Publications

Chamoli, U, Lam, M & Diwan, AD 2021, 'Replacing the Nucleus Pulposus for Degenerative Disc Disease and Disc Herniation: Disc Preservation Following Discectomy' in Handbook of Spine Technology, Springer International Publishing, pp. 1111-1129.
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Du, W, Di, X & Su, QP 2021, 'Studying Mitochondrial Network Formation by In Vivo and In Vitro Reconstitution Assay' in Methods in Molecular Biology, Springer US, pp. 333-341.
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Aboulkheyr Es, H, Bigdeli, B, Zhand, S, Aref, AR, Thiery, JP & Warkiani, ME 2021, 'Mesenchymal stem cells induce PD‐L1 expression through the secretion of CCL5 in breast cancer cells', Journal of Cellular Physiology, vol. 236, no. 5, pp. 3918-3928.
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AbstractVarious factors in the tumor microenvironment (TME) regulate the expression of PD‐L1 in cancer cells. In TME, mesenchymal stem cells (MSCs) play a crucial role in tumor progression, metastasis, and drug resistance. Emerging evidence suggests that MSCs can modulate the immune‐suppression capacity of TME through the stimulation of PD‐L1 expression in various cancers; nonetheless, their role in the induction of PD‐L1 in breast cancer remained elusive. Here, we assessed the potential of MSCs in the stimulation of PD‐L1 expression in a low PD‐L1 breast cancer cell line and explored its associated cytokine. We assessed the expression of MSCs‐related genes and their correlation with PD‐L1 across 1826 breast cancer patients from the METABRIC cohort. After culturing an ER+/differentiated/low PD‐L1 breast cancer cells with MSCs conditioned‐medium (MSC‐CM) in a microfluidic device, a variety of in‐vitro assays was carried out to determine the role of MSC‐CM in breast cancer cells' phenotype plasticity, invasion, and its effects on induction of PD‐L1 expression. In‐silico analysis showed a positive association between MSCs‐related genes and PD‐L1 expression in various types of breast cancer. Through functional assays, we revealed that MSC‐CM not only prompts a phenotype switch but also stimulates PD‐L1 expression at the protein level through secretion of various cytokines, especially CCL5. Treatment of MSCs with cytokine inhibitor pirfenidone showed a significant reduction in the secretion of CCL5 and consequently, expression of PD‐L1 in breast cancer cells. We concluded that MSCs‐derived CCL5 may act as a PD‐L1 stimulator in breast cancer.

Aghlmandi, A, Nikshad, A, Safaralizadeh, R, Warkiani, ME, Aghebati-Maleki, L & Yousefi, M 2021, 'Microfluidics as efficient technology for the isolation and characterization of stem cells.', EXCLI J, vol. 20, pp. 426-443.
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The recent years have been passed with significant progressions in the utilization of microfluidic technologies for cellular investigations. The aim of microfluidics is to mimic small-scale body environment with features like optical transparency. Microfluidics can screen and monitor different cell types during culture and study cell function in response to stimuli in a fully controlled environment. No matter how the microfluidic environment is similar to in vivo environment, it is not possible to fully investigate stem cells behavior in response to stimuli during cell proliferation and differentiation. Researchers have used stem cells in different fields from fundamental researches to clinical applications. Many cells in the body possess particular functions, but stem cells do not have a specific task and can turn into almost any type of cells. Stem cells are undifferentiated cells with the ability of changing into specific cells that can be essential for the body. Researchers and physicians are interested in stem cells to use them in testing the function of the body's systems and solving their complications. This review discusses the recent advances in utilizing microfluidic techniques for the analysis of stem cells, and mentions the advantages and disadvantages of using microfluidic technology for stem cell research.

Ahmadi, VE, Butun, I, Altay, R, Bazaz, SR, Alijani, H, Celik, S, Warkiani, ME & Koşar, A 2021, 'The effects of baffle configuration and number on inertial mixing in a curved serpentine micromixer: Experimental and numerical study', Chemical Engineering Research and Design, vol. 168, pp. 490-498.
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Recently, the application of micromixers in microfluidic systems including chemical and biological assays has been widely accomplished. Passive micromixers, benefitting from the low-cost and a less-complex fabrication process, rely solely on their geometry. In particular, Dean vortices generated in curved microchannels enhance the mixing performance through chaotic advection. To improve the mixing performance at relatively low Reynolds numbers (i.e. 1 ≤ Re ≤ 50), this study introduces baffles into the side walls of curved serpentine micromixers with curvature angles of 280°, which constantly agitate, stretch and fold the fluids streams. Six different baffle configurations were designed and the effects of geometry and the number of baffles were investigated both experimentally and numerically. According to the experimental results, while the maximum outlet mixing index of the micromixer with no baffles was 0.61, that of the micromixer with quasi-rectangular baffles was 0.98 at a low Reynolds number of 20, indicating the major contribution of the generated chaotic advection by baffles. Furthermore, numerical results, which were in good agreement with experimental results, shed more light onto the mechanisms involved in micromixing in terms of the flow behavior and mixing index.

Akar, S, Taheri, A, Bazaz, R, Warkiani, E & Shaegh, M 2021, 'Twisted architecture for enhancement of passive micromixing in a wide range of Reynolds numbers', Chemical Engineering and Processing - Process Intensification, vol. 160, pp. 108251-108251.
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Micromixers present essential roles in providing homogeneous mixtures in microfluidic systems. It is of critical importance to introduce strategies to increase the mixing efficiency of passive micromixers, capable of operating at high efficiency levels over a wide range of Reynolds (Re) numbers. To this end, a novel design of twisted microstructure for enhancing mixing performance in a wide range of Reynolds numbers was introduced. Incorporating this microstructure with straight and serpentine micromixers was numerically and experimentally investigated. Micromixers with twisted microstructures were fabricated in Poly(methyl methacrylate) (PMMA) using high-precision micromilling. The effects of Reynolds number, pitch number, and channel hydraulic diameter on mixing efficiency and pressure drop were analyzed. Results revealed that the twist architecture could increase mixing efficiency significantly with very low pressure drop of up to 0.89 kPa. The twisted serpentine micromixer could narrow the disparity of mixing efficiency from 87% (Re = 10) to 98% (Re = 400). High mixing efficiency could be achieved within a length of 4.8 mm in the twisted serpentine micromixer with a hydraulic diameter of 300 μm. Taken together, the twisted structure could be incorporated with various geometries to create compact and high efficiency micromixers for operation in a wide range of Re numbers.

Augustine, R, Dan, P, Hasan, A, Khalaf, IM, Prasad, P, Ghosal, K, Gentile, C, McClements, L & Maureira, P 2021, 'Stem cell-based approaches in cardiac tissue engineering: controlling the microenvironment for autologous cells', Biomedicine & Pharmacotherapy, vol. 138, pp. 111425-111425.
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Azadi, S, Tafazzoli Shadpour, M & Warkiani, ME 2021, 'Characterizing the effect of substrate stiffness on the extravasation potential of breast cancer cells using a 3D microfluidic model', Biotechnology and Bioengineering, vol. 118, no. 2, pp. 823-835.
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AbstractDifferent biochemical and biomechanical cues from tumor microenvironment affect the extravasation of cancer cells to distant organs; among them, the mechanical signals are poorly understood. Although the effect of substrate stiffness on the primary migration of cancer cells has been previously probed, its role in regulating the extravasation ability of cancer cells is still vague. Herein, we used a microfluidic device to mimic the extravasation of tumor cells in a 3D microenvironment containing cancer cells, endothelial cells, and the biological matrix. The microfluidic‐based extravasation model was utilized to probe the effect of substrate stiffness on the invasion ability of breast cancer cells. MCF7 and MDA‐MB‐231 cancer cells were cultured among substrates with different stiffness which followed by monitoring their extravasation capability through the microfluidic device. Our results demonstrated that acidic collagen at a concentration of 2.5 mg/ml promotes migration of cancer cells. Additionally, the substrate softening resulted in up to 46% reduction in the invasion of breast cancer cells. The substrate softening not only affected the number of extravasated cells but also reduced their migration distance up to 53%. We further investigated the secreted level of matrix metalloproteinase 9 (MMP9) and identified that there is a positive correlation between substrate stiffening, MMP9 concentration, and extravasation of cancer cells. These findings suggest that the substrate stiffness mediates the cancer cells extravasation in a microfluidic model. Changes in MMP9 level could be one of the possible underlying mechanisms which need more investigations to be addressed thoroughly.

Bai, X, Ni, J, Beretov, J, Wasinger, VC, Wang, S, Zhu, Y, Graham, P & Li, Y 2021, 'Activation of the eIF2α/ATF4 axis drives triple-negative breast cancer radioresistance by promoting glutathione biosynthesis', Redox Biology, vol. 43, pp. 101993-101993.
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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Radiotherapy is an effective option for the treatment of TNBC; however, acquired radioresistance is a major challenge to the modality. In this study, we show that the integrated stress response (ISR) is the most activated signaling pathway in radioresistant TNBC cells. The constitutive phosphorylation of eIF2α in radioresistant TNBC cells promotes the activation of ATF4 and elicits the transcription of genes implicated in glutathione biosynthesis, including GCLC, SLC7A11, and CTH, which increases the intracellular level of reduced glutathione (GSH) and the scavenging of reactive oxygen species (ROS) after irradiation (IR), leading to a radioresistant phenotype. The cascade is significantly up-regulated in human TNBC tissues and is associated with unfavorable survival in patients. Dephosphorylation of eIF2α increases IR-induced ROS accumulation in radioresistant TNBC cells by disrupting ATF4-mediated GSH biosynthesis and sensitizes them to IR in vitro and in vivo. These findings reveal ISR as a vital mechanism underlying TNBC radioresistance and propose the eIF2α/ATF4 axis as a novel therapeutic target for TNBC treatment.

Basirun, C, Ferlazzo, ML, Howell, NR, Liu, G-J, Middleton, RJ, Martinac, B, Narayanan, SA, Poole, K, Gentile, C & Chou, J 2021, 'Microgravity × Radiation: A Space Mechanobiology Approach Toward Cardiovascular Function and Disease', Frontiers in Cell and Developmental Biology, vol. 9, p. 750775.
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In recent years, there has been an increasing interest in space exploration, supported by the accelerated technological advancements in the field. This has led to a new potential environment that humans could be exposed to in the very near future, and therefore an increasing request to evaluate the impact this may have on our body, including health risks associated with this endeavor. A critical component in regulating the human pathophysiology is represented by the cardiovascular system, which may be heavily affected in these extreme environments of microgravity and radiation. This mini review aims to identify the impact of microgravity and radiation on the cardiovascular system. Being able to understand the effect that comes with deep space explorations, including that of microgravity and space radiation, may also allow us to get a deeper understanding of the heart and ultimately our own basic physiological processes. This information may unlock new factors to consider with space exploration whilst simultaneously increasing our knowledge of the cardiovascular system and potentially associated diseases.

Blake, C, Massey, O, Boyd-Moss, M, Firipis, K, Rifai, A, Franks, S, Quigley, A, Kapsa, R, Nisbet, DR & Williams, RJ 2021, 'Replace and repair: Biomimetic bioprinting for effective muscle engineering', APL Bioengineering, vol. 5, no. 3.
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The debilitating effects of muscle damage, either through ischemic injury or volumetric muscle loss (VML), can have significant impacts on patients, and yet there are few effective treatments. This challenge arises when function is degraded due to significant amounts of skeletal muscle loss, beyond the regenerative ability of endogenous repair mechanisms. Currently available surgical interventions for VML are quite invasive and cannot typically restore function adequately. In response to this, many new bioengineering studies implicate 3D bioprinting as a viable option. Bioprinting for VML repair includes three distinct phases: printing and seeding, growth and maturation, and implantation and application. Although this 3D bioprinting technology has existed for several decades, the advent of more advanced and novel printing techniques has brought us closer to clinical applications. Recent studies have overcome previous limitations in diffusion distance with novel microchannel construct architectures and improved myotubule alignment with highly biomimetic nanostructures. These structures may also enhance angiogenic and nervous ingrowth post-implantation, though further research to improve these parameters has been limited. Inclusion of neural cells has also shown to improve myoblast maturation and development of neuromuscular junctions, bringing us one step closer to functional, implantable skeletal muscle constructs. Given the current state of skeletal muscle 3D bioprinting, the most pressing future avenues of research include furthering our understanding of the physical and biochemical mechanisms of myotube development and expanding our control over macroscopic and microscopic construct structures. Further to this, current investigation needs to be expanded from immunocompromised rodent and murine myoblast models to more clinically applicable human cell lines as we move closer to viable therapeutic implementation.

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 2021, 'Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study', Journal of Bone and Mineral Research, vol. 36, no. 11, pp. 2106-2115.
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ABSTRACT Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women −0.33, interquartile range [IQR] −0.70 to +0.00; and men −0.34, IQR: −0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR).

Bliuc, D, Tran, T, Alarkawi, D, Chen, W, Blank, RD, Ensrud, KE, Blith, F, March, L & Center, J 2021, 'Multimorbidity Increases Risk of Osteoporosis Under-Diagnosis and Under-Treatment in Patients at High Fracture Risk: 45 and up a Prospective Population Based-Study', Journal of the Endocrine Society, vol. 5, no. Supplement_1, pp. A248-A249.
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Abstract Background: Management of osteoporosis following fracture is suboptimal. Multimorbidity adds to clinical management complexity in the elderly but its contribution to the osteoporosis treatment gap has never been investigated. Objectives: To determine the impact of multimorbidity on fracture risk and on osteoporosis investigation and treatment in patients at high fracture risk. Design and Setting: The 45 and Up Study is a prospective population-based cohort study in NSW, Australia with questionnaire data linked to hospital records by the Centre for Health Record Linkage (CHeReL) and the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Scheme (MBS) data provided by Department of Human Services. Fractures identified from hospital records, comorbidities from questionnaires, hospital and PBS records. Bone mineral density (BMD) investigation obtained from MBS and treatment for osteoporosis from PBS. Participants: 16191 women and 9089 men with incident low-trauma fracture (2000 - 2017) classified in a high and low-risk group based on 10-year fracture risk threshold of 20% from the Garvan Fracture Risk Calculator (age, gender, prior fracture and falls). Main Outcome Measurements: Association of Charlson comorbidity index (CCI) with fracture. Likelihood of BMD investigation and treatment initiation. Outcomes ascertained by logistic regression and re-fracture risk by Cox models. Results: Individuals at high fracture risk were significantly older [women (mean age ±SD) 77 ± 10 vs 57 ±4 for high- vs low risk and men 86±5 vs 65±8 for high vs low risk] and had a higher morbidity burden [women, CCI ≥ 2 40% vs 12% for high- vs low-risk and men 53% vs 26% for high vs low risk]. Being in the high-risk group as well as a higher CCI were independently associated with > 2-fold higher risk of re-fracture. However, in the high-risk group, only 28% (48% women and 17% men) had a BMD investigation and 31% (...

Brzozowska, MM, Tran, T, Bliuc, D, Jorgensen, J, Talbot, M, Fenton-Lee, D, Chen, W, Hong, A, Viardot, A, White, CP, Nguyen, TV, Pocock, N, Eisman, JA, Baldock, PA & Center, JR 2021, 'Roux-en-Y gastric bypass and gastric sleeve surgery result in long term bone loss', International Journal of Obesity, vol. 45, no. 1, pp. 235-246.
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Objectives

Little is known about the long-term skeletal impact of bariatric procedures, particularly the increasingly commonly performed gastric sleeve surgery (GS). We examined bone density (BMD) change following three types of bariatric surgery Roux-en-Y gastric bypass (RYGB), GS and laparoscopic adjustable gastric banding (LAGB), compared with diet, over 36 months.

