pneumonia and adverse pneumonia outcome, which guided the development of a pragmatic management algorithm. Results Of 3817 patients assessed, 2199 (57.6%) met World Health Organization (WHO) pneumonia criteria. In total, 1594 (41.7%) children were classified as having unlikely and 129 (3.4%) as having likely bacterial pneumonia. The remainder (2399; 62.9%) were considered to have disease of uncertain etiology. Factors predictive of unlikely bacterial pneumonia were no fever, no consolidation on chest radiograph, and absolute neutrophil count &lt;5 × 109/L at presentation, which had a negative predictive value (NPV) for likely bacterial pneumonia of 99.0%. Among those who met WHO pneumonia criteria, 8.6% (189/2199) experienced an adverse outcome. Not having any WHO danger sign or consolidation on chest radiograph had an NPV of 96.8% for adverse pneumonia outcome. Co...

Nguyen, TV 2020, 'Common methodological issues and suggested solutions in bone research', Osteoporosis and Sarcopenia, vol. 6, no. 4, pp. 161-167.
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Bone research is a dynamic area of scientific investigation that usually encompasses multidisciplines. Virtually all basic cellular research, clinical research and epidemiologic research rely on statistical concepts and methodology for inference. This paper discusses common issues and suggested solutions concerning the application of statistical thinking in bone research, particularly in clinical and epidemiological investigations. The issues are sample size estimation, biases and confounders, analysis of longitudinal data, categorization of continuous data, selection of significant variables, over-fitting, P-values, false positive finding, confidence interval, and Bayesian inference. It is hoped that by adopting the suggested measures the scientific quality of bone research can improve.

Nguyen, TV 2020, 'Toward the era of precision fracture risk assessment', The Journal of Clinical Endocrinology & Metabolism, vol. 105, no. 7, pp. e2636-e2638.
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Nguyen, TV & Eisman, JA 2020, 'Post‐GWAS Polygenic Risk Score: Utility and Challenges', JBMR Plus, vol. 4, no. 11, p. e10411.
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ABSTRACTOver the past decade, through genome‐wide association studies, more than 300 genetic variants have been identified to be associated with either BMD or fracture risk. These genetic variants are common in the general population, but they exert small to modest effects on BMD, suggesting that the utility of any single variant is limited. However, a combination of effect sizes from multiple variants in the form of the polygenic risk score (PRS) can provide a useful indicator of fracture risk beyond that obtained by conventional clinical risk factors. In this perspective, we review the progress of genetics of osteoporosis and approaches for creating PRSs, their uses, and caveats. Recent studies support the idea that the PRS, when integrated into existing fracture prediction models, can help clinicians and patients alike to better assess the fracture risk for an individual, and raise the possibility of precision risk assessment. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pang, B, Zhu, Y, Ni, J, Ruan, J, Thompson, J, Malouf, D, Bucci, J, Graham, P & Li, Y 2020, '<p>Quality Assessment and Comparison of Plasma-Derived Extracellular Vesicles Separated by Three Commercial Kits for Prostate Cancer Diagnosis</p>', International Journal of Nanomedicine, vol. Volume 15, pp. 10241-10256.
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Introduction

Current standard biomarkers in clinic are not specific enough for prostate cancer (PCa) diagnosis. Extracellular vesicles (EVs) are nano-scale vesicles released by most mammalian cells. EVs are promising biomarker source for PCa liquid biopsy due to its minimal invasive approach, rich information and improved accuracy compared to the clinical standard prostate-specific antigen (PSA). However, current EV separation methods cannot separate pure EVs and the quality characteristics from these methods remain largely unknown. In this study, we evaluated the quality characteristics of human plasma-derived EVs by comparing three clinical suitable separation kits.

Methods

We combined EV separation by commercial kits with magnetic beads capture and flow cytometry analysis, and compared three kits including ExoQuick Ultra based on precipitation and qEV35 and qEV70 based on size exclusion chromatography (SEC).

Results

Our results indicated that two SEC kits provided higher EV purity and lower protein contamination compared to ExoQuick Ultra precipitation and that qEV35 demonstrated a higher EV yield but lower EV purity compared to qEV70. Particle number correlated very well particularly with CD9/81/63 positive EVs for all three kits, which confirms that particle number can be used as the estimate for EV amount. At last, we found that several EV metrics including total EVs and PSA-specific EVs could not differentiate PCa patients from health controls.

Conclusion

We provided a systematic workflow for the comparison of three separation kits as well as a general analysis process in clinical laboratories for EV-based cancer diagnosis. Better EV-associated cancer biomarkers need to be explored in the future study with a larger cohort.

Pang, B, Zhu, Y, Ni, J, Thompson, J, Malouf, D, Bucci, J, Graham, P & Li, Y 2020, 'Extracellular vesicles: the next generation of biomarkers for liquid biopsy-based prostate cancer diagnosis', Theranostics, vol. 10, no. 5, pp. 2309-2326.
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Prostate cancer (PCa) is a leading cause of cancer death for males in western countries. The current gold standard for PCa diagnosis - template needle biopsies - often does not convey a true representation of the molecular profile given sampling error and complex tumour heterogeneity. Presently available biomarker blood tests have limited accuracy. There is a growing demand for novel diagnostic approaches to reduce both the number of men with an abnormal PSA/ DRE who undergo invasive biopsy and the number of cores collected per biopsy. 'Liquid biopsy' is a minimally invasive biofluid-based approach that has the potential to provide information and improve the accuracy of diagnosis for patients' treatment selection, prognostic counselling and development of risk-adjusted follow-up protocols. Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by tumour cells which may provide a real-time snapshot of the entire tumour in a non-invasive way. EVs can regulate physiological processes and mediate systemic dissemination of various types of cancers. Emerging evidence suggests that EVs have crucial roles in PCa development and metastasis. Most importantly, EVs are directly derived from their parent cells with their information. EVs contain components including proteins, mRNAs, DNA fragments, non-coding RNAs and lipids, and play a critical role in intercellular communication. Therefore, EVs hold promise for the discovery of liquid biopsy-based biomarkers for PCa diagnosis. Here, we review the current approaches for EV isolation and analysis, summarise the recent advances in EV protein biomarkers in PCa and focus on liquid biopsy-based EV biomarkers in PCa diagnosis for personalised medicine.

Piggin, CL, Roden, DL, Law, AMK, Molloy, MP, Krisp, C, Swarbrick, A, Naylor, MJ, Kalyuga, M, Kaplan, W, Oakes, SR, Gallego-Ortega, D, Clark, SJ, Carroll, JS, Bartonicek, N & Ormandy, CJ 2020, 'ELF5 modulates the estrogen receptor cistrome in breast cancer', PLOS Genetics, vol. 16, no. 1, pp. e1008531-e1008531.
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Poon, C, Chou, J, Cortie, M & Kabakova, I 2020, 'Brillouin imaging for studies of micromechanics in biology and biomedicine: from current state-of-the-art to future clinical translation', Journal of Physics: Photonics, vol. 3, no. 1, pp. 1-25.
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Brillouin imaging is increasingly recognized to be a powerful technique thatenables non-invasive measurement of the mechanical properties of cells andtissues on a microscopic scale. This provides an unprecedented tool forinvestigating cell mechanobiology, cell-matrix interactions, tissuebiomechanics in healthy and disease conditions and other fundamental biologicalquestions. Recent advances in optical hardware have particularly acceleratedthe development of the technique, with increasingly finer spectral resolutionand more powerful system capabilities. We envision that further developmentswill enable translation of Brillouin imaging to assess clinical specimens andsamples for disease screening and monitoring. The purpose of this review is tosummarize the state-of-the-art in Brillouin microscopy and imaging with aspecific focus on biological tissue and cell measurements. Key system andoperational requirements will be discussed to facilitate wider application ofBrillouin imaging along with current challenges for translation of thetechnology for clinical and medical applications.

Qin, J, Guo, Y, Xue, B, Shi, P, Chen, Y, Su, QP, Hao, H, Zhao, S, Wu, C, Yu, L, Li, D & Sun, Y 2020, 'ER-mitochondria contacts promote mtDNA nucleoids active transportation via mitochondrial dynamic tubulation', Nature Communications, vol. 11, no. 1, p. 4471.
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AbstractA human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) packaged into nucleoids. Currently, the segregation and allocation of nucleoids are thought to be passively determined by mitochondrial fusion and division. Here we provide evidence, using live-cell super-resolution imaging, that nucleoids can be actively transported via KIF5B-driven mitochondrial dynamic tubulation (MDT) activities that predominantly occur at the ER-mitochondria contact sites (EMCS). We further demonstrate that a mitochondrial inner membrane protein complex MICOS links nucleoids to Miro1, a KIF5B receptor on mitochondria, at the EMCS. We show that such active transportation is a mechanism essential for the proper distribution of nucleoids in the peripheral zone of the cell. Together, our work identifies an active transportation mechanism of nucleoids, with EMCS serving as a key platform for the interplay of nucleoids, MICOS, Miro1, and KIF5B to coordinate nucleoids segregation and transportation.