Methods

Non-randomized, prospective study of participants with severe obesity (n = 52), undergoing weight-loss interventions: RYGB (n = 7), GS (n = 21), LAGB (n = 11) and diet (n = 13). Measurements of calciotropic indices, gut hormones (fasting and post prandial) peptide YY (PYY), glucagon-like peptide 1 (GLP1) and adiponectin together with dual-X-ray absorptiometry and quantitative computed tomography scans were performed thorough the study.

Results

All groups lost weight during the first 12 months. Despite weight stability from 12 to 36 months and supplementation of calcium and vitamin D, there was progressive bone loss at the total hip (TH) over 36 months in RYGB -14% (95% CI: -12, -17) and GS -9% (95% CI: -7, -10). In RYGB forearm BMD also declined over 36 months -9% (95% CI: -6, -12) and LS BMD declined over the first 12 months -7% (95% CI: -3, -12). RYGB and GS groups experienced significantly greater bone loss until 36 months than LAGB and diet groups, which experienced no significant BMD loss. These bone losses remained significant after adjustment for weight loss and age. RYGB and GS procedures resulted in elevated postprandial PYY, adiponectin and bone turnover markers up to 36 months without such changes among LAGB and diet participants.

Conclusions

RYGB and GS but not LAGB resulted in ongoing TH bone loss for three postoperative years. For RYGB, bone loss was also observed at LS and non-weight-bearing forearms. These BMD changes were independent of weight and age differences. We, therefore, recommend close monitoring of bone health following RYGB a...

Cai, X, Li, JJ, Liu, T, Brian, O & Li, J 2021, 'Infectious disease mRNA vaccines and a review on epitope prediction for vaccine design', Briefings in Functional Genomics, vol. 20, no. 5, pp. 289-303.
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AbstractMessenger RNA (mRNA) vaccines have recently emerged as a new type of vaccine technology, showing strong potential to combat the COVID-19 pandemic. In addition to SARS-CoV-2 which caused the pandemic, mRNA vaccines have been developed and tested to prevent infectious diseases caused by other viruses such as Zika virus, the dengue virus, the respiratory syncytial virus, influenza H7N9 and Flavivirus. Interestingly, mRNA vaccines may also be useful for preventing non-infectious diseases such as diabetes and cancer. This review summarises the current progresses of mRNA vaccines designed for a range of diseases including COVID-19. As epitope study is a primary component in the in silico design of mRNA vaccines, we also survey on advanced bioinformatics and machine learning algorithms which have been used for epitope prediction, and review on user-friendly software tools available for this purpose. Finally, we discuss some of the unanswered concerns about mRNA vaccines, such as unknown long-term side effects, and present with our perspectives on future developments in this exciting area.

Chai, M, Razavi Bazaz, S, Daiyan, R, Razmjou, A, Ebrahimi Warkiani, M, Amal, R & Chen, V 2021, 'Biocatalytic micromixer coated with enzyme-MOF thin film for CO2 conversion to formic acid', Chemical Engineering Journal, vol. 426, pp. 130856-130856.
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In this study, a novel micromixer with a 3D helical, threaded channel was fabricated via 3D printing. The micromixer can enhance the mass transfer of reactants and product in an enzymatic cascade reaction converting CO2 to formic acid. Two enzymes, including carbonic anhydrase (CA) and formate dehydrogenase (FDH), were biomineralised in a zeolitic imidazolate framework-8 composite thin film on the micromixer channel that has been modified with polydopamine/polyethyleneimine. The biocatalytic performance of the micromixer was evaluated by testing at various liquid flow rates, and an optimum liquid flow rate at 1 mL/min (Rel = 8, Del = 3) was observed as the two-phase flow pattern in the micromixer channel transitioned from slug flow to bubbly flow. A comparison of the micromixer performance with and without threaded channels revealed ~ 170% enhancement in formic acid yield, indicating improved mixing with the presence of threads. In addition, the formic acid production rate for the micromixer with threaded channel was three folds higher than a conventional bubble column, demonstrating the superior performance of the proposed micromixer. The ease of assembling multiple micromixer units in series also enabled the immobilisation of different enzymes in separate units to carry out sequential reactions in a modular system. As a proof of concept, the solution product collected from long term biocatalysis was also tested in a direct formic acid fuel cell, which showed a promising prospect of integrating these two systems for a closed-loop energy generation system.

Chan, Y, Mehta, M, Paudel, KR, Madheswaran, T, Panneerselvam, J, Gupta, G, Su, QP, Hansbro, PM, MacLoughlin, R, Dua, K & Chellappan, DK 2021, 'Versatility of liquid crystalline nanoparticles in inflammatory lung diseases', Nanomedicine, vol. 16, no. 18, pp. 1545-1548.
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Chen, Y, Xu, X, Li, C, Bendavid, A, Westerhausen, MT, Bradac, C, Toth, M, Aharonovich, I & Tran, TT 2021, 'Bottom‐Up Synthesis of Hexagonal Boron Nitride Nanoparticles with Intensity‐Stabilized Quantum Emitters', Small, vol. 17, no. 17, pp. 1-7.
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AbstractFluorescent nanoparticles are widely utilized in a large range of nanoscale imaging and sensing applications. While ultra‐small nanoparticles (size ≤10 nm) are highly desirable, at this size range, their photostability can be compromised due to effects such as intensity fluctuation and spectral diffusion caused by interaction with surface states. In this article, a facile, bottom‐up technique for the fabrication of sub‐10‐nm hexagonal boron nitride (hBN) nanoparticles hosting photostable bright emitters via a catalyst‐free hydrothermal reaction between boric acid and melamine is demonstrated. A simple stabilization protocol that significantly reduces intensity fluctuation by ≈85% and narrows the emission linewidth by ≈14% by employing a common sol–gel silica coating process is also implemented. This study advances a promising strategy for the scalable, bottom‐up synthesis of high‐quality quantum emitters in hBN nanoparticles.

Cheung, BB, Kleynhans, A, Mittra, R, Kim, PY, Holien, JK, Nagy, Z, Ciampa, OC, Seneviratne, JA, Mayoh, C, Raipuria, M, Gadde, S, Massudi, H, Wong, IPL, Tan, O, Gong, A, Suryano, A, Diakiw, SM, Liu, B, Arndt, GM, Liu, T, Kumar, N, Sangfelt, O, Zhu, S, Norris, MD, Haber, M, Carter, DR, Parker, MW & Marshall, GM 2021, 'A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma', Oncogene, vol. 40, no. 13, pp. 2367-2381.
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AbstractHistone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.

Clarke, C, Singh, M, Tawfik, SA, Xu, X, Spencer, MJS, Ramanathan, R, Reineck, P, Bansal, V & Ton-That, C 2021, 'Mono- to few-layer non-van der Waals 2D lanthanide-doped NaYF₄nanosheets with upconversion luminescence', 2D Materials, vol. 8, no. 1, pp. 015005-015005.
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AbstractNaYF4is an efficient host material for lanthanide-based upconversion luminescence and has attracted immense interest for potential applications in photovoltaics, lasers and bioimaging. However, being a non-van der Waals (non-vdW) material, there have been thus far no reports on exfoliation of bulk NaYF4to nanosheets and their upconversion luminescence properties. Here, we demonstrate for the first time the fabrication of lanthanide-containing NaYF42D nanosheets using a soft liquid-phase exfoliation method and report on their optical, electronic and chemical characteristics. The nanosheets exfoliated from NaYF4:Yb,Er microcrystals consisting mainly ofβ-NaYF4become enriched inα-NaYF4post exfoliation and have a large micron-sized planar area with a preferential (100) surface orientation. X-ray absorption spectroscopy confirms that both Yb and Er doping ions are retained in the exfoliated nanosheets. Through centrifugation, NaYF42D nanosheets are successfully obtained with thicknesses ranging from a monolayer to tens of layers. Optical analysis of individual nanosheets shows that they exhibit both optical down-conversion and upconversion properties, albeit with reduced emission intensities compared with the parent microparticles. Further exploration of their electronic structure by density functional theory (DFT) calculations and photoelectron spectroscopy reveals the formation of surface F atom defects and a shrinkage of the electronic bandgap in ultrathin nanosheets. Our findings will trigger further interest in non-vdW 2D upconversion nanomaterials.

Deng, ZX, Tao, JW, Zhang, W, Mu, HJ, Wu, HJ, Wang, YB, Xu, XX & Zheng, W 2021, 'Effect of protein adsorption on electrospun hemoglobin/gelatin-MWCNTs microbelts modified electrode: Toward electrochemical measurement of hydrogen peroxide', Materials Chemistry and Physics, vol. 257, pp. 123827-123827.
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The on-line electrochemical analysis is one of powerful strategies in analytical chemistry and pathophysiology. To achieve high sensitivity and long-term stability of electrochemical biosensor, the bottleneck challenge is the spontaneous proteins adsorption onto the electrode surface within the biological fluids or in vivo environments. In this work, a hemoglobin/gelatin-multiwalled carbon nanotubes microbelts modified electrode (Hb/gelatin-MWCNTs/GC electrode) was successfully fabricated via one-step electrospinning process. The results of atomic force microscopy (AFM), scanning electron microscopy (SEM) and water contact angle test confirmed the electrospun Hb/gelatin-MWCNTs microbelts possessed smooth and hydrophilic surfaces. Furthermore, the electrospun Hb/gelatin-MWCNTs/GC electrode after protein adsorption displayed an excellent electrocatalytic sensitivity toward the reduction of hydrogen peroxide (H2O2). Moreover, the Hb/gelatin-MWCNTs/GC electrode presented very high biological affinity to H2O2 (Kmapp=503.4 ± 2.8 μmol L−1) after 360 min protein adsorption compared to that of the electrode before protein adsorption (Kmapp=298.1 ± 3.1 μmol L−1). The microbelts constructed H2O2 biosensor showed high selectivity, stability and reproducibility after protein adsorption. Therefore, this work provided the proof of the concept that the electrospun Hb/gelatin-MWCNTs/GC electrode displayed excellent sensing performance to H2O2 after protein adsorption, which could enable the implantable electrochemical biosensor for the on-line analysis.

Di, X, Wang, D, Zhou, J, Zhang, L, Stenzel, MH, Su, QP & Jin, D 2021, 'Quantitatively Monitoring In Situ Mitochondrial Thermal Dynamics by Upconversion Nanoparticles', Nano Letters, vol. 21, no. 4, pp. 1651-1658.
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Temperature dynamics reflect the physiological conditions of cells and organisms. Mitochondria regulate the temperature dynamics in living cells as they oxidize the respiratory substrates and synthesize ATP, with heat being released as a byproduct of active metabolism. Here, we report an upconversion nanoparticle-based thermometer that allows the in situ thermal 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^-1 in 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 thermodynamic profiles under different stimulations, which highlight the potential applications of this thermometer to study in situ vital processes related to mitochondrial metabolism pathways and interactions between organelles.

Ding, L, Moloudi, R & Warkiani, ME 2021, 'Bioreactor-Based Adherent Cells Harvesting from Microcarriers with 3D Printed Inertial Microfluidics', pp. 257-266.
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Ding, L, Radfar, P, Rezaei, M & Warkiani, ME 2021, 'An easy-to-operate method for single-cell isolation and retrieval using a microfluidic static droplet array', Microchimica Acta, vol. 188, no. 8, pp. 1-11.
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In-depth study of cellular heterogeneity of rare cells (e.g. circulating tumour cells (CTCs) and circulating foetal cells (CFCs)) is greatly needed in disease management but has never been completely explored due to the current technological limitations. We have developed a retrieval method for single-cell detection using a static droplet array (SDA) device through liquid segmentation with almost no sample loss. We explored the potential of using SDA for low sample input and retrieving the cells of interest using everyday laboratory equipment for downstream molecular analysis. This single-cell isolation and retrieval method is low-cost, rapid and provides a solution to the remaining challenge for single rare cell detection. The entire process takes less than 15 min, is easy to fabricate and allows for on-chip analysis of cells in nanolitre droplets and retrieval of desired droplets. To validate the applicability of our device and method, we mimicked detection of single CTCs by isolating and retrieving single cells and perform real-time PCR on their mRNA contents.

Dong, S, Zhao, Y, Li, JJ & Xing, D 2021, 'Global Research Trends in Revision Total Knee Arthroplasty: A Bibliometric and Visualized Study', Indian Journal of Orthopaedics, vol. 55, no. 5, pp. 1335-1347.
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Background: Revision total knee arthroplasty (TKA) is a longstanding area of research interest in orthopedics due to its increasing global demand and associated technical challenges. The present study aims to analyze and present the current state of research and trends in this active field. Methods: Articles on revision TKA published from inception to 2018 were retrieved from Web of Science. Bibliometric analysis was conducted using the metadata of the included articles. Visualized analysis was conducted using VOSviewer software to reveal global trends in revision TKA research, through analyses of bibliographic coupling, co-authorship, co-citation and co-occurrence. Results: A total of 6027 articles were included. The number of publications and relative research interest in the field of revision TKA displayed strong upward growth over the time period examined. The USA had the highest number of citations for publications in this field, as well as the highest H-index. Studies in the field could be categorized into five clusters: prosthesis design, periprosthetic fracture, periprosthetic joint infection, risk factors for revision TKA, and survivorship of implants. Studies focused on infection and risk factors for revision TKA are likely to become the most popular research topics in the field. Conclusion: Global trends over the past few years suggest that the field of revision TKA research will continue to grow and lead to increasing rates of publication output over the coming years. Future developments in the field will likely include more preventative and etiological studies relating to revision TKA.

Elazezy, M, Schwentesius, S, Stegat, L, Wikman, H, Werner, S, Mansour, WY, Failla, AV, Peine, S, Müller, V, Thiery, JP, Ebrahimi Warkiani, M, Pantel, K & Joosse, SA 2021, 'Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer', Cancers, vol. 13, no. 15, pp. 3869-3869.
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Keratins are the main identification markers of circulating tumor cells (CTCs); however, whether their deregulation is associated with the metastatic process is largely unknown. Previously we have shown by in silico analysis that keratin 16 (KRT16) mRNA upregulation might be associated with more aggressive cancer. Therefore, in this study, we investigated the biological role and the clinical relevance of K16 in metastatic breast cancer. By performing RT-qPCR, western blot, and immunocytochemistry, we investigated the expression patterns of K16 in metastatic breast cancer cell lines and evaluated the clinical relevance of K16 expression in CTCs of 20 metastatic breast cancer patients. High K16 protein expression was associated with an intermediate mesenchymal phenotype. Functional studies showed that K16 has a regulatory effect on EMT and overexpression of K16 significantly enhanced cell motility (p < 0.001). In metastatic breast cancer patients, 64.7% of the detected CTCs expressed K16, which was associated with shorter relapse-free survival (p = 0.0042). Our findings imply that K16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility. Furthermore, determining K16 status in CTCs provides prognostic information that helps to identify patients whose tumors are more prone to metastasize.

Es, HA, Cox, TR, Sarafraz-Yazdi, E, Thiery, JP & Warkiani, ME 2021, 'Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)', Cancers, vol. 13, no. 20, pp. 5118-5118.
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The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.

Es, HA, Mahdizadeh, H, Asl, AAH & Totonchi, M 2021, 'Genomic alterations and possible druggable mutations in carcinoma of unknown primary (CUP)', Scientific Reports, vol. 11, no. 1.
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AbstractCarcinoma of Unknown Primary (CUP) is a heterogeneous and metastatic disease where the primary site of origin is undetectable. Currently, chemotherapy is the only state-of-art treatment option for CUP patients. The molecular profiling of the tumour, particularly mutation detection, offers a new treatment approach for CUP in a personalized fashion using targeted agents. We analyzed the mutation and copy number alterations profile of 1709 CUP samples deposited in the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort and explored potentially druggable mutations. We identified 52 significant mutated genes (SMGs) among CUP samples, in which 13 (25%) of SMGs were potentially targetable with either drugs are approved for the know primary tumour or undergoing clinical trials. The most variants detected were TP53 (43%), KRAS (19.90%), KMT2D (12.60%), and CDKN2A (10.30%). Additionally, using pan-cancer analysis, we found similar variants of TERT promoter in CUP and NSCLC samples, suggesting that these mutations may serve as a diagnostic marker for identifying the primary tumour in CUP. Taken together, the mutation profiling analysis of the CUP tumours may open a new way of identifying druggable targets and consequently administrating appropriate treatment in a personalized manner.

Eyni, H, Ghorbani, S, Nazari, H, Hajialyani, M, Razavi Bazaz, S, Mohaqiq, M, Ebrahimi Warkiani, M & Sutherland, DS 2021, 'Advanced bioengineering of male germ stem cells to preserve fertility', Journal of Tissue Engineering, vol. 12, pp. 204173142110605-204173142110605.
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In modern life, several factors such as genetics, exposure to toxins, and aging have resulted in significant levels of male infertility, estimated to be approximately 18% worldwide. In response, substantial progress has been made to improve in vitro fertilization treatments (e.g. microsurgical testicular sperm extraction (m-TESE), intra-cytoplasmic sperm injection (ICSI), and round spermatid injection (ROSI)). Mimicking the structure of testicular natural extracellular matrices (ECM) outside of the body is one clear route toward complete in vitro spermatogenesis and male fertility preservation. Here, a new wave of technological innovations is underway applying regenerative medicine strategies to cell-tissue culture on natural or synthetic scaffolds supplemented with bioactive factors. The emergence of advanced bioengineered systems suggests new hope for male fertility preservation through development of functional male germ cells. To date, few studies aimed at in vitro spermatogenesis have resulted in relevant numbers of mature gametes. However, a substantial body of knowledge on conditions that are required to maintain and mature male germ cells in vitro is now in place. This review focuses on advanced bioengineering methods such as microfluidic systems, bio-fabricated scaffolds, and 3D organ culture applied to the germline for fertility preservation through in vitro spermatogenesis.

Fan, Q, Bao, G, Ge, D, Wang, K, Sun, M, Liu, T, Liu, J, Zhang, Z, Xu, X, Xu, X, He, B, Rao, J & Zheng, Y 2021, 'Effective easing of the side effects of copper intrauterine devices using ultra-fine-grained Cu-0.4Mg alloy', Acta Biomaterialia, vol. 128, pp. 523-539.
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Copper intrauterine device is one of the most adopted contraceptive methods with high effectiveness (over 99 %), low cost, spontaneous reversibility and long-lasting usage. However, the side effects induced from the initial burst release of copper ions (Cu2+) hinder the continuation of the Cu-IUD made of Coarse-Grained Copper (CG Cu). We proposed to tailor the bio-corrosion behaviors of better control of Cu2+ release via the addition of bioactive Mg into the Ultra-Fine Grained (UFG) Bulk Cu. Thus, UFG bulk Cu with 0.4 wt.% Mg was produced via equal-channel angular pressing. The microstructures of the UFG Cu-0.4Mg was observed using electron backscatter diffraction and transmission electron microscopy techniques. The in vitro long-term corrosion behaviors in simulated uterine fluid, cytotoxicity to four cell lines, in vivo biocompatibility and contraceptive efficacy were all studied on CG Cu, UFG Cu and UFG Cu-0.4Mg materials. The results demonstrate that both the ultrafine grains and the addition of bioactive Mg into Cu contribute to the suppression of the burst release of Cu2+ in the initial stage and the maintenance of high level Cu2+ in long-term release. Moreover, the UFG Cu-0.4Mg also exhibited much improved cell and tissue biocompatibility from both the in vitro and in vivo evaluations. Therefore, the contraceptive efficacy of UFG Cu-0.4Mg is still maintained as high as the CG Cu and UFG Cu while the side effects are significantly eased, suggesting the high potential of the UFG Cu-0.4Mg alloy as a new upgrading or alternative material for Cu-IUD. STATEMENT OF SIGNIFICANCE: The side effects from burst release of Cu2+ at the initial implantation stage of Cu-containing intrauterine devices (Cu-IUD) is one of the main drawbacks of these devices. In this work, an ultra-fine-grained Cu (UFG Cu) alloyed with a low amount of bioactive Mg was used for a Cu-IUD. The UFG Cu-0.4Mg alloy exhibited suppressed burst release of Cu2+ at initial implantation, while...

Fang, G, Lu, H, Aboulkheyr Es, H, Wang, D, Liu, Y, Warkiani, ME, Lin, G & Jin, D 2021, 'Unidirectional intercellular communication on a microfluidic chip', Biosensors and Bioelectronics, vol. 175, pp. 112833-112833.
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Cell co-culture serves as a standard method to study intercellular communication. However, random diffusion of signal molecules during co-culture may arouse crosstalk among different types of cells and hide directive signal-target responses. Here, a microfluidic chip is proposed to study unidirectional intercellular communication by spatially controlling the flow of the signal molecules. The chip contains two separated chambers connected by two channels where the culture media flows oppositely. A zigzag signal-blocking channel is designed to study the function of a specific signal. The chip is applied to study the unidirectional communication between tumor cells and stromal cells. It shows that the expression of α-smooth muscle actin (a marker of cancer-associated fibroblast (CAF)) of both MRC-5 fibroblasts and mesenchymal stem cells can be up-regulated only by the secreta from invasive MDA-MB-231 cells, but not from non-invasive MCF-7 cells. The proliferation of the tumor cells can be improved by the stromal cells. Moreover, transforming growth factor beta 1 is found as one of the main factors for CAF transformation via the signal-blocking function. The chip achieves unidirectional cell communication along X-axis, signal concentration gradient along Y-axis and 3D cell culture along Z-axis, which provides a useful tool for cell communication studies.

Fang, G, Lu, H, Rodriguez de la Fuente, L, Law, AMK, Lin, G, Jin, D & Gallego‐Ortega, D 2021, 'Mammary Tumor Organoid Culture in Non‐Adhesive Alginate for Luminal Mechanics and High‐Throughput Drug Screening', Advanced Science, vol. 8, no. 21, pp. 1-13.
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AbstractMammary tumor organoids have become a promising in vitro model for drug screening and personalized medicine. However, the dependency on the basement membrane extract (BME) as the growth matrices limits their comprehensive application. In this work, mouse mammary tumor organoids are established by encapsulating tumor pieces in non‐adhesive alginate. High‐throughput generation of organoids in alginate microbeads is achieved utilizing microfluidic droplet technology. Tumor pieces within the alginate microbeads developed both luminal‐ and solid‐like structures and displayed a high similarity to the original fresh tumor in cellular phenotypes and lineages. The mechanical forces of the luminal organoids in the alginate capsules are analyzed with the theory of the thick‐wall pressure vessel (TWPV) model. The luminal pressure of the organoids increase with the lumen growth and can reach 2 kPa after two weeks’ culture. Finally, the mammary tumor organoids are treated with doxorubicin and latrunculin A to evaluate their application as a drug screening platform. It is found that the drug response is related to the luminal size and pressures of organoids. This high‐throughput culture for mammary tumor organoids may present a promising tool for preclinical drug target validation and personalized medicine.

Fardjahromi, MA, Ejeian, F, Razmjou, A, Vesey, G, Mukhopadhyay, SC, Derakhshan, A & Warkiani, ME 2021, 'Enhancing osteoregenerative potential of biphasic calcium phosphates by using bioinspired ZIF8 coating', Materials Science and Engineering: C, vol. 123, pp. 111972-111972.
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Biphasic calcium phosphate ceramics (BCPs) have been extensively used as a bone graft in dental clinics to reconstruct lost bone in the jaw and peri-implant hard tissue due to their good bone conduction and similar chemical structure to the teeth and bone. However, BCPs are not inherently osteoinductive and need additional modification and treatment to enhance their osteoinductivity. The present study aims to develop an innovative strategy to improve the osteoinductivity of BCPs using unique features of zeolitic imidazolate framework-8 (ZIF8). In this method, commercial BCPs (Osteon II) were pre-coated with a zeolitic imidazolate framework-8/polydopamine/polyethyleneimine (ZIF8/PDA/PEI) layer to form a uniform and compact thin film of ZIF8 on the surface of BCPs. The surface morphology and chemical structure of ZIF8 modified Osteon II (ZIF8-Osteon) were confirmed using various analytical techniques such as XRD, FTIR, SEM, and EDX. We evaluated the effect of ZIF8 coating on cell attachment, growth, and osteogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs). The results revealed that altering the surface chemistry and topography of Osteon II using ZIF8 can effectively promote cell attachment, proliferation, and bone regeneration in both in vitro and in vivo conditions. In conclusion, the method applied in this study is simple, low-cost, and time-efficient and can be used as a versatile approach for improving osteoinductivity and osteoconductivity of other types of alloplastic bone grafts.

Fisher, BM, Tang, KD, Warkiani, ME, Punyadeera, C & Batstone, MD 2021, 'A pilot study for presence of circulating tumour cells in adenoid cystic carcinoma', International Journal of Oral and Maxillofacial Surgery, vol. 50, no. 8, pp. 994-998.
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Adenoid cystic carcinoma (ACC) is a rare salivary gland neoplasm with a poor long-term prognosis due to multiple recurrences and distant metastatic spread. Circulating tumour cells (CTCs) are tumour cells shed from a primary, recurrent, or metastatic cancer that are detectable in the blood or lymphatics. There is no literature to date confirming the presence of CTCs in ACC. The aim of this study was to determine whether CTCs are detectable in ACC. Blood samples were collected from eight patients with histologically confirmed ACC. The TNM stage of the tumour was recorded, as well as any prior treatment. CTCs were isolated by spiral microfluidics and detected by immunofluorescence staining. Three of the eight patients recruited (32.5%) had staining consistent with the presence of CTCs. Of these three patients with detectable CTCs, one had confirmed pulmonary metastasis, one had suspected pulmonary metastasis and was awaiting confirmation, and one had local recurrence confirmed on re-resection. One patient with known isolated pulmonary metastasis had previously undergone a lung metastasectomy and did not have CTCs detected. CTCs are detectable in ACC. In this small patient sample, CTCs were found to be present in those patients with recurrent local disease and known distant metastatic disease. CTCs in ACC should be investigated further for their potential use as an adjunct in staging, prognosis, and the detection of recurrence.

Fong, JSL, Booth, MA, Rifai, A, Fox, K & Gelmi, A 2021, 'Diamond in the Rough: Toward Improved Materials for the Bone−Implant Interface', Advanced Healthcare Materials, vol. 10, no. 14.
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AbstractThe ability of an orthopedic implant to integrate successfully with the surrounding bone tissue is imperative for optimal patient outcomes. Here, the recent advances and future prospects for diamond‐based coatings of conventional osteo‐implant materials (primarily titanium) are explored. The ability of these diamond coatings to enhance integration into existing bone, improved implant mechanical properties, facilitate surface chemical functionalization, and provide anti‐microbial properties are discussed in context of orthopedic implants. These diamond‐based materials may have the additional benefit of providing an osteo‐inductive effect, enabling better integration into existing bone via stem cell recruitment and bone regeneration. Current and timely research is highlighted to support the discussion and suggestions in further improving implant integration via an osseoinductive effect from the diamond composite materials.

Ghasemian, R, Shamshirian, A, Heydari, K, Malekan, M, Alizadeh‐Navaei, R, Ebrahimzadeh, MA, Ebrahimi Warkiani, M, Jafarpour, H, Razavi Bazaz, S, Rezaei Shahmirzadi, A, Khodabandeh, M, Seyfari, B, Motamedzadeh, A, Dadgostar, E, Aalinezhad, M, Sedaghat, M, Razzaghi, N, Zarandi, B, Asadi, A, Yaghoubi Naei, V, Beheshti, R, Hessami, A, Azizi, S, Mohseni, AR & Shamshirian, D 2021, 'The role of vitamin D in the age of COVID‐19: A systematic review and meta‐analysis', International Journal of Clinical Practice, vol. 75, no. 11, pp. 1-16.
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BackgroundEvidence recommends that vitamin D might be a crucial supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a systematic review and meta-analysis in order to maximise the use of everything that exists about the role of vitamin D in the COVID-19.MethodsA systematic search was performed in PubMed, Scopus, Embase and Web of Science up to December 18, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review.ResultsTwenty-three studies containing 11 901 participants entered into the meta-analysis. The meta-analysis indicated that 41% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 29%-55%), and in 42% of patients, levels of vitamin D were insufficient (95% CI, 24%-63%). The serum 25-hydroxyvitamin D concentration was 20.3 ng/mL among all COVID-19 patients (95% CI, 12.1-19.8). The odds of getting infected with SARS-CoV-2 are 3.3 times higher among individuals with vitamin D deficiency (95% CI, 2.5-4.3). The chance of developing severe COVID-19 is about five times higher in patients with vitamin D deficiency (OR: 5.1, 95% CI, 2.6-10.3). There is no significant association between vitamin D status and higher mortality rates (OR: 1.6, 95% CI, 0.5-4.4).ConclusionThis study found that most of the COVID-19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS-CoV-2 among vitamin-D-deficient individuals and about five times higher probability of developing the severe disease in vitamin-D-deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population.

Ghezelbash, F, Eskandari, AH, Shirazi-Adl, A, Kazempour, M, Tavakoli, J, Baghani, M & Costi, JJ 2021, 'Modeling of human intervertebral disc annulus fibrosus with complex multi-fiber networks', Acta Biomaterialia, vol. 123, pp. 208-221.
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Harley, W, Yoshie, H & Gentile, C 2021, 'Three-Dimensional Bioprinting for Tissue Engineering and Regenerative Medicine in Down Under: 2020 Australian Workshop Summary', ASAIO Journal, vol. 67, no. 4, pp. 363-369.
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Herath, S, Sadeghi Rad, H, Radfar, P, Ladwa, R, Warkiani, M, O’Byrne, K & Kulasinghe, A 2021, 'The Role of Circulating Biomarkers in Lung Cancer', Frontiers in Oncology, vol. 11, p. 801269.
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Lung cancer is the leading cause of cancer morbidity and mortality worldwide and early diagnosis is crucial for the management and treatment of this disease. Non-invasive means of determining tumour information is an appealing diagnostic approach for lung cancers as often accessing and removing tumour tissue can be a limiting factor. In recent years, liquid biopsies have been developed to explore potential circulating tumour biomarkers which are considered reliable surrogates for understanding tumour biology in a non-invasive manner. Most common components assessed in liquid biopsy include circulating tumour cells (CTCs), cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), microRNA and exosomes. This review explores the clinical use of circulating tumour biomarkers found in liquid biopsy for screening, early diagnosis and prognostication of lung cancer patients.