Ramakrishna, VAS, Chamoli, U, Rajan, G, Mukhopadhyay, SC, Prusty, BG & Diwan, AD 2020, 'Smart orthopaedic implants: A targeted approach for continuous postoperative evaluation in the spine', Journal of Biomechanics, vol. 104, pp. 109690-109690.
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Raoufi, MA, Razavi Bazaz, S, Niazmand, H, Rouhi, O, Asadnia, M, Razmjou, A & Ebrahimi Warkiani, M 2020, 'Fabrication of unconventional inertial microfluidic channels using wax 3D printing', Soft Matter, vol. 16, no. 10, pp. 2448-2459.
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A novel workflow for the fabrication of inertial microfluidic devices based on the wax 3D printing method.

Razavi Bazaz, S, Amiri, HA, Vasilescu, S, Abouei Mehrizi, A, Jin, D, Miansari, M & Ebrahimi Warkiani, M 2020, 'Obstacle-free planar hybrid micromixer with low pressure drop', Microfluidics and Nanofluidics, vol. 24, no. 8.
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© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Planar micromixers with repetitive units have received substantial research interest since they allow low cost, lab-on-a-chip (LOC), and point-of-care (POC) systems to achieve a proper level of mixing for any given process. This paper presents an efficient planar micromixer that combines four types of mixing units, including convergent–divergent, circular, rhombic, and G-shaped micromixers. Their combinations and resulting effects on the mixing efficiency are numerically and experimentally investigated. A comprehensive Taguchi design of experiment method was used to reduce the number of the combinations from 1024 to only 16, among which a micromixer made of rhombic and G-shaped units readily showed a mixing efficiency beyond 80% over a wide range of inlet Reynolds numbers 0.001–0.3 and 35–65; meanwhile, a pressure drop as low as 12 kPa was reported. The velocity and concentration fields and their gradients within the nominated micromixer were analyzed, providing a better understanding of the mixing mechanism. These results offer design insights for further development of planar micromixers with repetitive unites for low-cost LOC and POC devices.

Razavi Bazaz, S, Hazeri, AH, Rouhi, O, Mehrizi, AA, Jin, D & Warkiani, ME 2020, 'Volume-preserving strategies to improve the mixing efficiency of serpentine micromixers', Journal of Micromechanics and Microengineering, vol. 30, no. 11, pp. 115022-115022.
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Abstract In this study, we have proposed volume-preserving strategies to boost chaoticadvection and improve the mixing efficiency of serpentine micromixers. The proposed strategies revolve around the point that the volume of the micromixer is kept constant during the manipulation. The first strategy involves the utilization of a nozzle-diffuser (ND) shaped microchannel. Using this, the velocity of the fluids fluctuates in an alternating pattern, leading to additional chaotic advection, a decrease in the mixing path, and an increase in the mixing index. The second strategy uses non-aligned inlets to generate swirl inducing effects at the microchannel entrance, where the collision of two fluids generates angular momentum in the flow, providing more chaotic advection. These strategies proved to be effective in boosting the mixing efficiency over wide ranges of Re in which 60% enhancement (from 20.53% to 80.31%) was achieved for Re of 30 by applying an ND shaped microchannel, and 20% enhancement (from 12.71% to 32.21%) was achieved for a critical Re of 15 by applying both of the strategies simultaneously.

Razavi Bazaz, S, Mashhadian, A, Ehsani, A, Saha, SC, Krüger, T & Ebrahimi Warkiani, M 2020, 'Computational inertial microfluidics: a review', Lab on a Chip, vol. 20, no. 6, pp. 1023-1048.
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Schematic illustration of various kinds of geometries used for inertial microfluidics.

Razavi Bazaz, S, Rouhi, O, Raoufi, MA, Ejeian, F, Asadnia, M, Jin, D & Ebrahimi Warkiani, M 2020, '3D Printing of Inertial Microfluidic Devices', Scientific Reports, vol. 10, no. 1, p. 5929.
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AbstractInertial microfluidics has been broadly investigated, resulting in the development of various applications, mainly for particle or cell separation. Lateral migrations of these particles within a microchannel strictly depend on the channel design and its cross-section. Nonetheless, the fabrication of these microchannels is a continuous challenging issue for the microfluidic community, where the most studied channel cross-sections are limited to only rectangular and more recently trapezoidal microchannels. As a result, a huge amount of potential remains intact for other geometries with cross-sections difficult to fabricate with standard microfabrication techniques. In this study, by leveraging on benefits of additive manufacturing, we have proposed a new method for the fabrication of inertial microfluidic devices. In our proposed workflow, parts are first printed via a high-resolution DLP/SLA 3D printer and then bonded to a transparent PMMA sheet using a double-coated pressure-sensitive adhesive tape. Using this method, we have fabricated and tested a plethora of existing inertial microfluidic devices, whether in a single or multiplexed manner, such as straight, spiral, serpentine, curvilinear, and contraction-expansion arrays. Our characterizations using both particles and cells revealed that the produced chips could withstand a pressure up to 150 psi with minimum interference of the tape to the total functionality of the device and viability of cells. As a showcase of the versatility of our method, we have proposed a new spiral microchannel with right-angled triangular cross-section which is technically impossible to fabricate using the standard lithography. We are of the opinion that the method proposed in this study will open the door for more complex geometries with the bespoke passive internal flow. Furthermore, the proposed fabrication workflow can be adopted at the production level, enabling large-scale man...

Reza, AM, Tavakoli, J, Zhou, Y, Qin, J & Tang, Y 2020, 'Synthetic fluorescent probes to apprehend calcium signalling in lipid droplet accumulation in microalgae—an updated review', Science China Chemistry, vol. 63, no. 3, pp. 308-324.
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Rezaei, M, Razavi Bazaz, S, Zhand, S, Sayyadi, N, Jin, D, Stewart, MP & Ebrahimi Warkiani, M 2020, 'Point of Care Diagnostics in the Age of COVID-19', Diagnostics, vol. 11, no. 1, pp. 9-9.
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The recent outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated serious respiratory disease, coronavirus disease 2019 (COVID-19), poses a major threat to global public health. Owing to the lack of vaccine and effective treatments, many countries have been overwhelmed with an exponential spread of the virus and surge in the number of confirmed COVID-19 cases. Current standard diagnostic methods are inadequate for widespread testing as they suffer from prolonged turn-around times (>12 h) and mostly rely on high-biosafety-level laboratories and well-trained technicians. Point-of-care (POC) tests have the potential to vastly improve healthcare in several ways, ranging from enabling earlier detection and easier monitoring of disease to reaching remote populations. In recent years, the field of POC diagnostics has improved markedly with the advent of micro- and nanotechnologies. Due to the COVID-19 pandemic, POC technologies have been rapidly innovated to address key limitations faced in existing standard diagnostic methods. This review summarizes and compares the latest available POC immunoassay, nucleic acid-based and clustered regularly interspaced short palindromic repeats- (CRISPR)-mediated tests for SARS-CoV-2 detection that we anticipate aiding healthcare facilities to control virus infection and prevent subsequent spread.

Roche, CD & Gentile, C 2020, 'Transplantation of a 3D Bioprinted Patch in a Murine Model of Myocardial Infarction', Journal of Visualized Experiments, vol. 2020, no. 163, pp. 1-12.
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© 2020 JoVE Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Testing regenerative properties of 3D bioprinted cardiac patches in vivo using murine models of heart failure via permanent left anterior descending (LAD) ligation is a challenging procedure and has a high mortality rate due to its nature. We developed a method to consistently transplant bioprinted patches of cells and hydrogels onto the epicardium of an infarcted mouse heart to test their regenerative properties in a robust and feasible way. First, a deeply anesthetized mouse is carefully intubated and ventilated. Following left lateral thoracotomy (surgical opening of the chest), the exposed LAD is permanently ligated and the bioprinted patch transplanted onto the epicardium. The mouse quickly recovers from the procedure after chest closure. The advantages of this robust and quick approach include a predicted 28-day mortality rate of up to 30% (lower than the 44% reported by other studies using a similar model of permanent LAD ligation in mice). Moreover, the approach described in this protocol is versatile and could be adapted to test bioprinted patches using different cell types or hydrogels where high numbers of animals are needed to optimally power studies. Overall, we present this as an advantageous approach which may change preclinical testing in future studies for the field of cardiac regeneration and tissue engineering.