Heravi, FS, Zakrzewski, M, Aboulkheyr Estarabadi, H, Vickery, K & Hu, H 2021, 'Evaluation of Host Immune Response in Diabetic Foot Infection Tissues Using an RNA Sequencing-Based Approach', Frontiers in Microbiology, vol. 12.
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The normal continuity of skin tissue can be affected by invading pathogens and lead to a series of complicated physiological events. Using an RNA sequencing-based approach, we have captured a metatranscriptomic landscape from diabetic foot infections (DFIs). The hierarchical clustering of the top 2,000 genes showed the expression of four main clusters in DFIs (A, B, C, and D). Clusters A and D were enriched in genes mainly involved in the recruitment of inflammatory cells and immune responses and clusters B and C were enriched in genes related to skin cell development and wound healing processes such as extracellular structure organization and blood vessel development. Differential expression analysis showed more than 500 differentially expressed genes (DEGs) between samples with a low number of virulence factors and samples with a high number of virulence factors. Up-regulated and down-regulated genes were mainly involved in adaptive/native immune responses and transport of mature mRNAs, respectively. Our results demonstrated the importance of inflammatory cytokines of adaptive/native immunity in the progression of DFIs and provided a useful groundwork for capturing gene snapshots in DFIs. In addition, we have provided a general introduction to the challenges and opportunities of RNA sequencing technology in the evaluation of DFIs. Pathways identified in this study such as immune chemokines, Rho GTPases, and corresponding effectors might be important therapeutic targets in the management of DFIs.

Hoang, DK, Le, NM, Vo‐Thi, UP, Nguyen, HG, Ho‐Pham, LT & Nguyen, TV 2021, 'Mechanography assessment of fall risk in older adults: the Vietnam Osteoporosis Study', Journal of Cachexia, Sarcopenia and Muscle, vol. 12, no. 5, pp. 1161-1167.
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AbstractBackgroundJumping mechanography is a technology for quantitatively assessing muscular function and balance in older adults. This study sought to define the association between jumping mechanography parameters and fall risk in Vietnamese individuals.MethodsThe study involved 375 women and 244 men aged 50 years and older, who were recruited from the general population in Ho Chi Minh City (Vietnam). The individuals had been followed for 2 years. At baseline, Esslinger Fitness index (EFI), jumping power, force, velocity of lower limbs, and the ability to maintain balance were measured by a Leonardo Mechanograph Ground Reaction Force system (Novotec Medical, Pforxheim, Germany). The incidence of falls during the follow‐up period was ascertained from self‐report. Logistic regression analysis was used to analyse the association between jumping mechanography parameters and fall risk.ResultsThe average age of participants at baseline was 56.7 years (SD 5.85). During the 2 year follow‐up, 92 falls were reported, making the incidence of fall at ~15% [95% confidence interval (CI), 12.1 to 18.2]. The incidence of fall increased with advancing age, and women had a higher incidence than men (17.6% vs. 10.7%; P = 0.024). In univariate analysis, maximal velocity [odds ratio (OR) 0.65; 95% CI, 0.52 to 0.82], maximal force (OR 0.83; 95% CI, 0.65 to 1.04), and maximal power (OR 0.68; 95% CI, 0.52 to 0.88) were each significantly associated with fall risk. EFI was not significantly associated with fall risk (OR 1.09; 95% CI, 0.86 to 1.39). However, in a multiple logistic regression model, greater maximum velocity was associated with lower odds of fall (OR 0.38; 95% CI, 0.16 to 0.92).Conclusions<...

Hofer, OJ, McKinlay, CJD, Tran, T & Crowther, CA 2021, 'Antenatal corticosteroids, maternal body mass index and infant morbidity within the ASTEROID trial', Australian and New Zealand Journal of Obstetrics and Gynaecology, vol. 61, no. 3, pp. 380-385.
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BackgroundAntenatal corticosteroids (ACSs) administered to women before preterm birth improve neonatal health. Proportionately more women are obese or overweight in current obstetric populations than those who were included in the original trials of ACSs, and it remains uncertain if higher doses are required for such women.AimOur aim was to assess the association between maternal body mass index (BMI) and infant morbidity after the administration of ACSs.MethodsIn the secondary analysis of the ASTEROID trial cohort, women at risk of preterm birth at <34 weeks’ gestation were randomised to betamethasone or dexamethasone. Infant outcomes were compared according to whether women were of normal weight (BMI < 25 kg/m2), overweight (BMI 25–29.9 kg/m2) or obese (BMI ≥ 30 kg/m2).ResultsOf 982 women with a singleton pregnancy and BMI data, 519 (52.9%) were of normal size, 241 (24.5%) were overweight and 222 (22.6%) were obese. Compared with infants born to women of normal weight, there was little or no difference in respiratory distress syndrome in infants born to women who were overweight (odds ratio (OR) = 0.92, 95% confidence interval (CI) 0.57, 1.49) or obese (OR = 1.44, 95% CI 0.90, 2.31). Similarly, there were no significant differences between infants born to women in the three BMI groups for other morbidities, including bronchopulmonary dysplasia, mechanical ventilation, intraventricular haemorrhage, retinopathy of prematurity, patent ductus arteriosus, necrotising enterocolitis, perinatal death or combined serious morbidity.ConclusionsMaternal body size is not associated with infant morbidity aft...

Ho-Le, TP, Tran, HTT, Center, JR, Eisman, JA, Nguyen, HT & Nguyen, TV 2021, 'Assessing the clinical utility of genetic profiling in fracture risk prediction: a decision curve analysis', Osteoporosis International, vol. 32, no. 2, pp. 271-280.
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Using decision curve analysis on 2188 women and 1324 men, we found that an osteogenomic profile constructed from 62 genetic variants improved the clinical net benefit of fracture risk prediction over and above that of clinical risk factors and BMD.

Introduction

Genetic profiling is a promising tool for assessing fracture risk. This study sought to use the decision curve analysis (DCA), a novel approach to determine the impact of genetic profiling on fracture risk prediction.

Methods

The study involved 2188 women and 1324 men, aged 60 years and above, who were followed for up to 23 years. Bone mineral density (BMD) and clinical risk factors were obtained at baseline. The incidence of fracture and mortality were recorded. A weighted individual genetic risk score (GRS) was constructed from 62 BMD-associated genetic variants. Four models were considered: CRF (clinical risk factors); CRF + GRS; Garvan model (GFRC) including CRF and femoral neck BMD; and GFRC + GRS. The DCA was used to evaluate the clinical net benefit of predictive models at a range of clinically reasonable risk thresholds.

Results

In both women and men, the full model GFRC + GRS achieved the highest net benefits. For 10-year risk threshold > 18% for women and > 15% for men, the GRS provided net benefit above those of the CRF models. At 20% risk threshold, adding the GRS could help to avoid 1 additional treatment per 81 women or 1 per 24 men compared with the Garvan model. At lower risk thresholds, there was no significant difference between the four models.

Conclusions

The addition of genetic profiling into the clinical risk factors can improve the net clinical benefit at higher risk thresholds of fracture. Although the contribution of genetic profiling was modest in the presence of BMD + CRF, it appeared to be able to replace BMD for fracture prediction.

Ho-Le, TP, Tran, TS, Bliuc, D, Pham, HM, Frost, SA, Center, JR, Eisman, JA & Nguyen, TV 2021, 'Epidemiological transition to mortality and refracture following an initial fracture', eLife, vol. 10, pp. 1-15.
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This study sought to redefine the concept of fracture risk that includes refracture and mortality, and to transform the risk into 'skeletal age'. We analysed data obtained from 3521 women and men aged 60 years and older, whose fracture incidence, mortality, and bone mineral density (BMD) have been monitored since 1989. During the 20-year follow-up period, among 632 women and 184 men with a first incident fracture, the risk of sustaining a second fracture was higher in women (36%) than in men (22%), but mortality risk was higher in men (41%) than in women (25%). The increased risk of mortality was not only present with an initial fracture, but was accelerated with refractures. Key predictors of post-fracture mortality were male gender (hazard ratio [HR] 2.4; 95% CI, 1.79–3.21), advancing age (HR 1.67; 1.53–1.83), and lower femoral neck BMD (HR 1.16; 1.01–1.33). A 70-year-old man with a fracture is predicted to have a skeletal age of 75. These results were incorporated into a prediction model to aid patient-doctor discussion about fracture vulnerability and treatment decisions.

Holmes, NP, Chambon, S, Holmes, A, Xu, X, Hirakawa, K, Deniau, E, Lartigau-Dagron, C & Bousquet, A 2021, 'Organic semiconductor colloids: From the knowledge acquired in photovoltaics to the generation of solar hydrogen fuel', Current Opinion in Colloid & Interface Science, vol. 56, pp. 101511-101511.
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Houshyar, S, Bhattacharyya, A, Khalid, A, Rifai, A, Dekiwadia, C, Kumar, GS, Tran, PA & Fox, K 2021, 'Multifunctional Sutures with Temperature Sensing and Infection Control', Macromolecular Bioscience, vol. 21, no. 3.
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AbstractThe next‐generation sutures should provide in situ monitoring of wound condition such as temperature while reducing surgical site infection during wound closure. In this study, functionalized nanodiamond (FND) and reduced graphene oxide (rGO) into biodegradable polycaprolactone (PCL) are incorporated to develop a new multifunctional suture with such capabilities. Incorporation of FND and rGO into PCL enhances its tensile strength by about 43% and toughness by 35%. The sutures show temperature sensing capability in the range of 25–40 °C based on the shift in zero‐splitting frequency of the nitrogen‐vacancy (NV–) centers in FND via optically detected magnetic resonance, paving the way for potential detection of infection or excessive inflammation in healing wounds. The suture surface readily coats with antibiotics to reduce bacterial infection risk to the wounds. The new suture thus is promising in monitoring and supporting wound closure.

Huo, L, Jiao Li, J, Chen, L, Yu, Z, Hutvagner, G & Li, J 2021, 'Single-cell multi-omics sequencing: application trends, COVID-19, data analysis issues and prospects', Briefings in Bioinformatics, vol. 22, no. 6, p. bbab229.
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AbstractSingle-cell sequencing is a biotechnology to sequence one layer of genomic information for individual cells in a tissue sample. For example, single-cell DNA sequencing is to sequence the DNA from every single cell. Increasing in complexity, single-cell multi-omics sequencing, or single-cell multimodal omics sequencing, is to profile in parallel multiple layers of omics information from a single cell. In practice, single-cell multi-omics sequencing actually detects multiple traits such as DNA, RNA, methylation information and/or protein profiles from the same cell for many individuals in a tissue sample. Multi-omics sequencing has been widely applied to systematically unravel interplay mechanisms of key components and pathways in cell. This survey overviews recent developments in single-cell multi-omics sequencing, and their applications to understand complex diseases in particular the COVID-19 pandemic. We also summarize machine learning and bioinformatics techniques used in the analysis of the intercorrelated multilayer heterogeneous data. We observed that variational inference and graph-based learning are popular approaches, and Seurat V3 is a commonly used tool to transfer the missing variables and labels. We also discussed two intensively studied issues relating to data consistency and diversity and commented on currently cared issues surrounding the error correction of data pairs and data imputation methods. The survey is concluded with some open questions and opportunities for this extraordinary field.

Iranpour, H, Hosseini, SN, Hosseini Far, H, Zhand, S, Mohammadi Ghanbarlu, M, Shahsavarani, H, Bouzari, S & Shokrgozar, MA 2021, 'Self-assembling of chimeric mussel-inspired bio-adhesives originated from Mytilus californianus and Anabaena flos-aquae: A new approach to develop underwater adhesion', International Journal of Adhesion and Adhesives, vol. 110, pp. 102938-102938.
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Bio-adhesives play a pivotal role in a wide range of medical applications. However, there are some problems about their application in different pH values and low adhesion force under wet conditions. Here, we report new recombinant fusion protein achieved by mussel foot proteins (Mfps) of Mytilus Californianus and gas vesicle protein A (GvpA) of Anabaena flos-aquae by genetic engineering methods. Transmission electron microscopy verified that these chimeric proteins self-assembled into β-sheet rich fibres because of GvpA amyloid structure. Also, in comparison to other studies, their adhesion forces were significantly increased, especially in the alkaline environments based on Mfp-3 and Mfp-5, confirmed by the colloidal probe atomic force microscope. This study illustrates that copolymer of Mfp-5-GvpA:GvpA-Mfp-3 can be used as a sturdy underwater adhesive with tolerance to auto-oxidation, especially at basic conditions.

Iuliano, S, Poon, S, Robbins, J, Bui, M, Wang, X, De Groot, L, Van Loan, M, Zadeh, AG, Nguyen, T & Seeman, E 2021, 'Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial', BMJ, vol. 375, pp. n2364-n2364.
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AbstractObjectiveTo assess the antifracture efficacy and safety of a nutritional intervention in institutionalised older adults replete in vitamin D but with mean intakes of 600 mg/day calcium and <1 g/kg body weight protein/day.DesignTwo year cluster randomised controlled trial.Setting60 accredited residential aged care facilities in Australia housing predominantly ambulant residents.Participants7195 permanent residents (4920 (68%) female; mean age 86.0 (SD 8.2) years).InterventionFacilities were stratified by location and organisation, with 30 facilities randomised to provide residents with additional milk, yoghurt, and cheese that contained 562 (166) mg/day calcium and 12 (6) g/day protein achieving a total intake of 1142 (353) mg calcium/day and 69 (15) g/day protein (1.1 g/kg body weight). The 30 control facilities maintained their usual menus, with residents consuming 700 (247) mg/day calcium and 58 (14) g/day protein (0.9 g/kg body weight).Main outcome measuresGroup differences in incidence of fractures, falls, and all cause mortality.ResultsData from 27 intervention facilities and 29 control facilities were analysed. A total of 324 fractures (135 hip fractures), 4302 falls, and 1974 deaths were observed. The intervention was associated with risk reductions of 33% for all fractures (121v203; hazard ratio 0.67, 95% confidence interval 0.48 to 0.93; P=0.02), 46% for hip fractures (42v93; 0.54, 0.35 to 0.83; P=0.005), and 11% for falls (1879v<...

Lan, T, Hutvagner, G, Lan, Q, Liu, T & Li, J 2021, 'Sequencing dropout-and-batch effect normalization for single-cell mRNA profiles: a survey and comparative analysis', Briefings in Bioinformatics, vol. 22, no. 4.
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AbstractSingle-cell mRNA sequencing has been adopted as a powerful technique for understanding gene expression profiles at the single-cell level. However, challenges remain due to factors such as the inefficiency of mRNA molecular capture, technical noises and separate sequencing of cells in different batches. Normalization methods have been developed to ensure a relatively accurate analysis. This work presents a survey on 10 tools specifically designed for single-cell mRNA sequencing data preprocessing steps, among which 6 tools are used for dropout normalization and 4 tools are for batch effect correction. In this survey, we outline the main methodology for each of these tools, and we also compare these tools to evaluate their normalization performance on datasets which are simulated under the constraints of dropout inefficiency, batch effect or their combined effects. We found that Saver and Baynorm performed better than other methods in dropout normalization, in most cases. Beer and Batchelor performed better in the batch effect normalization, and the Saver–Beer tool combination and the Baynorm–Beer combination performed better in the mixed dropout-and-batch effect normalization. Over-normalization is a common issue occurred to these dropout normalization tools that is worth of future investigation. For the batch normalization tools, the capability of retaining heterogeneity between different groups of cells after normalization can be another direction for future improvement.

Law, AMK, Rodriguez de la Fuente, L, Grundy, TJ, Fang, G, Valdes-Mora, F & Gallego-Ortega, D 2021, 'Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies', Frontiers in Oncology, vol. 11, p. 782766.
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Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulatesin vivocharacteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements thatin vitrotechnologies can provide to improve cancer therapeutics.

Li, H, Li, Y, Wang, K, Lai, L, Xu, X, Sun, B, Yang, Z & Ding, G 2021, 'Ultra-high sensitive micro-chemo-mechanical hydrogen sensor integrated by palladium-based driver and high-performance piezoresistor', International Journal of Hydrogen Energy, vol. 46, no. 1, pp. 1434-1445.
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AbstractA novel resistive chemical-mechanical sensor for hydrogen gas detection was designed and manufactured by using MEMS processing technology. The sensor combines a composite piezoresistor of silver nanowires-polyimide and a palladium sputtered microcantilever, and the optimized structure of which has been obtained through theoretical and simulation analysis. With a series of experimental testing, the fabricated sensor achieved the ultra-high sensitivity of 2825, 8071, 28250 and 47083 for hydrogen detection at the concentration of 0.4%, 0.8%, 1.2%, 1.6% and 2.0%, respectively. The ultra-high sensitive detection for hydrogen was enabled from the synergistic function of both the surface resistance effect between the palladium coated cantilever and silver nanowires-polyimide piezoresistor, and the bulk resistance effect of the silver nanowires-polyimide piezoresistor. In addition, the sensor also demonstrates excellent stability, which has high potential for practical hydrogen gas detection.

Li, Y, Xue, B, Zhang, M, Zhang, L, Hou, Y, Qin, Y, Long, H, Su, QP, Wang, Y, Guan, X, Jin, Y, Cao, Y, Li, G & Sun, Y 2021, 'Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency', Genome Biology, vol. 22, no. 1, pp. 1-29.
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Abstract Background Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined. Results We apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired. Conclusion Our work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination bet...

Liu Chung Ming, C, Sesperez, K, Ben-Sefer, E, Arpon, D, McGrath, K, McClements, L & Gentile, C 2021, 'Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease', Cells, vol. 10, no. 4, pp. 899-899.
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Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD), including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion; however, this therapeutic approach leads to ischemic/reperfusion injury (IRI), often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

Liu, D, Xu, X, Du, Y, Liao, J, Wen, S, Dong, X, Jin, Y, Liu, L, Jin, D, Capobianco, JA & Shen, D 2021, 'Reconstructing the Surface Structure of NaREF₄ Upconversion Nanocrystals with a Novel K⁺ Treatment', Chemistry of Materials, vol. 33, no. 7, pp. 2548-2556.
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Property of the nanocrystals' surface structure plays a key role in developing novel nanomaterials with high performance and new functionalities. Conventional methods of nanocrystal surface engineering are commonly based on tuning the synthesis reaction parameters or growing core-shell structures, which usually results in increasing the size of the nanoparticles. Here, we report an approach to tailoring the surface crystalline structure of β-NaYF4 nanocrystals by reheating the nanocrystals in a K+-rich environment of the oleic acid-1-octadecene (OA-ODE) system. We found that the crystal surface stability of nanocrystals was decreased in the K+-rich solution, which reconstructs the nanocrystals' surface into a porous surface structure. With a systematic design of experiments, the roles of the cations, such as K+, K+-Gd3+, and Na+-Y3+, are individually identified, which leads to a reformation of the surface structure of the hexagonal NaYF4 nanocrystal into different forms, e.g., a mesostructured, spherical, and diamond surface. The technique of tailoring the surface crystalline structures will provide new insight for the shape and surface-dependent property studies and luminescence enhancement without a size increase.

Liu, Y, Li, H, Li, Y, Xu, X, Yang, Z & Ding, G 2021, 'Optimization of the Discrete Structure in a Pressure Sensor Based on a Multiple-Contact Mechanism to Improve Sensitivity and Nonlinearity', IEEE Sensors Journal, vol. 21, no. 19, pp. 21259-21267.
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Liu, Y, Zhou, Z, Wang, F, Kewes, G, Wen, S, Burger, S, Ebrahimi Wakiani, M, Xi, P, Yang, J, Yang, X, Benson, O & Jin, D 2021, 'Axial localization and tracking of self-interference nanoparticles by lateral point spread functions', Nature Communications, vol. 12, no. 1, pp. 1-9.
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AbstractSub-diffraction limited localization of fluorescent emitters is a key goal of microscopy imaging. Here, we report that single upconversion nanoparticles, containing multiple emission centres with random orientations, can generate a series of unique, bright and position-sensitive patterns in the spatial domain when placed on top of a mirror. Supported by our numerical simulation, we attribute this effect to the sum of each single emitter’s interference with its own mirror image. As a result, this configuration generates a series of sophisticated far-field point spread functions (PSFs), e.g. in Gaussian, doughnut and archery target shapes, strongly dependent on the phase difference between the emitter and its image. In this way, the axial locations of nanoparticles are transferred into far-field patterns. We demonstrate a real-time distance sensing technology with a localization accuracy of 2.8 nm, according to the atomic force microscope (AFM) characterization values, smaller than 1/350 of the excitation wavelength.

Lyu, J, Ling, SH, Banerjee, S, Zheng, JY, Lai, KL, Yang, D, Zheng, YP, Bi, X, Su, S & Chamoli, U 2021, 'Ultrasound volume projection image quality selection by ranking from convolutional RankNet', Computerized Medical Imaging and Graphics, vol. 89, pp. 101847-101847.
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Periodic inspection and assessment are important for scoliosis patients. 3D ultrasound imaging has become an important means of scoliosis assessment as it is a real-time, cost-effective and radiation-free imaging technique. With the generation of a 3D ultrasound volume projection spine image using our Scolioscan system, a series of 2D coronal ultrasound images are produced at different depths with different qualities. Selecting a high quality image from these 2D images is the crucial task for further scoliosis measurement. However, adjacent images are similar and difficult to distinguish. To learn the nuances between these images, we propose selecting the best image automatically, based on their quality rankings. Here, the ranking algorithm we use is a pairwise learning-to-ranking network, RankNet. Then, to extract more efficient features of input images and to improve the discriminative ability of the model, we adopt the convolutional neural network as the backbone due to its high power of image exploration. Finally, by inputting the images in pairs into the proposed convolutional RankNet, we can select the best images from each case based on the output ranking orders. The experimental result shows that convolutional RankNet achieves better than 95.5% top-3 accuracy, and we prove that this performance is beyond the experience of a human expert.

Mah, D, Chamoli, U & Smith, GCS 2021, 'Usefulness of computed tomography based three-dimensional reconstructions to assess the critical shoulder angle', World Journal of Orthopedics, vol. 12, no. 5, pp. 301-309.
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BACKGROUND: The critical shoulder angle (CSA) is a radiographic measurement that provides an assessment of both glenoid inclination and acromial length. Higher values may correlate with the presence of rotator cuff tears. However, it is difficult to obtain a high-quality true anteroposterior (AP) radiograph of the shoulder, with any excess scapular version or flexion/extension resulting in deviation from the true CSA value. Three-dimensional (3D) bony reconstructions of computed tomography (CT) shoulder scans may be able to be rotated to obtain a similar view to that of true AP radiographs. AIM: To compare CSA measurements performed on 3D bony CT reconstructions, with those on corresponding true AP radiographs. METHODS: CT shoulder scans were matched with true AP radiographs that were classified as either Suter-Henninger type A or C quality. 3D bony reconstructions were segmented from the CT scans, and rotated to replicate an ideal true AP view. Two observers performed CSA measurements using both CT and radiographic images. Measurements were repeated after a one week interval. Reliability was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman plots [bias, limits of agreement (LOA)]. RESULTS: Twenty CT shoulder scans were matched. The mean CSA values were 32.55° (± 4.26°) with radiographs and 29.82° (± 3.49°) with the CT-based method [mean difference 2.73° (± 2.86°); P < 0.001; bias +2.73°; LOA -2.17° to +7.63°]. There was a strong correlation between the two methods (r = 0.748; P < 0.001). Intra-observer reliability was similar, but the best intra-observer values were achieved by the most experienced observer using the CT-based method [ICC: 0.983 (0.958-0.993); bias +0.03°, LOA -1.28° to +1.34°]. Inter-observer reliability was better with the CT-based method [ICC: 0.897 (0.758-0.958), bias +0.24°, LOA -2.93° to +3.41°]. CONCLUSION: The described CT-based method may be a suitable alternative for critical shoulder angle measurement...

Mayer, JU, Hilligan, KL, Chandler, JS, Eccles, DA, Old, SI, Domingues, RG, Yang, J, Webb, GR, Munoz-Erazo, L, Hyde, EJ, Wakelin, KA, Tang, S-C, Chappell, SC, von Daake, S, Brombacher, F, Mackay, CR, Sher, A, Tussiwand, R, Connor, LM, Gallego-Ortega, D, Jankovic, D, Le Gros, G, Hepworth, MR, Lamiable, O & Ronchese, F 2021, 'Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization', Nature Immunology, vol. 22, no. 12, pp. 1538-1550.
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Mehta, M, Paudel, KR, Shukla, SD, Allam, VSRR, Kannaujiya, VK, Panth, N, Das, A, Parihar, VK, Chakraborty, A, Ali, MK, Jha, NK, Xenaki, D, Su, QP, Wich, PR, Adams, J, Hansbro, PM, Chellappan, DK, Oliver, BGG & Dua, K 2021, 'Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases', Journal of Controlled Release, vol. 337, pp. 629-644.
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Miao, MZ, Collins, JA, Bahnson, EM, Diekman, BO, Su, PQ, Chubinskaya, S & Loeser, RF 2021, 'Temporospatial production of reactive oxygen species in articular chondrocytes is induced by the endocytosis of fibronectin fragments, alpha 5 beta 1 integrin and NADPH oxidase 2', Osteoarthritis and Cartilage, vol. 29, pp. S114-S115.
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Mirkhalaf, M, Wang, X, Entezari, A, Dunstan, CR, Jiang, X & Zreiqat, H 2021, 'Redefining architectural effects in 3D printed scaffolds through rational design for optimal bone tissue regeneration', Applied Materials Today, vol. 25, pp. 101168-101168.
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Mirzaie, M, Lakzian, E, Khan, A, Warkiani, ME, Mahian, O & Ahmadi, G 2021, 'COVID-19 spread in a classroom equipped with partition – A CFD approach', Journal of Hazardous Materials, vol. 420, pp. 126587-126587.
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In this study, the motion and distribution of droplets containing coronaviruses emitted by coughing of an infected person in front of a classroom (e.g., a teacher) were investigated using CFD. A 3D turbulence model was used to simulate the airflow in the classroom, and a Lagrangian particle trajectory analysis method was used to track the droplets. The numerical model was validated and was used to study the effects of ventilation airflow speeds of 3, 5, and 7 m/s on the dispersion of droplets of different sizes. In particular, the effect of installing transparent barriers in front of the seats on reducing the average droplet concentration was examined. The results showed that using the seat partitions for individuals can prevent the infection to a certain extent. An increase in the ventilation air velocity increased the droplets’ velocities in the airflow direction, simultaneously reducing the trapping time of the droplets by solid barriers. As expected, in the absence of partitions, the closest seats to the infected person had the highest average droplet concentration (3.80 × 10−8 kg/m3 for the case of 3 m/s).

Morshedi Rad, D, Alsadat Rad, M, Razavi Bazaz, S, Kashaninejad, N, Jin, D & Ebrahimi Warkiani, M 2021, 'A Comprehensive Review on Intracellular Delivery', Advanced Materials, vol. 33, no. 13, pp. e2005363-2005363.
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AbstractIntracellular delivery is considered an indispensable process for various studies, ranging from medical applications (cell‐based therapy) to fundamental (genome‐editing) and industrial (biomanufacture) approaches. Conventional macroscale delivery systems critically suffer from such issues as low cell viability, cytotoxicity, and inconsistent material delivery, which have opened up an interest in the development of more efficient intracellular delivery systems. In line with the advances in microfluidics and nanotechnology, intracellular delivery based on micro‐ and nanoengineered platforms has progressed rapidly and held great promises owing to their unique features. These approaches have been advanced to introduce a smorgasbord of diverse cargoes into various cell types with the maximum efficiency and the highest precision. This review differentiates macro‐, micro‐, and nanoengineered approaches for intracellular delivery. The macroengineered delivery platforms are first summarized and then each method is categorized based on whether it employs a carrier‐ or membrane‐disruption‐mediated mechanism to load cargoes inside the cells. Second, particular emphasis is placed on the micro‐ and nanoengineered advances in the delivery of biomolecules inside the cells. Furthermore, the applications and challenges of the established and emerging delivery approaches are summarized. The topic is concluded by evaluating the future perspective of intracellular delivery toward the micro‐ and nanoengineered approaches.

Müller Bark, J, Kulasinghe, A, Hartel, G, Leo, P, Warkiani, ME, Jeffree, RL, Chua, B, Day, BW & Punyadeera, C 2021, 'Isolation of Circulating Tumour Cells in Patients With Glioblastoma Using Spiral Microfluidic Technology – A Pilot Study', Frontiers in Oncology, vol. 11, p. 681130.
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Glioblastoma (GBM) is the most common and aggressive type of tumour arising from the central nervous system. GBM remains an incurable disease despite advancement in therapies, with overall survival of approximately 15 months. Recent literature has highlighted that GBM releases tumoural content which crosses the blood-brain barrier (BBB) and is detected in patients’ blood, such as circulating tumour cells (CTCs). CTCs carry tumour information and have shown promise as prognostic and predictive biomarkers in different cancer types. Currently, there is limited data for the clinical utility of CTCs in GBM. Here, we report the use of spiral microfluidic technology to isolate CTCs from whole blood of newly diagnosed GBM patients before and after surgery, followed by characterization for GFAP, cell-surface vimentin protein expression and EGFR amplification. CTCs were found in 13 out of 20 patients (9/20 before surgery and 11/19 after surgery). Patients with CTC counts equal to 0 after surgery had a significantly longer recurrence-free survival (p=0.0370). This is the first investigation using the spiral microfluidics technology for the enrichment of CTCs from GBM patients and these results support the use of this technology to better understand the clinical value of CTCs in the management of GBM in future studies.

Nagy, Z, Seneviratne, JA, Kanikevich, M, Chang, W, Mayoh, C, Venkat, P, Du, Y, Jiang, C, Salib, A, Koach, J, Carter, DR, Mittra, R, Liu, T, Parker, MW, Cheung, BB & Marshall, GM 2021, 'An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability', Nature Communications, vol. 12, no. 1, pp. 1-20.
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AbstractTo achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.