Roche, CD, Brereton, RJL, Ashton, AW, Jackson, C & Gentile, C 2020, 'Current challenges in three-dimensional bioprinting heart tissues for cardiac surgery', European Journal of Cardio-Thoracic Surgery, vol. 58, no. 3, pp. 500-510.
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Abstract Summary Previous attempts in cardiac bioengineering have failed to provide tissues for cardiac regeneration. Recent advances in 3-dimensional bioprinting technology using prevascularized myocardial microtissues as ‘bioink’ have provided a promising way forward. This review guides the reader to understand why myocardial tissue engineering is difficult to achieve and how revascularization and contractile function could be restored in 3-dimensional bioprinted heart tissue using patient-derived stem cells.

Rzhevskiy, AS, Razavi Bazaz, S, Ding, L, Kapitannikova, A, Sayyadi, N, Campbell, D, Walsh, B, Gillatt, D, Ebrahimi Warkiani, M & Zvyagin, AV 2020, 'Rapid and Label-Free Isolation of Tumour Cells from the Urine of Patients with Localised Prostate Cancer Using Inertial Microfluidics', Cancers, vol. 12, no. 1, pp. 81-81.
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During the last decade, isolation of circulating tumour cells via blood liquid biopsy of prostate cancer (PCa) has attracted significant attention as an alternative, or substitute, to conventional diagnostic tests. However, it was previously determined that localised forms of PCa shed a small number of cancer cells into the bloodstream, and a large volume of blood is required just for a single test, which is impractical. To address this issue, urine has been used as an alternative to blood for liquid biopsy as a truly non-invasive, patient-friendly test. To this end, we developed a spiral microfluidic chip capable of isolating PCa cells from the urine of PCa patients. Potential clinical utility of the chip was demonstrated using anti-Glypican-1 (GPC-1) antibody as a model of the primary antibody in immunofluorescent assay for identification and detection of the collected tumour cells. The microchannel device was first evaluated using DU-145 cells in a diluted Dulbecco’s phosphate-buffered saline sample, where it demonstrated >85 (±6) % efficiency. The microchannel proved to be functional in at least 79% of cases for capturing GPC1+ putative tumour cells from the urine of patients with localised PCa. More importantly, a correlation was found between the amount of the captured GPC1+ cells and crucial diagnostic and prognostic parameter of localised PCa—Gleason score. Thus, the technique demonstrated promise for further assessment of its diagnostic value in PCa detection, diagnosis, and prognosis.

Sadeghi Rad, H, Bazaz, SR, Monkman, J, Ebrahimi Warkiani, M, Rezaei, N, O'Byrne, K & Kulasinghe, A 2020, 'The evolving landscape of predictive biomarkers in immuno‐oncology with a focus on spatial technologies', Clinical & Translational Immunology, vol. 9, no. 11.
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AbstractImmunotherapies have shown long‐lasting and unparalleled responses for cancer patients compared to conventional therapy. However, they seem to only be effective in a subset of patients. Therefore, it has become evident that a greater understanding of the tumor microenvironment (TME) is required to understand the nuances which may be at play for a favorable outcome to therapy. The immune contexture of the TME is an important factor in dictating how well a tumor may respond to immune checkpoint inhibitors. While traditional immunohistochemistry techniques allow for the profiling of cells in the tumor, this is often lost when tumors are analysed using bulk tissue genomic approaches. Moreover, the actual cellular proportions, cellular heterogeneity and deeper spatial distribution are lacking in characterisation. Advances in tissue interrogation technologies have given rise to spatially resolved characterisation of the TME. This review aims to provide an overview of the current methodologies that are used to profile the TME, which may provide insights into the immunopathology associated with a favorable outcome to immunotherapy.

Salik, B, Yi, H, Hassan, N, Santiappillai, N, Vick, B, Connerty, P, Duly, A, Trahair, T, Woo, AJ, Beck, D, Liu, T, Spiekermann, K, Jeremias, I, Wang, J, Kavallaris, M, Haber, M, Norris, MD, Liebermann, DA, D'Andrea, RJ, Murriel, C & Wang, JY 2020, 'Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia', Cancer Cell, vol. 38, no. 2, pp. 263-278.e6.
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Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.

Salomon, R, Martelotto, L, Valdes‐Mora, F & Gallego‐Ortega, D 2020, 'Genomic Cytometry and New Modalities for Deep Single‐Cell Interrogation', Cytometry Part A, vol. 97, no. 10, pp. 1007-1016.
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AbstractIn the past few years, the rapid development of single‐cell analysis techniques has allowed for increasingly in‐depth analysis of DNA, RNA, protein, and epigenetic states, at the level of the individual cell. This unprecedented characterization ability has been enabled through the combination of cytometry, microfluidics, genomics, and informatics. Although traditionally discrete, when properly integrated, these fields create the synergistic field of Genomic Cytometry. In this review, we look at the individual methods that together gave rise to the broad field of Genomic Cytometry. We further outline the basic concepts that drive the field and provide a framework to understand this increasingly complex, technology‐intensive space. Thus, we introduce Genomic Cytometry as an emerging field and propose that synergistic rationalization of disparate modalities of cytometry, microfluidics, genomics, and informatics under one banner will enable massive leaps forward in the understanding of complex biology. © 2020 International Society for Advancement of Cytometry

Shamshirian, A, Aref, AR, Yip, GW, Ebrahimi Warkiani, M, Heydari, K, Razavi Bazaz, S, Hamzehgardeshi, Z, Shamshirian, D, Moosazadeh, M & Alizadeh-Navaei, R 2020, 'Diagnostic value of serum HER2 levels in breast cancer: a systematic review and meta-analysis', BMC Cancer, vol. 20, no. 1, p. 1049.
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Abstract Background Measurement of serum human epidermal growth factor receptor-2 (HER-2/neu) levels might play an essential role as a diagnostic/screening marker for the early selection of therapeutic approaches and predict prognosis in breast cancer patients. We aimed to undertake a systematic review and meta-analysis focusing on the diagnostic/screening value of serum HER-2 levels in comparison to routine methods. Methods We performed a systematic search via PubMed, Scopus, Cochrane-Library, and Web of Science databases for human diagnostic studies reporting the levels of serum HER-2 in breast cancer patients, which was confirmed using the histopathological examination. Meta-analyses were carried out for sensitivity, specificity, accuracy, area under the ROC curve (AUC), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Results Fourteen studies entered into this investigation. The meta-analysis indicated the low sensitivity for serum HER2 levels (Sensitivity: 53.05, 95%CI 40.82–65.28), but reasonable specificity of 79.27 (95%CI 73.02–85.51), accuracy of 72.06 (95%CI 67.04–77.08) and AUC of 0.79 (95%CI 0.66–0.92). We also found a significant differences for PPV (PPV: 56.18, 95%CI 44.16–68.20), NPV (NPV: 76.93, 95%CI 69.56–84.31), PLR (PLR: 2.10, 95%CI 1.69–2.50) and NLR (NLR: 0.58, 95%CI 0.44–0.71). Conclusion Our findings revealed that although serum HER-2 le...

Sharbatoghli, M, Vafaei, S, Aboulkheyr Es, H, Asadi-Lari, M, Totonchi, M & Madjd, Z 2020, 'Prediction of the treatment response in ovarian cancer: a ctDNA approach', Journal of Ovarian Research, vol. 13, no. 1.
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AbstractOvarian cancer is the eighth most commonly occurring cancer in women. Clinically, the limitation of conventional screening and monitoring approaches inhibits high throughput analysis of the tumor molecular markers toward prediction of treatment response. Recently, analysis of liquid biopsies including circulating tumor DNA (ctDNA) open new way toward cancer diagnosis and treatment in a personalized manner in various types of solid tumors. In the case of ovarian carcinoma, growing pre-clinical and clinical studies underscored promising application of ctDNA in diagnosis, prognosis, and prediction of treatment response. In this review, we accumulate and highlight recent molecular findings of ctDNA analysis and its associations with treatment response and patient outcome. Additionally, we discussed the potential application of ctDNA in the personalized treatment of ovarian carcinoma.Graphical abstractctDNA-monitoring usage during the ovarian cancer treatments procedures.

Shrestha, J, Razavi Bazaz, S, Aboulkheyr Es, H, Yaghobian Azari, D, Thierry, B, Ebrahimi Warkiani, M & Ghadiri, M 2020, 'Lung-on-a-chip: the future of respiratory disease models and pharmacological studies', Critical Reviews in Biotechnology, vol. 40, no. 2, pp. 213-230.
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© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Recently, organ-on-a-chip models, which are microfluidic devices that mimic the cellular architecture and physiological environment of an organ, have been developed and extensively investigated. The chips can be tailored to accommodate the disease conditions pertaining to many organs; and in the case of this review, the lung. Lung-on-a-chip models result in a more accurate reflection compared to conventional in vitro models. Pharmaceutical drug testing methods traditionally use animal models in order to evaluate pharmacological and toxicological responses to a new agent. However, these responses do not directly reflect human physiological responses. In this review, current and future applications of the lung-on-a-chip in the respiratory system will be discussed. Furthermore, the limitations of current conventional in vitro models used for respiratory disease modeling and drug development will be addressed. Highlights of additional translational aspects of the lung-on-a-chip will be discussed in order to demonstrate the importance of this subject for medical research.

Sritharan, K, Chamoli, U, Kuan, J & Diwan, AD 2020, 'Assessment of degenerative cervical stenosis on T2-weighted MR imaging: sensitivity to change and reliability of mid-sagittal and axial plane metrics', Spinal Cord, vol. 58, no. 2, pp. 238-246.
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STUDY DESIGN:A retrospective cross-sectional study. OBJECTIVE:To assess the sensitivity to change and reliability of various mid-sagittal and axial plane metrics in the assessment of patients with single-level degenerative cervical stenosis on T2-weighted MR imaging. SETTING:A diagnostic MR imaging facility in Sydney (Australia). METHODS:We retrospectively reviewed T2-weighted MR images of 85 consecutive patients (48 M and 37 F) with single-level degenerative cervical stenosis. Canal compromise and cord compression were evaluated using three mid-sagittal plane metrics (M1, M2, and M3) and two axial plane metrics (M4 and M5), at the level of stenosis and nonstenotic cephalad and caudal levels (controls). Sensitivity to change (SC) for each metric was evaluated as the percentage deviation of the measured value from the estimated normal value based on cephalad and caudal controls. Reliability for each metric was evaluated using intraclass correlation coefficients. RESULTS:Degenerative cervical stenosis showed a bimodal distribution peaking at C5-6 (n = 32) and C3-4 (n = 29) levels. The changes in the canal and cord geometry along the rostrocaudal axis were inconsistent. Across all individual subjects (reflecting a range of stenosis severity), M3 (-32.87% ± 10.60%) was more sensitive to change compared with M1 (16.64% ± 16.48%) and M2 (-23.95% ± 11.12%). Similarly, M4 (-24.62% ± 12.17%) was more sensitive to change compared with M5 (-6.71% ± 11.08%). The level of reliability was "moderate" to "excellent" for mid-sagittal plane measurements, and "poor" to "excellent" for axial plane measurements. CONCLUSION:Changes in canal dimensions in the mid-sagittal plane and cord shape in the axial plane are sensitive indicators of degenerative cervical stenosis on T2-weighted MR images.

Su, QP, Zhao, ZW, Meng, L, Ding, M, Zhang, W, Li, Y, Liu, M, Li, R, Gao, Y-Q, Xie, XS & Sun, Y 2020, 'Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures', Proceedings of the National Academy of Sciences, vol. 117, no. 26, pp. 15036-15046.
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Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a “CTCF-organized REplication Propagation” (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.

Syed, MS, Mirakhorli, F, Marquis, C, Taylor, RA & Warkiani, ME 2020, 'Particle movement and fluid behavior visualization using an optically transparent 3D-printed micro-hydrocyclone', Biomicrofluidics, vol. 14, no. 6, pp. 064106-064106.
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A hydrocyclone is a macroscale separation device employed in various industries, with many advantages, including high-throughput and low operational costs. Translating these advantages to microscale has been a challenge due to the microscale fabrication limitations that can be surmounted using 3D printing technology. Additionally, it is difficult to simulate the performance of real 3D-printed micro-hydrocyclones because of turbulent eddies and the deviations from the design due to printing resolution. To address these issues, we propose a new experimental method for the direct observation of particle motion in 3D printed micro-hydrocyclones. To do so, wax 3D printing and soft lithography were used in combination to construct a transparent micro-hydrocyclone in a single block of polydimethylsiloxane. A high-speed camera and fluorescent particles were employed to obtain clear in situ images and to confirm the presence of the vortex core. To showcase the use of this method, we demonstrate that a well-designed device can achieve a 95% separation efficiency for a sample containing a mixture of (desired) stem cells and (undesired) microcarriers. Overall, we hope that the proposed method for the direct visualization of particle trajectories in micro-hydrocyclones will serve as a tool, which can be leveraged to accelerate the development of micro-hydrocyclones for biomedical applications.

Tavakoli, J, Diwan, AD & Tipper, JL 2020, 'Advanced Strategies for the Regeneration of Lumbar Disc Annulus Fibrosus', International Journal of Molecular Sciences, vol. 21, no. 14, pp. 4889-4889.
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Damage to the annulus fibrosus (AF), the outer region of the intervertebral disc (IVD), results in an undesirable condition that may accelerate IVD degeneration causing low back pain. Despite intense research interest, attempts to regenerate the IVD have failed so far and no effective strategy has translated into a successful clinical outcome. Of particular significance, the failure of strategies to repair the AF has been a major drawback in the regeneration of IVD and nucleus replacement. It is unlikely to secure regenerative mediators (cells, genes, and biomolecules) and artificial nucleus materials after injection with an unsealed AF, as IVD is exposed to significant load and large deformation during daily activities. The AF defects strongly change the mechanical properties of the IVD and activate catabolic routes that are responsible for accelerating IVD degeneration. Therefore, there is a strong need to develop effective therapeutic strategies to prevent or reconstruct AF damage to support operational IVD regenerative strategies and nucleus replacement. By the way of this review, repair and regenerative strategies for AF reconstruction, their current status, challenges ahead, and future outlooks were discussed.

Tavakoli, J, Diwan, AD & Tipper, JL 2020, 'Elastic fibers: The missing key to improve engineering concepts for reconstruction of the Nucleus Pulposus in the intervertebral disc', Acta Biomaterialia, vol. 113, pp. 407-416.
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Tavakoli, J, Diwan, AD & Tipper, JL 2020, 'The ultrastructural organization of elastic fibers at the interface of the nucleus and annulus of the intervertebral disk', Acta Biomaterialia, vol. 114, pp. 323-332.
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There has been no study to describe the ultrastructural organization of elastic fibers at the interface of the nucleus pulposus and annulus fibrosus of the intervertebral disk (IVD), a region called the transition zone (TZ). A previously developed digestion technique was optimized to eliminate cells and non-elastin ECM components except for the elastic fibers from the anterolateral (AL) and posterolateral (PL) regions of the TZ in ovine IVDs. Not previously reported, the current study identified a complex elastic fiber network across the TZ for both AL and PL regions. In the AL region, this network consisted of major thick elastic fibers (≈ 1 µm) that were interconnected with delicate (< 200 nm) elastic fibers. While the same ultrastructural organization was observed in the PL region, interestingly the size of the elastic fibers was smaller (< 100 nm) compared to those that were located in the AL region. Quantitative analysis of the elastic fibers revealed significant differences in the size (p < 0.001) and the orientation of elastic fibers (p = 0.001) between the AL and PL regions, with a higher orientation and larger size of elastic fibers observed in the AL region. The gradual elimination of cells and non-elastin extracellular matrix components identified that elastic fibers in the TZ region in combination with the extracellular matrix created a honeycomb structure that was more compact at the AF interface compared to that located close to the NP. Three different symmetrically organized angles of rotation (0⁰ and ±90⁰) were detected for the honeycomb structure at both interfaces, and the structure was significantly orientated at the TZ-AF compared to the TZ-NP interface (p = 0.003).

Tavakoli, J, Joseph, N, Chuah, C, Raston, CL & Tang, Y 2020, 'Vortex fluidic enabling and significantly boosting light intensity of graphene oxide with aggregation induced emission luminogen', Materials Chemistry Frontiers, vol. 4, no. 7, pp. 2126-2130.
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We have discovered a novel and cost-effective approach to produce GO/aggregation-induced emission demonstrating high fluorescent performance.

Tavakoli, J, Pye, S, Reza, AHMM, Xie, N, Qin, J, Raston, CL, Tang, BZ & Tang, Y 2020, 'Tuning aggregation-induced emission nanoparticle properties under thin film formation', Materials Chemistry Frontiers, vol. 4, no. 2, pp. 537-545.
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The preparation of AIE nanoparticles under thin film formation controls their size and the associated fluorescent intensity, with the smaller nanoparticles significantly increasing brightness.