Nguyen, HG, Le, NV, Nguyen-Duong, KH, Ho-Pham, LT & Nguyen, TV 2021, 'Reference values of body composition parameters for Vietnamese men and women', European Journal of Clinical Nutrition, vol. 75, no. 8, pp. 1283-1290.
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Nguyen, HG, Lieu, KB, Ho-Le, TP, Ho-Pham, LT & Nguyen, TV 2021, 'Discordance between quantitative ultrasound and dual-energy X-ray absorptiometry in bone mineral density: The Vietnam Osteoporosis Study', Osteoporosis and Sarcopenia, vol. 7, no. 1, pp. 6-10.
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Nguyen, TV 2021, 'Personalized fracture risk assessment: where are we at?', Expert Review of Endocrinology & Metabolism, vol. 16, no. 4, pp. 191-200.
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Introduction: Osteoporotic fracture imposes a significant health care burden globally. Personalized assessment of fracture risk can potentially guide treatment decisions. Over the past decade, a number of risk prediction models, including the Garvan Fracture Risk Calculator (Garvan) and FRAX®, have been developed and implemented in clinical practice. Areas covered: This article reviews recent development and validation results concerning the prognostic performance of the two tools. The main areas of review are the need for personalized fracture risk prediction, purposes of risk prediction, predictive performance in terms of discrimination and calibration, concordance between the Garvan and FRAX tools, genetic profiling for improving predictive performance, and treatment thresholds. In some validation studies, FRAX tended to underestimate fracture by as high as 50%. Studies have shown that the predicted risk from the Garvan tool is highly concordant with clinical decision. Expert opinion: Although there are some discrepancy in fracture risk prediction between Garvan and FRAX, both tools are valid and can aid patients and doctors communicate about risk and make informed decision. The ideal of personalized risk assessment for osteoporosis patients will be realized through the incorporation of genetic profiling into existing fracture risk assessment tools.

Nguyen, TV 2021, 'Uncertain effects of hydroxychloroquine and azithromycin on SARS-Cov-2 viral load', International Journal of Antimicrobial Agents, vol. 57, no. 1, pp. 106169-106169.
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Nguyen, TV & Frost, SA 2021, 'Effect of Steroids on Coronavirus Disease 2019 (COVID-19) Mortality Risk: A Bayesian Interpretation', Clinical Infectious Diseases, vol. 73, no. 7, pp. e1774-e1775.
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Nikshad, A, Aghlmandi, A, Safaralizadeh, R, Aghebati-Maleki, L, Warkiani, ME, Khiavi, FM & Yousefi, M 2021, 'Advances of microfluidic technology in reproductive biology', Life Sciences, vol. 265, pp. 118767-118767.
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According to World Health Organization (WHO) reports about 70 million couples suffer from infertility all over the world. A lot of research groups are working on this issue and have made therapeutic approaches by integrating biology, medicine, genetics, chemistry, psychology, mechanic, and many other branches of science. However, these methods have their own pros and cons. Assisted Reproductive Technologies (ART) has appeared to solve infertility problems. In Vitro Fertilization (IVF), Intracytoplasmic Sperm Injection (ICSI), Intrauterine Insemination (IUI) are the most common and conventional technologies in this regard. There are at least two characteristics of microfluidics, mechanical and biochemical, which can be influential in the field of mammalian gamete and preimplantation embryo biology. These microfluidic characteristics can assist in basic biological studies on sperm, oocyte and preimplantation embryo structure, function and environment. Using microfluidics in sorting sperm, conducting different steps of oocyte selection and preparation, and transferring embryo by passing sub-microliter fluid through microchannels results in low cost and short time. The size and shape of microchannels and the volume of used fluid differs from non-human cells to human cells. The most progressions have been seen in animal models. Results suggest that microfluidic systems will lead to improved efficiencies in assisted reproduction.

Oey, O, Ghaffari, M, Li, JJ & Hosseini-Beheshti, E 2021, 'Application of extracellular vesicles in the diagnosis and treatment of prostate cancer: Implications for clinical practice', Critical Reviews in Oncology/Hematology, vol. 167, pp. 103495-103495.
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Extracellular vesicles (EV) are cell-derived lipid bilayer-delimited structures providing an important means of intercellular communication. Recent studies have shown that EV, particularly exosomes and large-oncosomes contain miRNA and proteins crucial in prostate cancer (PCa) progression, metastasis and treatment resistance. This includes not just EV released from PCa cells, but also from other cells in the tumor microenvironment. PCa patient derived EV have a unique composition compared to healthy and benign prostatic diseases. As such, EV show promise as diagnostic liquid biopsy biomarkers, both as an adjunct and alternative to the invasive current gold-standard. EV could also be utilized to stratify patients' risk and predict response to hormonal, chemo, immune- and targeted therapy, which will direct future treatment decisions in PCa. We present a summary of the current evidence on the role of EV in PCa and the application of EV in PCa diagnosis and treatment to optimize patient outcomes.

Pateetin, P, Hutvagner, G, Bajan, S, Padula, MP, McGowan, EM & Boonyaratanakornkit, V 2021, 'Author Correction: Triple SILAC identified progestin-independent and dependent PRA and PRB interacting partners in breast cancer', Scientific Data, vol. 8, no. 1, p. 145.
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The original version of this Data Descriptor omitted the following author from the Author List: Sarah Bajan. This error has now been corrected in both the PDF and HTML versions of the Article.

Pateetin, P, Hutvagner, G, Bajan, S, Padula, MP, McGowan, EM & Boonyaratanakornkit, V 2021, 'Triple SILAC identified progestin-independent and dependent PRA and PRB interacting partners in breast cancer', Scientific Data, vol. 8, no. 1, p. 100.
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AbstractProgesterone receptor (PR) isoforms, PRA and PRB, act in a progesterone-independent and dependent manner to differentially modulate the biology of breast cancer cells. Here we show that the differences in PRA and PRB structure facilitate the binding of common and distinct protein interacting partners affecting the downstream signaling events of each PR-isoform. Tet-inducible HA-tagged PRA or HA-tagged PRB constructs were expressed in T47DC42 (PR/ER negative) breast cancer cells. Affinity purification coupled with stable isotope labeling of amino acids in cell culture (SILAC) mass spectrometry technique was performed to comprehensively study PRA and PRB interacting partners in both unliganded and liganded conditions. To validate our findings, we applied both forward and reverse SILAC conditions to effectively minimize experimental errors. These datasets will be useful in investigating PRA- and PRB-specific molecular mechanisms and as a database for subsequent experiments to identify novel PRA and PRB interacting proteins that differentially mediated different biological functions in breast cancer.

Pham, DX, Nguyen, HD, Phung, AHT, Bui, TD, Tran, TS, Tran, BNH, Ho-Pham, LT & Nguyen, TV 2021, 'Trends in incidence and histological pattern of thyroid cancer in Ho Chi Minh City, Vietnam (1996–2015): a population-based study', BMC Cancer, vol. 21, no. 1, pp. 1-8.
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Abstract Background The burden and trend of thyroid cancer in Vietnam have not been well documented. This study aimed to investigate the trends in incidence and histological pattern of thyroid cancer in Ho Chi Minh City from 1996 to 2015. Methods A population-based study retrieved data from the Ho Chi Minh City Cancer Registry during 1996–2015. Trends in the incidence of thyroid cancer were investigated based on age, gender, and histology for each 5-year period. Annual percentage change (APC) in incidence rates was estimated using Joinpoint regression analysis. Results In the study period, there were 5953 thyroid cancer cases (men-to-women ratio 1:4.5) newly diagnosed in Ho Chi Minh City with the mean age of 42.9 years (±14.9 years). The age-standardized incidence rate of thyroid cancer increased from 2.4 per 100,000 during 1996–2000 (95% confidence interval [95% CI]: 2.2–2.6) to 7.5 per 100,000 during 2011–2015 (95% CI: 7.3–7.9), corresponded to an overall APC of 8.7 (95% CI 7.6–9.9). The APC in men and women was 6.2 (95% CI: 4.2–8.2) and 9.2 (95% CI: 8.0–10.4), respectively. The incidence rate in the < 45 years age group was the highest diagnosed overall and increased significantly in both men (APC 11.0) and women (APC 10.1). Both genders shared similar distribution of subtype incidences, with papillary thyroid cancer constituted the most diagnosed (73.3% in men and 85.2% in women). The papillary thyroid cancer observed a markedly increase overall (APC of 10.7 (95% CI 9.3–12.0)). Conclusions There were appreciable increases in...

Polonchuk, L, Surija, L, Lee, MH, Sharma, P, Liu Chung Ming, C, Richter, F, Ben-Sefer, E, Rad, MA, Mahmodi Sheikh Sarmast, H, Shamery, WA, Tran, HA, Vettori, L, Haeusermann, F, Filipe, EC, Rnjak-Kovacina, J, Cox, T, Tipper, J, Kabakova, I & Gentile, C 2021, 'Towards engineering heart tissues from bioprinted cardiac spheroids', Biofabrication, vol. 13, no. 4, pp. 045009-045009.
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Abstract Current in vivo and in vitro models fail to accurately recapitulate the human heart microenvironment for biomedical applications. This study explores the use of cardiac spheroids (CSs) to biofabricate advanced in vitro models of the human heart. CSs were created from human cardiac myocytes, fibroblasts and endothelial cells (ECs), mixed within optimal alginate/gelatin hydrogels and then bioprinted on a microelectrode plate for drug testing. Bioprinted CSs maintained their structure and viability for at least 30 d after printing. Vascular endothelial growth factor (VEGF) promoted EC branching from CSs within hydrogels. Alginate/gelatin-based hydrogels enabled spheroids fusion, which was further facilitated by addition of VEGF. Bioprinted CSs contracted spontaneously and under stimulation, allowing to record contractile and electrical signals on the microelectrode plates for industrial applications. Taken together, our findings indicate that bioprinted CSs can be used to biofabricate human heart tissues for long term in vitro testing. This has the potential to be used to study biochemical, physiological and pharmacological features of human heart tissue.

Qiu, S, Ji, J, Sun, W, Pei, J, He, J, Li, Y, Li, JJ & Wang, G 2021, 'Recent advances in surface manipulation using micro-contact printing for biomedical applications', Smart Materials in Medicine, vol. 2, pp. 65-73.
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Surface properties are largely responsible for the biological performance of biomedical devices, suggesting the great necessity of surface modification. Micro-contact printing (μCP) is a versatile surface modification technique that is capable of not only producing defined topographical features but also manipulating surface chemical and biological cues through customized inks. Compared to other surface patterning techniques, μCP offers distinct advantages of low cost combined with high reliability and versatility. This review summarizes the principles and characteristics of μCP and presents the latest advances enabled by μCP in the biomedical field, categorized by its applications in constructing cell culture platforms, biosensing platforms, and devices for other biological applications.

Rad, HS, Rad, HS, Shiravand, Y, Radfar, P, Arpon, D, Warkiani, ME, O'Byrne, K & Kulasinghe, A 2021, 'The Pandora’s box of novel technologies that may revolutionize lung cancer', Lung Cancer, vol. 159, pp. 34-41.
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Non-small cell lung cancer (NSCLC) is one of the most common cancers globally and has a 5-year survival rate ~20%. Immunotherapies have demonstrated long-term and durable responses in NSCLC patients, although they appear to be effective in only a subset of patients. A more comprehensive understanding of the underlying tumour biology may contribute to identifying those patients likely to achieve optimal outcomes. Profiling the tumour microenvironment (TME) has shown to be beneficial in addressing fundamental tumour-immune cell interactions. Advances in multiplexing immunohistochemistry and molecular barcoding has led to recent advances in profiling genes and proteins in NSCLC. Here, we review the recent advancements in spatial profiling technologies for the analysis of NSCLC tissue samples to gain new insights and therapeutic options for NSCLC. The combination of spatial transcriptomics combined with advanced imaging is likely to lead to deep insights into NSCLC tissue biology, which can be a powerful tool to predict likelihood of response to therapy.

Rad, HS, Röhl, J, Stylianou, N, Allenby, MC, Bazaz, SR, Warkiani, ME, Guimaraes, FSF, Clifton, VL & Kulasinghe, A 2021, 'The Effects of COVID-19 on the Placenta During Pregnancy', Frontiers in Immunology, vol. 12, p. 743022.
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Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.

Radfar, P, Bazaz, SR, Mirakhorli, F & Warkiani, ME 2021, 'The role of 3D printing in the fight against COVID-19 outbreak', Journal of 3D Printing in Medicine, vol. 5, no. 1, pp. 51-60.
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Along with the COVID-19 pandemic, urgent needs for medical and specialized products, especially personal protective equipment, has been overwhelming. The conventional production line of medical devices has been challenged by excessive global demand, and the need for an easy, low-cost and rapid fabrication method is felt more than ever. In a scramble to address this shortfall, manufacturers referred to additive manufacturing or 3D printing to fill the gap and increase the production line of medical devices. Various previously/conventionally fabricated designs have been modified and redesigned to suit the 3D printing requirement to fight against COVID-19. In this perspective, various designs accommodated for the current worldwide outbreak of COVID-19 are discussed and how 3D printing could help the global community against the current and future conditions has been explored.

Ramezankhani, R, Solhi, R, Es, HA, Vosough, M & Hassan, M 2021, 'Novel molecular targets in gastric adenocarcinoma', Pharmacology & Therapeutics, vol. 220, pp. 107714-107714.
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Raoufi, MA, Joushani, HAN, Razavi Bazaz, S, Ding, L, Asadnia, M & Ebrahimi Warkiani, M 2021, 'Effects of sample rheology on the equilibrium position of particles and cells within a spiral microfluidic channel', Microfluidics and Nanofluidics, vol. 25, no. 9, pp. 1-13.
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Elasto-inertial migration in non-Newtonian fluids is a rapidly growing field with tremendous potentials for manipulating micron to submicron particles. Previous research attempts were mainly carried out in straight channels due to the complexity of particle migration, solution tuning, and data analysis in elasto-inertial microfluidics. Consequently, the combined effects of Dean drag force and solution rheology on coupled Dean drag elasto-inertial focusing phenomena have not been carefully analyzed. This study delved thoroughly into the combined effects of solution rheology and Dean drag force on elasto-inertial focusing of particles and cells within a spiral microchannel. Polyethylene oxide (PEO) of 1MDa, 2MDa, and 4MDa molecular weights were used to prepare 250, 500, and 1000 ppm non-Newtonian solutions to investigate the focusing behavior of particles and cells over a wide range of flow rates and solution rheologies. Dean coupled elasto-inertial effects were systematically investigated to demonstrate its potentials for position-adjustable and size-tunable particle and cell focusing phenomenon. Various cells and microbeads with diameters ranging from 1 to 17 μm were employed to carefully study the equilibrium position, focusing band, and migration behavior under different elastic, inertial, and Dean conditions. Following the focusing, cell viability, morphology, and growth rate were evaluated which showed cells remained undamaged from viscosity, shear rate, and chemical properties of PEO solutions. We are of the opinion that the current study can provide scientists with a better understanding of focusing phenomena in viscoelastic fluids within spiral microfluidic channels.