Tavakoli, J, Raston, CL & Tang, Y 2020, 'Tuning Surface Morphology of Fluorescent Hydrogels Using a Vortex Fluidic Device', Molecules, vol. 25, no. 15, pp. 3445-3445.
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In recent decades, microfluidic techniques have been extensively used to advance hydrogel design and control the architectural features on the micro- and nanoscale. The major challenges with the microfluidic approach are clogging and limited architectural features: notably, the creation of the sphere, core-shell, and fibers. Implementation of batch production is almost impossible with the relatively lengthy time of production, which is another disadvantage. This minireview aims to introduce a new microfluidic platform, a vortex fluidic device (VFD), for one-step fabrication of hydrogels with different architectural features and properties. The application of a VFD in the fabrication of physically crosslinked hydrogels with different surface morphologies, the creation of fluorescent hydrogels with excellent photostability and fluorescence properties, and tuning of the structure–property relationship in hydrogels are discussed. We conceive, on the basis of this minireview, that future studies will provide new opportunities to develop hydrogel nanocomposites with superior properties for different biomedical and engineering applications.

Tavakoli, J, Raston, CL, Ma, Y & Tang, Y 2020, 'Vortex fluidic mediated one-step fabrication of polyvinyl alcohol hydrogel films with tunable surface morphologies and enhanced self-healing properties', Science China Materials, vol. 63, no. 7, pp. 1310-1317.
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Tavakoli, J, Wang, J, Chuah, C & Tang, Y 2020, 'Natural-based Hydrogels: A Journey from Simple to Smart Networks for Medical Examination', Current Medicinal Chemistry, vol. 27, no. 16, pp. 2704-2733.
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Natural hydrogels, due to their unique biological properties, have been used extensively for various medical and clinical examinations that are performed to investigate the signs of disease. Recently, complex-crosslinking strategies improved the mechanical properties and advanced approaches have resulted in the introduction of naturally derived hydrogels that exhibit high biocompatibility, with shape memory and self-healing characteristics. Moreover, the creation of self-assembled natural hydrogels under physiological conditions has provided the opportunity to engineer fine-tuning properties. To highlight recent studies of natural-based hydrogels and their applications for medical investigation, a critical review was undertaken using published papers from the Science Direct database. This review presents different natural-based hydrogels (natural, natural-synthetic hybrid and complex-crosslinked hydrogels), their historical evolution, and recent studies of medical examination applications. The application of natural-based hydrogels in the design and fabrication of biosensors, catheters and medical electrodes, detection of cancer, targeted delivery of imaging compounds (bioimaging) and fabrication of fluorescent bioprobes is summarised here. Without doubt, in future, more useful and practical concepts will be derived to identify natural-based hydrogels for a wide range of clinical examination applications.

Tee, AE, Ciampa, OC, Wong, M, Fletcher, JI, Kamili, A, Chen, J, Ho, N, Sun, Y, Carter, DR, Cheung, BB, Marshall, GM, Liu, PY & Liu, T 2020, 'Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN‐amplified neuroblastoma', International Journal of Cancer, vol. 147, no. 7, pp. 1928-1938.
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Patients with neuroblastoma due to MYCN oncogene amplification and consequent N‐Myc oncoprotein overexpression have very poor prognosis. The cyclin‐dependent kinase 7 (CDK7)/super‐enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c‐Myc protein and suppresses c‐Myc protein degradation. Here we screened the U.S. Food and Drug Administration‐Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN‐amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N‐Myc protein but not N‐Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N‐Myc protein but not mRNA expression and decreased MYCN‐amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients, our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients.

Tran, T, Bliuc, D, O’Donoghue, S, Hansen, L, Abrahamsen, B, Bergh, JVD, Geel, TV, Geusens, P, Vestergaard, P, Nguyen, TV, Eisman, JA & Center, J 2020, 'OR13-03 Understanding Why Older People with Low Trauma Fractures Die Prematurely', Journal of the Endocrine Society, vol. 4, no. Supplement_1.
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Abstract There is increasing evidence that all proximal and not just hip fractures are associated with increased mortality risk. However, the cause of this increased mortality is unknown. We sought to determine the post-fracture trajectories of subsequent hospital admissions and mortality to develop an understanding of why patients with non-hip fractures die prematurely. This nationwide Danish population-based study included all individuals aged 50+ years who sustained an incident fragility fracture between 2001 and 2014. High-trauma fractures or individuals with fracture prior to 2001 were excluded. Fracture patients were matched 1:4 by sex, age and comorbidity status with non-fracture subjects alive at the time of fracture. Comorbidities included 33 unique medical conditions of the Charlson or Elixhauser comorbidity index. We modelled the contribution of specific fractures on the risk of subsequent admissions or death within the following 2 years. There were 212,498 women and 95,372 men with fracture followed by 30,677 and 19,519 deaths, respectively over 163,482 and 384,995 person-years of follow up. Mean age at fracture was 72± 11 for women and 75± 11 for men. Proximal fractures including hip, femur, pelvis, rib, clavicle and humerus had increased mortality compared with their matched non-fracture counterparts with HRs ranging from 1.5-4.0, while distal fractures such as ankle, forearm, hand or foot fractures had similar or lower mortality risk. Almost 75% of men and 60% of women had ≥1 comorbidity. For every additional comorbidity, risk of mortality increased for all fracture types. However, only for proximal fractures did the fracture itself independently increase mortality risk over and above co-morbidity status. The 2-yr post fracture admission and mortality patterns diffe...

Tran, T, Bliuc, D, Pham, HM, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, Josse, RG, Kaiser, SM, Kovacs, CS, Langsetmo, L, Prior, JC, Nguyen, TV & Center, JR 2020, 'A Risk Assessment Tool for Predicting Fragility Fractures and Mortality in the Elderly', Journal of Bone and Mineral Research, vol. 35, no. 10, pp. 1923-1934.
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ABSTRACT Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged ≥60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7–15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with a T-score of −1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, f...

Vasilescu, SA, Bazaz, SR, Jin, D, Shimoni, O & Warkiani, ME 2020, '3D printing enables the rapid prototyping of modular microfluidic devices for particle conjugation', Applied Materials Today, vol. 20, pp. 100726-100726.
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© 2020 Elsevier Ltd Antibody micro/nano-particle conjugates have proven to be essential tools in many diagnostic and nanomedicine applications. However, their production with homogenous coating and in a continuous fashion remains a tedious, labor-intensive, and costly process. In this regard, 3D micromixer-based microfluidic devices offer significant advantages over existing methods, where manipulating the flow in three dimensions increases fluid contact area and surface disruption, facilitating efficient mixing. While conventional softlithography is capable of fabricating simple 2D micromixers, complications arise when processing 3D structures. In this paper, we report the direct fabrication of a 3D complex microchannel design using additive manufacturing for the continuous conjugation of antibodies onto particle surfaces. This method benefits from a reduction in cost and time (from days to hours), simplified fabrication process, and limited post-processing. The flexibility of direct 3D printing allows quick and easy tailoring of design features to facilitate the production of micro and nanoparticles conjugated with functional antibodies in a continuous mixing process. We demonstrate that the produced antibody-functionalized particles retain their functionality by a firm and specific interaction with antigen presenting cells. By connecting 3D printed micromixers across the conjugation process, we illustrate the role of 3D printed microchannels as modularized components. The 3D printing method we report enables a broad spectrum of researchers to produce complex microfluidic geometries within a short time frame.

Wang, B, Liu, H, Zhu, Y, Yan, L, Li, JJ & Zhao, B 2020, 'Risk Factors with Multilevel Evidence for Dislocation in Patients with Femoral Neck Fractures After Hip Hemiarthroplasty: A Systematic Review', Indian Journal of Orthopaedics, vol. 54, no. 6, pp. 795-804.
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Background

Hip hemiarthroplasty (HA) is a standard surgical procedure for elderly patients with displaced fracture of the femoral neck, where dislocation is a possible complication. This study is a systematic review on the risk factors of implant dislocation in patients with femoral neck fracture following hip hemiarthroplasty (HA), and evaluates the methodological quality of the included studies.

Methods

Studies on risk factor assessment of dislocation following hip HA were sourced from EMBASE, Ovid, PubMed and ScienceDirect databases. The quality of included studies was evaluated using an improved quality evaluation method combined with a best-evidence synthesis method.

Results

A total of 130,127 patients were involved in 17 observational studies included in this systematic review, with a dislocation rate that ranged between 0.76 and 12.2% (overall incidence was 4-5% by meta-analysis). According to the applied quality evaluation criteria, eight studies were considered to be of high quality, six to be of medium quality, and three to be of low quality. The posterolateral surgical approach was identified as the only risk factor supported by strong evidence, while patients with small acetabular coverage and low postoperative offset were identified as risk factors supported by moderate evidence, and 11 other risk factors were supported by limited evidence.

Conclusion

This systematic review provides some evidence in helping surgeons develop optimal prevention strategies for dislocation following hip HA during the perioperative period based on common risk factors identified in the literature. However, conclusive evidence supporting most of these risk factors is lacking and more methodologically rigorous studies are required to increase the confidence of recommendations.

Wang, H, Roche, CD & Gentile, C 2020, 'Omentum support for cardiac regeneration in ischaemic cardiomyopathy models: a systematic scoping review', European Journal of Cardio-Thoracic Surgery, vol. 58, no. 6, pp. 1118-1129.
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Abstract OBJECTIVES Preclinical in vivo studies using omental tissue as a biomaterial for myocardial regeneration are promising and have not previously been collated. We aimed to evaluate the effects of the omentum as a support for bioengineered tissue therapy for cardiac regeneration in vivo.  METHODS A systematic scoping review was performed. Only English-language studies that used bioengineered cardio-regenerative tissue, omentum and ischaemic cardiomyopathy in vivo models were included. RESULTS We initially screened 1926 studies of which 17 were included in the final qualitative analysis. Among these, 11 were methodologically comparable and 6 were non-comparable. The use of the omentum improved the engraftment of bioengineered tissue by improving cell retention and reducing infarct size. Vascularization was also improved by the induction of angiogenesis in the transplanted tissue. Omentum-supported bioengineered grafts were associated with enhanced host reverse remodelling and improved haemodynamic measurements. CONCLUSIONS The omentum is a promising support for myocardial regenerative bioengineering in vivo. Future studies would benefit from more homogenous methodologies and reporting of outcomes to allow for direct comparison.

Wu, C, Fang, J, Zhang, Z, Entezari, A, Sun, G, Swain, MV & Li, Q 2020, 'Fracture modeling of brittle biomaterials by the phase-field method', Engineering Fracture Mechanics, vol. 224, pp. 106752-106752.
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© 2019 Elsevier Ltd Biomaterials have been extensively used in prosthetic applications for their proven biocompatibility and osseointegration characteristics. Nevertheless, one of the critical issues of some synthetic biomaterials is brittleness prone to experience fracture failure due to low tensile strength and low fracture toughness. This study aims to employ a recently-developed phase-field model to simulate the crack propagation in brittle biomaterials. Unlike discrete fracture modeling methods, the phase-field approach allows simulating crack path in a continuous manner, thereby avoiding remeshing that may not be trivial for complicated fracture surfaces and facilitate iterative procedure commonly required for structural optimization. The phase-field model is formulated to treat the fracture path as a localized region of diffusive damage that can be described in terms of a phase-field function, in which the discreteness in cracked materials is assumed to be smeared. In this study, three representative case studies from the biomedical context, namely a zirconia-based dental bridge (or namely fixed partial denture (FPD)), a ceramic tissue scaffold and an analog saw-bone femur, are employed as illustrative examples. The phase-field modeling results are compared with the in-house experimental tests, demonstrating the effectiveness of the phase-field technique for predicting brittle fracture failure in several typical biomedical case scenarios. The phase-field model provides a useful tool for the computational fracture analysis and design optimization of other brittle biomaterials.

Xiang, Y, Basirun, C, Chou, J, Warkiani, ME, Török, P, Wang, Y, Gao, S & Kabakova, IV 2020, 'Background-free fibre optic Brillouin probe for remote mapping of micromechanics', Biomedical Optics Express, vol. 11, no. 11, pp. 6687-6687.
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Brillouin spectroscopy is a century-old technique that has recently receivedrenewed interest, as modern instrumentation has transformed it into a powerfulcontactless and label-free probe of micromechanical properties for biomedicalapplications. In particular, to fully harness the non-contact andnon-destructive nature of Brillouin imaging, there is strong motivation todevelop a fibre-integrated device and extend the technology into the domain ofin vivo and in situ operation, such as for medical diagnostics. This workpresents the first demonstration of a fibre optic Brillouin probe that iscapable of mapping the mechanical properties of a tissue-mimicking phantom.This is achieved through combination of miniaturised optical design, advancedhollow-core fibre fabrication and high-resolution 3D printing. The protypeprobe is compact, background-free and possesses the highest collectionefficiency to date, thus provides the foundation of a fibre-based Brillouindevice for remote in situ measurements in challenging and otherwisedifficult-to-reach environments, for biomedical, material science andindustrial applications.

Xing, D, Liu, W, Li, JJ, Liu, L, Guo, A, Wang, B, Yu, H, Zhao, Y, Chen, Y, You, Z, Lyu, C, Li, W, Liu, A, Du, Y & Lin, J 2020, 'Engineering 3D functional tissue constructs using self-assembling cell-laden microniches', Acta Biomaterialia, vol. 114, pp. 170-182.
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Tissue engineering using traditional size fixed scaffolds and injectable biomaterials are faced with many limitations due to the difficulties of producing macroscopic functional tissues. In this study, 3D functional tissue constructs were developed by inducing self-assembly of microniches, which were cell-laden gelatin microcryogels. During self-assembly, the accumulation of extracellular matrix (ECM) components was found to strengthen cell-cell and cell-ECM interactions, leading to the construction of a 'native' microenvironment that better preserved cell viability and functions. MSCs grown in self-assembled constructs showed increased maintenance of stemness, reduced senescence and improved paracrine activity compared with cells grown in individual microniches without self-assembly. As an example of applying the self-assembled constructs in tissue regeneration, the constructs were used to induce in vivo articular cartilage repair and successfully regenerated hyaline-like cartilage tissue in the absence of other extrinsic factors. This unique approach of developing self-assembled 3D functional constructs holds great promise for the generation of tissue engineered organoids and repair of challenging tissue defects. STATEMENT OF SIGNIFICANCE: We developed 3D functional tissue constructs using a unique gelatin-based microscopic hydrogel (microcryogels). Mesenchymal stem cells (MSCs) were loaded into gelatin microcryogels to form microscopic cell-laden units (microniches), which were induced to undergo self-assembly using a specially designed 3D printed frame. Extracellular matrix accumulation among the microniches resulted in self-assembled macroscopic constructs with superior ability to maintain the phenotypic characteristics and stemness of MSCs, together with the suppression of senescence and enhanced paracrine function. As an example of application in tissue regeneration, the self-assembled constructs were shown to successfully repair articular cartil...

Xing, D, Liu, W, Wang, B, Li, JJ, Zhao, Y, Li, H, Liu, A, Du, Y & Lin, J 2020, 'Intra-articular Injection of Cell-laden 3D Microcryogels Empower Low-dose Cell Therapy for Osteoarthritis in a Rat Model', Cell Transplantation, vol. 29, pp. 096368972093214-096368972093214.
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Intra-articular injection of mesenchymal stem cells (MSCs) in an osteoarthritic joint can help slow down cartilage destruction. However, cell survival and the efficiency of repair are generally low due to mechanical damage during injection and a high rate of cell loss. We, thus, investigated an improved strategy for cell delivery to an osteoarthritic joint through the use of three-dimensional (3D) microcryogels. MSCs were seeded into 3D microcryogels. The viability and proliferation of MSCs in microcryogels were determined over 5 d, and the phenotype of MSCs was confirmed through trilineage differentiation tests and flow cytometry. In Sprague Dawley rats with induced osteoarthritis (OA) of the knee joint, a single injection was made with the following groups: saline control, low-dose free MSCs (1 × 105 cells), high-dose free MSCs (1 × 106 cells), and microcryogels + MSCs (1 × 105 cells). Cartilage degeneration was evaluated by macroscopic examination, micro-computed tomographic analysis, and histology. MSCs grown in microcryogels exhibited optimal viability and proliferation at 3 d with stable maintenance of phenotype in vitro. Microcryogels seeded with MSCs were, therefore, primed for 3 d before being used for in vivo experiments. At 4 and 8 wk, the microcryogels + MSCs and high-dose free MSC groups had significantly higher International Cartilage Repair Society macroscopic scores, histological evidence of more proteoglycan deposition and less cartilage loss accompanied by a lower Mankin score, and minimal radiographic evidence of osteoarthritic changes in the joint compared to the other two groups. In conclusion, intra-articular injection of cell-laden 3D microcryogels containing a low dose of MSCs can achieve similar effects as a high dose of free MSCs for OA in a rat model. Primed MSCs in 3D microcryogels can be considered as an improved delivery strategy for cell therapy in tre...