Rezaei, M, Radfar, P, Winter, M, McClements, L, Thierry, B & Warkiani, ME 2021, 'Simple-to-Operate Approach for Single Cell Analysis Using a Hydrophobic Surface and Nanosized Droplets', Analytical Chemistry, vol. 93, no. 10, pp. 4584-4592.
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Microfluidics-based technologies for single-cell analysis are becoming increasingly important tools in biological studies. With the increasing sophistication of microfluidics, cellular barcoding techniques, and next-generation sequencing, a more detailed picture of cellular subtype is emerging. Unfortunately, the majority of the methods developed for single-cell analysis are high-throughput and not suitable for rare cell analysis as they require a high input cell number. Here, we report a low-cost and reproducible method for rare single-cell analysis using a highly hydrophobic surface and nanosized static droplets. Our method allows rapid and efficient on-chip single-cell lysis and subsequent collection of genetic materials in nanoliter droplets using a micromanipulator or a laboratory pipette before subsequent genetic analysis. We show precise isolation of single cancer cells with high purity using two different strategies (i- cytospin and ii- static droplet array) for subsequent RNA analysis using droplet digital polymerase chain reaction (PCR) and real-time PCR. Our highly controlled isolation method opens a new avenue for the study of subcellular functional mechanisms, enabling the identification of rare cells of potential functional or pathogenic consequence.

Rezaei, M, Razavi Bazaz, S, Morshedi Rad, D, Shimoni, O, Jin, D, Rawlinson, W & Ebrahimi Warkiani, M 2021, 'A Portable RT-LAMP/CRISPR Machine for Rapid COVID-19 Screening', Biosensors, vol. 11, no. 10, pp. 369-369.
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The COVID-19 pandemic has changed people’s lives and has brought society to a sudden standstill, with lockdowns and social distancing as the preferred preventative measures. To lift these measurements and reduce society’s burden, developing an easy-to-use, rapid, and portable system to detect SARS-CoV-2 is mandatory. To this end, we developed a portable and semi-automated device for SARS-CoV-2 detection based on reverse transcription loop-mediated isothermal amplification followed by a CRISPR/Cas12a reaction. The device contains a heater element mounted on a printed circuit board, a cooler fan, a proportional integral derivative controller to control the temperature, and designated areas for 0.2 mL Eppendorf® PCR tubes. Our system has a limit of detection of 35 copies of the virus per microliter, which is significant and has the capability of being used in crisis centers, mobile laboratories, remote locations, or airports to diagnose individuals infected with SARS-CoV-2. We believe the current methodology that we have implemented in this article is beneficial for the early screening of infectious diseases, in which fast screening with high accuracy is necessary.

Rhee, H, Navaratnam, A, Oleinikova, I, Gilroy, D, Scuderi, Y, Heathcote, P, Nguyen, T, Wood, S & Ho, KKY 2021, 'A Novel Liver-targeted Testosterone Therapy for Sarcopenia in Androgen Deprived Men With Prostate Cancer', Journal of the Endocrine Society, vol. 5, no. 9.
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Abstract Objective Androgen deprivation therapy (ADT) reduces muscle and bone mass, increasing frailty in men with prostate cancer. The liver mediates the whole body anabolic effects of testosterone. Based on first-pass metabolism, liver-targeted testosterone treatment (LTTT) entails oral delivery of a small dose of testosterone that does not raise peripheral blood testosterone levels. LTTT reduces blood urea and stimulates protein anabolism in hypogonadal men and postmenopausal women. We investigated whether LTTT prevents loss of lean and bone mass during ADT. Method A 6-month, double-blind, placebo-controlled study of testosterone 40 mg/day in 50 men. Primary outcome measures were lean mass and bone mineral content (BMC). Testosterone, urea and prostate-specific antigen (PSA) were monitored. Patients were withdrawn if PSA exceeded 4 ng/mL. Results 42 patients completed the study. Mean (95% CI) testosterone rose during LTTT but not placebo treatment [∆ 2.2 (1.3-3.0) vs −0.7 (−1.5 to 0.2) nmol/L; P &lt; 0.01]. Mean PSA level did not change significantly during either treatment. Blood urea fell [∆ −0.4 (−0.9 to −0.1) mmol/L] during LTTT but not placebo [∆ 0.05 (−0.8 to 0.9) mmol/L]. BMC [∆ 49 (5 to 93) g; P &lt; 0.02] and lean mass [∆ 0.8 (−0.1 to 1.7) kg; P = 0.04) increased compared to placebo. Five patients on LTTT withdrew from increased PSA levels, all returning to baseline levels. Conclusion LTTT shows promise as a simple therapy for pre...

Richards, C, Sesperez, K, Chhor, M, Ghorbanpour, S, Rennie, C, Ming, CLC, Evenhuis, C, Nikolic, V, Orlic, NK, Mikovic, Z, Stefanovic, M, Cakic, Z, McGrath, K, Gentile, C, Bubb, K & McClements, L 2021, 'Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia', Biology of Sex Differences, vol. 12, no. 1.
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Abstract Background Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. Methods The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results The RUPP procedure induced ...

Rifai, A, Creedon, D, Tran, N, Hejazi, M, Garrett, D, Greentree, AD, Pirogova, E, Stacey, A & Fox, K 2021, 'Highly uniform polycrystalline diamond coatings of three-dimensional structures', Surface and Coatings Technology, vol. 408, pp. 126815-126815.
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Rifai, A, Houshyar, S & Fox, K 2021, 'Progress towards 3D-printing diamond for medical implants: A review', Annals of 3D Printed Medicine, vol. 1, pp. 100002-100002.
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Rifai, A, Tran, N, Leitch, V, Booth, MA, Williams, R & Fox, K 2021, 'Osteoblast Cell Response on Polycrystalline Diamond-Coated Additively Manufactured Scaffolds', ACS Applied Bio Materials, vol. 4, no. 10, pp. 7509-7516.
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Roche, CD, Iyer, GR, Nguyen, MH, Mabroora, S, Dome, A, Sakr, K, Pawar, R, Lee, V, Wilson, CC & Gentile, C 2021, 'Cardiac Patch Transplantation Instruments for Robotic Minimally Invasive Cardiac Surgery: Initial Proof-of-concept Designs and Surgery in a Porcine Cadaver', Frontiers in Robotics and AI, vol. 8, p. 714356.
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Background: Damaged cardiac tissues could potentially be regenerated by transplanting bioengineered cardiac patches to the heart surface. To be fully paradigm-shifting, such patches may need to be transplanted using minimally invasive robotic cardiac surgery (not only traditional open surgery). Here, we present novel robotic designs, initial prototyping and a new surgical operation for instruments to transplant patches via robotic minimally invasive heart surgery.Methods: Robotic surgical instruments and automated control systems were designed, tested with simulation software and prototyped. Surgical proof-of-concept testing was performed on a pig cadaver.Results: Three robotic instrument designs were developed. The first (called “Claw” for the claw-like patch holder at the tip) operates on a rack and pinion mechanism. The second design (“Shell-Beak”) uses adjustable folding plates and rods with a bevel gear mechanism. The third (“HeartStamp”) utilizes a stamp platform protruding through an adjustable ring. For the HeartStamp, rods run through a cylindrical structure designed to fit a uniportal Video-Assisted Thorascopic Surgery (VATS) surgical port. Designed to work with or without a sterile sheath, the patch is pushed out by the stamp platform as it protrudes. Two instrument robotic control systems were designed, simulated in silico and one of these underwent early ‘sizing and learning’ prototyping as a proof-of-concept. To reflect real surgical conditions, surgery was run “live” and reported exactly (as-it-happened). We successfully picked up, transferred and released a patch onto the heart using the HeartStamp in a pig cadaver model.Conclusion: These world-first designs, early prototypes and a novel surgical operation pave the way for robotic instr...

Rodriguez de la Fuente, L, Law, AMK, Gallego-Ortega, D & Valdes-Mora, F 2021, 'Tumor dissociation of highly viable cell suspensions for single-cell omic analyses in mouse models of breast cancer', STAR Protocols, vol. 2, no. 4, pp. 100841-100841.
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Cell preparation with a high rate of viable cells is required to obtain reliable single-cell transcriptomic and epigenomic data. This protocol describes a technique for digestion and single-cell isolation from mouse mammary tumors to achieve ∼90% of viable cells, which can be subsequently processed in a diverse array of high-throughput single-cell 'omic platforms,' both in an unbiased manner or after selection of a specific cell population. For complete details on the use and execution of this protocol, please refer to Valdes-Mora et al. (2021).

Rouhi, O, Razavi Bazaz, S, Niazmand, H, Mirakhorli, F, Mas-hafi, S, A. Amiri, H, Miansari, M & Ebrahimi Warkiani, M 2021, 'Numerical and Experimental Study of Cross-Sectional Effects on the Mixing Performance of the Spiral Microfluidics', Micromachines, vol. 12, no. 12, pp. 1470-1470.
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Mixing at the microscale is of great importance for various applications ranging from biological and chemical synthesis to drug delivery. Among the numerous types of micromixers that have been developed, planar passive spiral micromixers have gained considerable interest due to their ease of fabrication and integration into complex miniaturized systems. However, less attention has been paid to non-planar spiral micromixers with various cross-sections and the effects of these cross-sections on the total performance of the micromixer. Here, mixing performance in a spiral micromixer with different channel cross-sections is evaluated experimentally and numerically in the Re range of 0.001 to 50. The accuracy of the 3D-finite element model was first verified at different flow rates by tracking the mixing index across the loops, which were directly proportional to the spiral radius and were hence also proportional to the Dean flow. It is shown that higher flow rates induce stronger vortices compared to lower flow rates; thus, fewer loops are required for efficient mixing. The numerical study revealed that a large-angle outward trapezoidal cross-section provides the highest mixing performance, reaching efficiencies of up to 95%. Moreover, the velocity/vorticity along the channel length was analyzed and discussed to evaluate channel mixing performance. A relatively low pressure drop (<130 kPa) makes these passive spiral micromixers ideal candidates for various lab-on-chip applications.

Rozova, VS, Anwer, AG, Guller, AE, Es, HA, Khabir, Z, Sokolova, AI, Gavrilov, MU, Goldys, EM, Warkiani, ME, Thiery, JP & Zvyagin, AV 2021, 'Machine learning reveals mesenchymal breast carcinoma cell adaptation in response to matrix stiffness', PLOS Computational Biology, vol. 17, no. 7, pp. e1009193-e1009193.
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Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are believed to play key roles in facilitating the metastatic cascade. Metastatic lesions often exhibit a similar epithelial-like state to that of the primary tumour, in particular, by forming carcinoma cell clusters via E-cadherin-mediated junctional complexes. However, the factors enabling mesenchymal-like micrometastatic cells to resume growth and reacquire an epithelial phenotype in the target organ microenvironment remain elusive. In this study, we developed a workflow using image-based cell profiling and machine learning to examine morphological, contextual and molecular states of individual breast carcinoma cells (MDA-MB-231). MDA-MB-231 heterogeneous response to the host organ microenvironment was modelled by substrates with controllable stiffness varying from 0.2kPa (soft tissues) to 64kPa (bone tissues). We identified 3 distinct morphological cell types (morphs) varying from compact round-shaped to flattened irregular-shaped cells with lamellipodia, predominantly populating 2-kPa and >16kPa substrates, respectively. These observations were accompanied by significant changes in E-cadherin and vimentin expression. Furthermore, we demonstrate that the bone-mimicking substrate (64kPa) induced multicellular cluster formation accompanied by E-cadherin cell surface localisation. MDA-MB-231 cells responded to different substrate stiffness by morphological adaptation, changes in proliferation rate and cytoskeleton markers, and cluster formation on bone-mimicking substrate. Our results suggest that the stiffest microenvironment can induce MET.

Ryan, ST, Hosseini-Beheshti, E, Afrose, D, Ding, X, Xia, B, Grau, GE, Little, CB, McClements, L & Li, JJ 2021, 'Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions', International Journal of Molecular Sciences, vol. 22, no. 6, pp. 3023-3023.
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Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.

Rzhevskiy, A, Kapitannikova, A, Malinina, P, Volovetsky, A, Aboulkheyr Es, H, Kulasinghe, A, Thiery, JP, Maslennikova, A, Zvyagin, AV & Ebrahimi Warkiani, M 2021, 'Emerging role of circulating tumor cells in immunotherapy', Theranostics, vol. 11, no. 16, pp. 8057-8075.
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Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer. At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients. In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy. Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner. The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management. In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy.

Sadeghi Rad, H, Monkman, J, Warkiani, ME, Ladwa, R, O'Byrne, K, Rezaei, N & Kulasinghe, A 2021, 'Understanding the tumor microenvironment for effective immunotherapy', Medicinal Research Reviews, vol. 41, no. 3, pp. 1474-1498.
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AbstractAdvances in immunotherapy have led to durable and long‐term benefits in a subset of patients across a number of solid tumor types. Understanding of the subsets of patients that respond to immune checkpoint inhibitors at the cellular level, and in the context of their tumor microenvironment (TME) is becoming increasingly important. The TME is composed of a heterogeneous milieu of tumor and immune cells. The immune landscape of the TME can inhibit or promote tumor initiation and progression; thus, a deeper understanding of tumor immunity is necessary to develop immunotherapeutic strategies. Recent developments have focused on characterizing the TME immune contexture (type, density, and function) to discover mechanisms and biomarkers that may predict treatment outcomes. This has, in part, been powered by advancements in spatial characterization technologies. In this review article, we address the role of specific immune cells within the TME at various stages of tumor progression and how the immune contexture determinants affecting tumor growth are used therapeutically.

Sais, D, Munger, K & Tran, N 2021, 'The dynamic interactome of microRNAs and the human papillomavirus in head and neck cancers', Current Opinion in Virology, vol. 51, pp. 87-95.
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The Human Papillomavirus type 16 is a major etiologic factor for a subset of Head and Neck cancers. These cancers of the oropharyngeal region are growing, and it is expected to exceed cervical cancers in the near future. The major oncogenes E6 and E7 mediate many of the early transformation stages targeting p53 and other tumour suppressor genes. The majority of this regulation is centred on protein coding genes but more recently small non-coding RNAs, such as miRNAs are also regulated by HPV16. However, the system-wide impact of HPV16 on miRNAs is yet to be fully understood. To fully gauge the overall relationship between HPV16 and miRNAs, several studies have devised dynamic interactomes which encompass viral oncogenes, miRNAs and gene targets. These interactomes map potential pathways which permit the identification of possible mechanistic links. Our review will discuss the latest developments in using viral interactomes to understand viral mechanisms and how these approaches may aid in the elucidation of potential druggable pathways.

Sang, R, Stratton, B, Engel, A & Deng, W 2021, 'Liposome technologies towards colorectal cancer therapeutics', Acta Biomaterialia, vol. 127, pp. 24-40.
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Colorectal cancer (CRC) is the third most common cancer and the fourth most common deadly cancer worldwide. After treatment with curative intent recurrence rates vary with staging 0-13% in Stage 1, 11-61% in S2 and 28-73% in Stage 3. The toxicity to healthy tissues from chemotherapy and radiotherapy and drug resistance severely affect the quality of life and cancer specific outcomes of CRC patients. To overcome some of these limitations, many efforts have been made to develop nanomaterial-based drug delivery systems. Among these nanocarriers, liposomes represented one of the most successful candidates in delivering targeted oncological treatment, improving safety profile and therapeutic efficacy of encapsulated drugs. In this review we will discuss liposome design with a particular focus on the targeting feature and triggering functions. We will also summarise the recent advances in liposomal delivery system for CRC treatment in both the preclinical and clinical studies. We will finally provide our perspectives on the liposome technology development for the future clinical translation. Statement of significance: Conventional treatments for colorectal cancer (CRC) severely affect the therapeutic effects for advanced patients. With the development of nanomedicines, liposomal delivery system appears to be one of the most promising nanocarriers for CRC treatment. In last three years several reviews in this area have been published focusing on the preclinical research and drug delivery function, which is a fairly narrow focus in the field of liposome technology for CRC therapy. Our review presented the most recent advances of the liposome technology (both clinical and preclinical applications) for CRC with strong potential for further clinical translation. We believe it will attract lots of attention from various audiences, including researchers, clinicians and the industry.