Xing, D, Wu, J, Wang, B, Liu, W, Liu, W, Zhao, Y, Wang, L, Li, JJ, Liu, A, Zhou, Q, Hao, J & Lin, J 2020, 'Intra‐articular delivery of umbilical cord‐derived mesenchymal stem cells temporarily retard the progression of osteoarthritis in a rat model', International Journal of Rheumatic Diseases, vol. 23, no. 6, pp. 778-787.
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AbstractAimMesenchymal stem cell (MSC)‐based therapy is being explored in treating osteoarthritis (OA). Human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) are least reported. In this study, we investigated the effects of single intra‐articular injections of hUC‐MSCs on a rat OA model.MethodhUC‐MSCs were isolated from the Wharton's jelly of the human umbilical cord and identified. Eighteen Sprague‐Dawley rats were used for the OA model. All rats were divided into 3 groups: hyaluronic acid (HA)+MSCs (n = 6), HA (n = 6), and control group (n = 6). One by 106 hUC‐MSCs in 100 μL HA, 100 μL HA or 100 μL saline were injected into the knee joint 4 weeks post‐surgery as a single dose. Cartilage degeneration was evaluated at 6 and 12 weeks after treatment with macroscopic examination, micro‐computed tomography analysis, behavioral analysis, and histology.ResultsAt 6 weeks, the HA + MSCs group had a significantly better International Cartilage Repair Society score in the femoral condyle compared to the HA and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, with lower modified Mankin score in the HA + MSCs group. However, at 12 weeks there were no significant differences between groups from macroscopic examination and histological analysis. Subchondral bone sclerosis of the medial femoral condyle and behavioral tests showed no significant differences between groups at 6 and 12 weeks.ConclusionThese findings indicate that single injection of hUC‐MSCs can have temporary effects on decelerating the progression of cartilage degeneration in OA rats, but may not inhibit OA progression in the long‐term.

Xu, X, Lu, H & Lee, R 2020, 'Near Infrared Light Triggered Photo/Immuno-Therapy Toward Cancers', Frontiers in Bioengineering and Biotechnology, vol. 8.
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Nanomaterials-based phototherapies, mainly including photothermal therapy (PTT), photodynamic therapy (PDT) and photoimmunotherapy (PIT), present high efficacy, minimal invasion and negligible adverse effects in cancer treatment. The integrated phototherapeutic modalities can enhance the efficiency of cancer immunotherapy for clinical application transformation. The near-infrared (NIR) light source enables phototherapies with the high penetration depth in the biological tissues, less toxic to normal cells and tissues and a low dose of light irradiation. Mediated via the novel NIR-responsive nanomaterials, PTT and PDT are able to provoke cancer cells apoptosis from the generated heat and reactive oxygen species, respectively. The released cancer-specific antigens and membrane damage danger signals from the damaged cancer cells trigger immune responses, which would enhance the antitumor efficacy via a variety of immunotherapy. This review summarized the recent advances in NIR-triggered photo-/immune-therapeutic modalities and their synergistic mechanisms and applications toward cancers. Furthermore, the challenges, potential solutions and future directions of NIR-triggered photo-/immunotherapy were briefly discussed.

Yang, Y, Xing, D, Wang, Y, Jia, H, Li, B & Li, JJ 2020, 'A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway', BMC Molecular and Cell Biology, vol. 21, no. 1, pp. 53-11.
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Abstract Background Long noncoding RNAs (lncRNAs) are recently found to be critical regulators of the epigenome. However, our knowledge of their role in osteoarthritis (OA) development is limited. This study investigates the mechanism by which HOTAIR, a key lncRNA with elevated expression in OA, affects OA disease progression. Results HOTAIR expression was greatly elevated in osteoarthritic compared to normal chondrocytes. Silencing and over-expression of HOTAIR in SW1353 cells respectively reduced and increased the expression of genes associated with cartilage degradation in OA. Investigation of molecular pathways revealed that HOTAIR acted directly on Wnt inhibitory factor 1 (WIF-1) by increasing histone H3K27 trimethylation in the WIF-1 promoter, leading to WIF-1 repression that favours activation of the Wnt/β-catenin pathway. Conclusions Activation of Wnt/β-catenin signalling by HOTAIR through WIF-1 repression in osteoarthritic chondrocytes increases catabolic gene expression and promotes cartilage degradation. This is the first study to demonstrate a direct link between HOTAIR, WIF-1 and OA progression, which may be useful for future investigations into disease biomarkers or therapeutic targets.

Zhand, S, Razmjou, A, Azadi, S, Bazaz, SR, Shrestha, J, Jahromi, MAF & Warkiani, ME 2020, 'Metal–Organic Framework-Enhanced ELISA Platform for Ultrasensitive Detection of PD-L1', ACS Applied Bio Materials, vol. 3, no. 7, pp. 4148-4158.
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© 2020 American Chemical Society. The programmed cell death ligand 1 (PD-L1) protein has emerged as a predictive cancer biomarker and sensitivity to immune checkpoint blockade-based cancer immunotherapies. Current technologies for the detection of protein-based biomarkers, including the enzyme-linked immunosorbent assay (ELISA), have limitations such as low sensitivity and limit of detection (LOD) in addition to degradation of antibodies in exposure to environmental changes such as temperature and pH. To address these issues, we have proposed a metal-organic framework (MOF)-based ELISA for the detection of the PD-L1. A protective coating based on Zeolitic Imidazolate Framework 8 (ZIF-8) MOF thin film and polydopamine-polyethylenimine (PDA-PEI) was introduced on an ELISA plate for the improvement of antibody immobilization. Sensitivity and LOD of the resulting platform were compared with a conventional ELISA kit, and the bioactivity of the antibody in the proposed immunoassay was investigated in response to various pH and temperature values. The LOD and sensitivity of the MOF-based PD-L1 ELISA were 225 and 15.12 times higher, respectively, compared with those of the commercial ELISA kit. The antibody@ZIF-8/PDA-PEI was stable up to 55 °C and the pH range 5-10. The proposed platform can provide sensitive detection for target proteins, in addition to being resistant to elevated temperature and pH. The proposed MOF-based ELISA has significant potential for the clinical and diagnostic studies.

Zhand, S, Saghaeian Jazi, M, Mohammadi, S, Tarighati Rasekhi, R, Rostamian, G, Kalani, MR, Rostamian, A, George, J & Douglas, MW 2020, 'COVID-19: The Immune Responses and Clinical Therapy Candidates', International Journal of Molecular Sciences, vol. 21, no. 15, pp. 5559-5559.
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The pandemic of coronavirus disease 2019 (COVID-19), with rising numbers of patients worldwide, presents an urgent need for effective treatments. To date, there are no therapies or vaccines that are proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection. The most promising therapy to date is remdesivir, which is US Food and Drug Administration (FDA) approved for emergency use in adults and children hospitalized with severe suspected or laboratory-confirmed COVID-19. Herein we summarize the general features of SARS-CoV-2’s molecular and immune pathogenesis and discuss available pharmacological strategies, based on our present understanding of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Finally, we outline clinical trials currently in progress to investigate the efficacy of potential therapies for COVID-19.

Zheng, P, Su, QP, Jin, D, Yu, Y & Huang, X-F 2020, 'Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons', Frontiers in Neuroscience, vol. 14.
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Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R) - disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.

Zhu, Y, Li, JJ, Reng, J, Wang, S, Zhang, R & Wang, B 2020, 'Global trends of Pseudomonas aeruginosa biofilm research in the past two decades: A bibliometric study', MicrobiologyOpen, vol. 9, no. 6, pp. 1102-1112.
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AbstractPseudomonas aeruginosa biofilm formation is a primary cause of chronic infections. This has been a highly active area of research over the past two decades due to causing high mortality risks in immunocompromised patients. This study evaluates global trends in the dynamic and rapidly evolving field of P. aeruginosa biofilm research through bibliometric and visualized analyses. Publications from 1994 to 2018 on P. aeruginosa biofilm research were retrieved from Web of Science, Scopus, and PubMed, and their bibliometric data were systematically studied. The VOSviewer software was used to conduct global analyses of bibliographic coupling, coauthorship, cocitation, and co‐occurrence. A total of 9,527 publications were included in this study. The overall number of publications and research interest in the field displayed a strongly rising trend. The USA made the greatest contributions to the field, with the highest h‐index and number of citations compared with other countries, while Denmark had the highest average citation per publication. The Journal of Bacteriology had the highest number of publications in the field, while the University of Copenhagen was the institution with the highest contribution influence. Co‐occurrence network maps revealed that the most prominent topics in P. aeruginosa biofilm research were mechanistic studies, in vitro/in vivo studies, and biofilm formation studies. Pseudomonas aeruginosa biofilms constitute a dynamic research area in microbiology with increasing global research interest. Future studies will likely focus on investigating the mechanisms of biofilm formation to solve infection‐associated clinical problems.

Ho-Le, TP, Tran, TS, Pham, HM, Frost, SA, Center, J, Eisman, JA & Nguyen, TV 1970, 'Predicting Mortality and Re-fracture Following an Initital Fracture', JOURNAL OF BONE AND MINERAL RESEARCH, Annual Meeting of the American-Society-for-Bone-and Mineral Research (ASBMR), WILEY, ELECTR NETWORK, pp. 198-199.

Hossain, A, Tipper, JL & Wei, D 1970, 'Analysis of a Multi-Material Bone Plate and its Effect on Interfragmentary Strain for Bone Remodeling Processes', Volume 1: Additive Manufacturing; Advanced Materials Manufacturing; Biomanufacturing; Life Cycle Engineering; Manufacturing Equipment and Automation, ASME 2020 15th International Manufacturing Science and Engineering Conference, American Society of Mechanical Engineers.
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Abstract The success of bone repair using an internal fracture fixation technique is critically dependent on the stability and biological process between the fragmented bones. However, the currently used bone plates mainly focus on stability rather than biology of healing, which subsequently (a) results in significant stress-shielding effects and (b) prevents stress from transferring from the bone plate to the bone during the healing process. This study proposes a novel design of a bone plate for the fixation of long fractured bones, which can mitigate these disadvantages to strike a balance between stability and biology. The new multi-material design adopts stainless steel (SS316L) and magnesium alloy (AZ31B) of three thicknesses such as SS316L (1mm)-AZ31B (2mm), SS316L (1.5mm)-AZ31B (1.5mm), and SS316L (2mm)-AZ31B (1mm). The mechanical properties (bending stiffness and moment) of the bone plates were evaluated according to the ASTM: F382-17 standard. Static corrosion tests were conducted in Hank’s Balanced Salt Solution (HBSS) at 37.5 °C. Compared with those of the original (non-corroded) bone plates, the maximum load-carrying capacities of the corroded bone plates decreased from 670 N to 495 N, 891 N to 518 N, and 928 N to 709 N in the case of SS316L (1mm)-AZ31B (2mm), SS316L (1.5mm)-AZ31B (1.5mm), and SS316L (2mm)-AZ31B(1mm), respectively. Digital image correlation was utilized to evaluate the inter-fragmentary strain (IFS) in the physical model of fractured bone plates. The IFS increased from 0.526 to 0.815, 0.484 to 0.784, and 0.455 to 0.533 in the case of SS316L (1mm)-AZ31B (2mm), SS316L (1.5mm)-AZ31B (1.5mm), and SS316L (2mm)-AZ31B (1mm), respectively, when a load of 200 N was applied. An optimized design of the bone plate of SS316L and AZ31B for granulation tissue formation based on Perren’s theory and IFS was successfully proposed.

Kulasinghe, A, Kapeleris, J, Kenny, L, Hughes, B, Warkiani, M, Vela, I, Thiery, J-P, O'Byrne, K & Punyadeera, C 1970, 'Abstract 3384: Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer', Cancer Research, American Association for Cancer Research (AACR), pp. 3384-3384.
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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=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) 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 (Hazard ratio [HR]: 4.946; 95% [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 and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (T...

Kulasinghe, A, Kapeleris, J, Kenny, L, Warkiani, M, Vela, I, Thiery, JP, O'Byrne, K & Punyadeera, C 1970, 'Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers', CLINICAL CANCER RESEARCH, AACR-AHNS Head and Neck Conference - Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research, AMER ASSOC CANCER RESEARCH, TX, Austin, pp. 31-31.

Kulasinghe, A, O’Leary, C, Ladwa, R, Warkiani, M & O’byrne, K 1970, '43 Highly multiplexed digital spatial profiling of the tumor microenvironment of non-small-cell lung cancer (NSCLC)', Regular and young investigator award abstracts, 35th Anniversary Annual Meeting (SITC 2020), BMJ Publishing Group Ltd.
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O'Byrne, KJ, Kapeleris, J, Kulasinghe, A, Warkiani, ME, O'Leary, CG, Ladwa, R, Vela, I, Leo, P, Sternes, P & Punyadeera, C 1970, 'Culture of circulating tumour cells derived from non-small cell lung cancer.', JOURNAL OF CLINICAL ONCOLOGY, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), LIPPINCOTT WILLIAMS & WILKINS, ELECTR NETWORK.

Sofela, S, Sahloul, S, Kwon, T, Han, J, Warkiani, ME & Song, YA 1970, 'Synchronization of C. Elegans through high-throughput separation of eggs in a spiral microfluidic chip', 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017, pp. 1100-1101.
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In this work, we report a high-throughput sorting of C. elegans embryos from a mixed-age worm population in a spiral microfluidic chip for synchronization. Using inertial forces in the spiral chip, C. elegans eggs could efficiently be focused along the inner channel wall and separated out with high sorting efficiency and purity.

Syed, MS, Rafeie, M, Vandamme, D, Henderson, R & Warkiani, ME 1970, 'Selective separation of microalgae cells using inertial microfluidics', 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017, pp. 1375-1376.
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Microalgae are considered to be the most promising new source of biomass to meet world's growing demands. However, microalgal cultures are often contaminated, by bacteria or invading diatoms. The invasion of diatoms in a cell culture results in an overall decrease of biomass productivity and quality. This work demonstrates the application of inertial microfluidics for the selective separation and sorting of green microalgae cells from diatoms to obtain monocultures, at optimum conditions.

Fröch, JE, Kim, S, Stewart, C, Xu, X, Du, Z, Lockrey, M, Toth, M & Aharonovich, I 2020, 'Photonic nanobeam cavities with nano-pockets for efficient integration of fluorescent nanoparticles'.

Liu, B, Chen, C, Di, X, Liao, J, Wen, S, Su, QP, Shan, X, Xu, Z-Q, Ju, LA, Wang, F & Jin, D 2020, 'Upconversion nonlinear structured illumination microscopy', arXiv.
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Richards, C, Sesperez, K, Chhor, M, Ghorbanpour, S, Rennie, C, Ming, CLC, Evenhuis, C, Nikolic, VN, Orlic, NK, Mikovic, Z, Stefanovic, M, Cakic, Z, McGrath, K, Gentile, C, Bubb, K & McClements, L 2020, 'Characterisation of Cardiac Health in the Reduced Uterine Perfusion Pressure Model and a 3D Cardiac Spheroid Model, of Preeclampsia', Research Square Platform LLC.
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Thoms, JAI, Knezevic, K, Harvey, G, Huang, Y, Seneviratne, JA, Carter, DR, Subramanian, S, Skhinas, J, Chacon, D, Shah, A, de Jong, I, Beck, D, Göttgens, B, Larsson, J, Wong, JWH, Zanini, F & Pimanda, JE 2020, 'Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells', Cold Spring Harbor Laboratory.
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Yeola, A, Subramanian, S, Oliver, RA, Lucas, CA, Thoms, JAI, Yan, F, Olivier, J, Chacon, D, Tursky, ML, Hung, T, Power, C, Hardy, P, Ma, DD, McCarroll, J, Kavallaris, M, Hesson, LB, Beck, D, Curtis, DJ, Wong, JWH, Hardeman, EC, Walsh, WR, Mobbs, R, Chandrakanthan, V & Pimanda, JE 2020, 'Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine', Cold Spring Harbor Laboratory.
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ABSTRACTTerminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor–AB and 5-Azacytidine into multipotent stem cells with stromal cell characteristics. To generate a product that is amenable for therapeutic application, we have modified and optimised culture conditions to reprogram human adipocytes into induced multipotent stem cells (iMS) and expand them in vitro. The basal transcriptomes of adipocyte-derived iMS cells and matched adipose-tissue-derived mesenchymal stem cells were remarkably similar. However, there were distinct changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to new muscle, bone, cartilage and blood vessels with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibres without ectopic tissue formation. Taken together, human adipocyte derived iMS cells regenerate tissues in a context dependent manner without ectopic or neoplastic growth.

Yuan, X, Seneviratne, JA, Du, S, Xu, Y, Chen, Y, Jin, Q, Jin, X, Balachandran, A, Huang, S, Xu, Y, Zhai, Y, Lu, L, Tang, M, Dong, Y, Cheung, BB, Marshall, GM, Shi, W, Zhang, C & Carter, DR 2020, 'Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory', Cold Spring Harbor Laboratory.
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