Sayyadi, N, Zhand, S, Razavi Bazaz, S & Warkiani, ME 2021, 'Affibody Functionalized Beads for the Highly Sensitive Detection of Cancer Cell-Derived Exosomes', International Journal of Molecular Sciences, vol. 22, no. 21, pp. 12014-12014.
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Exosomes belong to the class of extracellular vesicles of endocytic origin, which are regarded as a promising source of cancer biomarkers in liquid biopsy. As a result, an accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affinity-based approaches are recognized as the most valuable technique for exosome isolation and characterization. Indeed, Affibody biomolecules are a type of protein scaffold engineered with small size and enjoy the features of high thermal stability, affinity, and specificity. While the utilization of antibodies, aptamers, and other biologically active substances for exosome detection has been reported widely, there are no reports describing Affibody molecules’ usage for exosome detection. In this study, for the first time, we have proposed a novel strategy of using Affibody functionalized microbeads (AffiBeads) for exosome detection with a high degree of efficiency. As a proof-of-concept, anti-EGFR-AffiBeads were fabricated and applied to capture and detect human lung A549 cancer cell-derived EGFR-positive exosomes using flow cytometry and fluorescent microscopy. Moreover, the capture efficiency of the AffiBeads were compared with its counterpart antibody. Our results showed that the Affibody probe had a detection limit of 15.6 ng exosomes per mL (~12 exosomes per AffiBead). The approach proposed in the current study can be used for sensitive detection of low expression level markers on tumor-derived exosomes, providing a basis for early-stage cancer diagnosis.

Sharma, P & Gentile, C 2021, 'Cardiac Spheroids as in vitro Bioengineered Heart Tissues to Study Human Heart Pathophysiology', Journal of Visualized Experiments, vol. 2021, no. 167.
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Despite several advances in cardiac tissue engineering, one of the major challenges to overcome remains the generation of a fully functional vascular network comprising several levels of complexity to provide oxygen and nutrients within bioengineered heart tissues. Our laboratory has developed a three-dimensional in vitro model of the human heart, known as the 'cardiac spheroid' or 'CS'. This presents biochemical, physiological, and pharmacological features typical of the human heart and is generated by co-culturing its three major cell types, such as cardiac myocytes, endothelial cells, and fibroblasts. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs or iCMs) are co-cultured at ratios approximating the ones found in vivo with human cardiac fibroblasts (HCFs) and human coronary artery endothelial cells (HCAECs) in hanging drop culture plates for three to four days. The confocal analysis of CSs stained with antibodies against cardiac Troponin T, CD31 and vimentin (markers for cardiac myocytes, endothelial cells and fibroblasts, respectively) shows that CSs present a complex endothelial cell network, resembling the native one found in the human heart. This is confirmed by the 3D rendering analysis of these confocal images. CSs also present extracellular matrix (ECM) proteins typical of the human heart, such as collagen type IV, laminin and fibronectin. Finally, CSs present a contractile activity measured as syncytial contractility closer to the one typical of the human heart compared to CSs that contain iCMs only. When treated with a cardiotoxic anti-cancer agent, such as doxorubicin (DOX, used to treat leukemia, lymphoma and breast cancer), the viability of DOX-treated CSs is significantly reduced at 10 µM genetic and chemical inhibition of endothelial nitric oxide synthase, a downstream target of DOX in HCFs and HCAECs, reduced its toxicity in CSs. Given these unique features, CSs are currently used as in vitro models to study hea...

Sharma, P, Wang, X, Ming, CLC, Vettori, L, Figtree, G, Boyle, A & Gentile, C 2021, 'Advanced Cardiac Models: Considerations for the Bioengineering of Advanced Cardiac In Vitro Models of Myocardial Infarction (Small 15/2021)', Small, vol. 17, no. 15, pp. 2170067-2170067.
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Sharma, P, Wang, X, Ming, CLC, Vettori, L, Figtree, G, Boyle, A & Gentile, C 2021, 'Considerations for the Bioengineering of Advanced Cardiac In Vitro Models of Myocardial Infarction', Small, vol. 17, no. 15, pp. e2003765-2003765.
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AbstractDespite the latest advances in cardiovascular biology and medicine, myocardial infarction (MI) remains one of the major causes of deaths worldwide. While reperfusion of the myocardium is critical to limit the ischemic damage typical of a MI event, it causes detrimental morphological and functional changes known as “reperfusion injury.” This complex scenario is poorly represented in currently available models of ischemia/reperfusion injury, leading to a poor translation of findings from the bench to the bedside. However, more recent bioengineered in vitro models of the human heart represent more clinically relevant tools to prevent and treat MI in patients. These include 3D cultures of cardiac cells, the use of patient‐derived stem cells, and 3D bioprinting technology. This review aims at highlighting the major features typical of a heart attack while comparing current in vitro, ex vivo, and in vivo models. This information has the potential to further guide in developing novel advanced in vitro cardiac models of ischemia/reperfusion injury. It may pave the way for the generation of advanced pathophysiological cardiac models with the potential to develop personalized therapies.

Shokoohian, B, Negahdari, B, Aboulkheyr Es, H, Abedi‐Valugerdi, M, Baghaei, K, Agarwal, T, Maiti, TK, Hassan, M, Najimi, M & Vosough, M 2021, 'Advanced therapeutic modalities in hepatocellular carcinoma: Novel insights', Journal of Cellular and Molecular Medicine, vol. 25, no. 18, pp. 8602-8614.
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AbstractHepatocellular carcinoma (HCC), the most common type of liver cancer, is usually a latent and asymptomatic malignancy caused by different aetiologies, which is a result of various aberrant molecular heterogeneity and often diagnosed at advanced stages. The incidence and prevalence have significantly increased because of sedentary lifestyle, diabetes, chronic infection with hepatotropic viruses and exposure to aflatoxins. Due to advanced intra‐ or extrahepatic metastasis, recurrence is very common even after radical resection. In this paper, we highlighted novel therapeutic modalities, such as molecular‐targeted therapies, targeted radionuclide therapies and epigenetic modification‐based therapies. These topics are trending headlines and their combination with cell‐based immunotherapies, and gene therapy has provided promising prospects for the future of HCC treatment. Moreover, a comprehensive overview of current and advanced therapeutic approaches is discussed and the advantages and limitations of each strategy are described. Finally, very recent and approved novel combined therapies and their promising results in HCC treatment have been introduced.

Shrestha, J, Ryan, ST, Mills, O, Zhand, S, Razavi Bazaz, S, Hansbro, PM, Ghadiri, M & Ebrahimi Warkiani, M 2021, 'A 3D-printed microfluidic platform for simulating the effects of CPAP on the nasal epithelium', Biofabrication, vol. 13, no. 3, pp. 035028-035028.
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Abstract Obstructive sleep apnea (OSA) is a chronic disorder that involves a decrease or complete cessation of airflow during sleep. It occurs when the muscles supporting the soft tissues in the throat relax during sleep, causing narrowing or closure of the upper airway. Sleep apnea is a serious medical condition with an increased risk of cardiovascular complications and impaired quality of life. Continuous positive airway pressure (CPAP) is the most effective treatment for moderate to severe cases of OSA and is effective in mild sleep apnea. However, CPAP therapy is associated with the development of several nasal side effects and is inconvenient for the user, leading to low compliance rates. The effects of CPAP treatment on the upper respiratory system, as well as the pathogenesis of side effects, are incompletely understood and not adequately researched. To better understand the effects of CPAP treatment on the upper respiratory system, we developed an in vitro 3D-printed microfluidic platform. A nasal epithelial cell line, RPMI 2650, was then exposed to certain conditions to mimic the in vivo environment. To create these conditions, the microfluidic device was utilized to expose nasal epithelial cells grown and differentiated at the air–liquid interface. The airflow was similar to what is experienced with CPAP, with pressure ranging between 0 and 20 cm of H2O. Cells exposed to pressure showed decreased barrier integrity, change in cellular shape, and increased cell death (lactate dehydrogenase release into media) compared to unstressed cells. Stressed cells also showed increased secretions of inflammatory markers IL-6 and IL-8 and had increased production of ATP. Our results suggest that stress induced by airflow leads to structural, metabolic, and inflammatory changes in the nasal epithelium, which may be responsible for develo...

Si, L, Eisman, JA, Winzenberg, T, Sanders, KM, Center, JR, Nguyen, TV, Tran, T & Palmer, AJ 2021, 'Development and validation of the risk engine for an Australian Health Economics Model of Osteoporosis', Osteoporosis International, vol. 32, no. 10, pp. 2073-2081.
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The Australian Health Economics Model of Osteoporosis (AusHEMO) has shown good face, internal and cross validities, and can be used to assist healthcare decision-making in Australia. PURPOSE: This study aimed to document and validate the risk engine of the Australian Health Economics Model of Osteoporosis (AusHEMO). METHODS: AusHEMO is a state-transition microsimulation model. The fracture risks were simulated using fracture incidence rates from the Dubbo Osteoporosis Epidemiology Study. The AusHEMO was validated regarding its face, internal and cross validities. Goodness-of-fit analysis was conducted and Lin's coefficient of agreement and mean absolute difference with 95% limits of agreement were reported. RESULTS: The development of AusHEMO followed general and osteoporosis-specific health economics guidelines. AusHEMO showed good face validity regarding the model's structure, evidence, problem formulation and results. In addition, the model has been proven good internal and cross validities in goodness-of-fit test. Lin's coefficient was 0.99, 1 and 0.94 for validation against the fracture incidence rates, Australian life expectancies and residual lifetime fracture risks, respectively. CONCLUSIONS: In summary, the development of the risk engine of AusHEMO followed the best practice for osteoporosis disease modelling and the model has been shown to have good face, internal and cross validities. The AusHEMO can be confidently used to predict long-term fracture-related outcomes and health economic evaluations when costs data are included. Health policy-makers in Australia can use the AusHEMO to select which osteoporosis interventions such as medications and public health interventions represent good value for money.

Smith, C, Cokcetin, N, Truong, T, Harry, E, Hutvagner, G & Bajan, S 2021, 'Cataloguing the small RNA content of honey using next generation sequencing', Food Chemistry: Molecular Sciences, vol. 2, pp. 100014-100014.
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Soleimanian, A, Khalilzadeh, B, Mahdipour, M, Aref, AR, Kalbasi, A, Bazaz, SR, Warkiani, ME, Rashidi, MR & Mahdavi, M 2021, 'An Efficient Graphene Quantum Dots-Based Electrochemical Cytosensor for the Sensitive Recognition of CD123 in Acute Myeloid Leukemia Cells', IEEE Sensors Journal, vol. 21, no. 15, pp. 16451-16463.
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Leukemia stem cells (LSCs) are suitable candidates to be deployed for the diagnosis and therapy of acute myeloid leukemia (AML) patients. In this study, a novel electrochemical cytosensor was designed for the sensitive detection and quantification of KG1a cells as a model of LSCs. The developed cytosensor was based on the overexpression of cell surface protein CD123 by leukemia KG1a cells. For this purpose, the glassy carbon electrode was modified by graphene quantum dots (GQDs), Au nanoparticles, streptavidin coated AuNPs, biotinylated CD123 antibody and target cells. The dense loading of CD123 antibody and electrical enhancement on the modified electrode were carried out using GQDs, this resulting in a sensitive detection of CD123 positive cells within KG1a cells. Step by step preparation of the nanomaterial-based cytosensor and its optimization steps were confirmed by different electrochemical techniques. The field emission scanning electron microscopy (FE-SEM) images also confirmed the proper attachment of the materials and the cells on the surface of the modified electrode. The linear detection range (LDR) and limit of detection (LOD) of the developed electrochemical biosensor were recorded as 1 cell/mL and 1-25 cells/mL, respectively, which is remarkable. Importantly, the present findings are precise and highly selective in the presence of other leukemia cells (NB4, HL60, and U937 cells). Further, the versatility and accuracy of the proposed cytosensor were evaluated using clinical samples. We believe that the cytosensor proposed in this study has the potential to serve as a next generation sensor for the early detection of leukemia stem cells.

Song, X, Liu, F, Qiu, C, Coy, E, Liu, H, Aperador, W, Załęski, K, Li, JJ, Song, W, Lu, Z, Pan, H, Kong, L & Wang, G 2021, 'Nanosurfacing Ti alloy by weak alkalinity-activated solid-state dewetting (AAD) and its biointerfacial enhancement effect', Materials Horizons, vol. 8, no. 3, pp. 912-924.
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A weak alkalinity-activated solid-state dewetting (AAD) method is developed to produce quasi-periodic nanopimple-like titanium oxide on biomedical Ti6Al4V alloy. The nanostructures modulated the cross-talk between osteoblasts and macrophages.

Syed, MS, Marquis, C, Taylor, R & Warkiani, ME 2021, 'A two-step microengineered system for high-density cell retention from bioreactors', Separation and Purification Technology, vol. 254, pp. 117610-117610.
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Large-scale cell culture processes are required to produce biopharmaceuticals, cells for tissue engineering, and vaccine production while being effective in toxicity testing, gene therapy vector production for cancer research, and drug development. A growing trend in these industries, particularly for suspension cells, involves implementation of continuous cell perfusion processes, which require an aseptic, efficient, cost-effective, and reliable cell separation and retention scheme. Many cell separation techniques (membrane-based systems, lateral displacement devices, and acoustophoresis) have proven to be highly efficient, but suffer from issue of clogging and high cost, limiting their reliability, and thus, their overall feasibility. Some cell retention devices—those based on inertial microfluidics—offer high reliability (i.e., clog-free), but their efficiency reduces at higher cell concentrations. To overcome this apparent trade-off, we report the development of an integrated system consisting of two different membrane-less microfiltration techniques for cell separation from spent cell media. Although it could be adapted to numerous cell culture applications, this system was optimized and tested for suspension-adapted Chinese Hamster Ovary (CHO) cells. As the first step of the cell retention system, a miniaturised hydrocyclone was developed that could separate the cells with macroscopic volume processing rates (~200 mL/min). At this stage, up to 75% of the cells were isolated with minimal (<5%) change in the viability. The remaining cells passed through the overflow of the device and entered to a multiplexed spiral microchannel system, where more than 90% of the remaining cells were recovered, yielding an overall efficiency of up to 95%. The proposed integrated system is thus ideal for continuous and high throughput cell retention even at high cell concentrations (~80 million cells/mL), which is in range of current need in the bioprocessing industry.

Tavakoli, J, Geargeflia, S, Tipper, JL & Diwan, AD 2021, 'Magnetic resonance elastography: A non-invasive biomarker for low back pain studies', Biomedical Engineering Advances, vol. 2, pp. 100014-100014.
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Tavakoli, J, Ghahfarokhi, AJ & Tang, Y 2021, 'Aggregation-Induced Emission Fluorescent Gels: Current Trends and Future Perspectives', Topics in Current Chemistry, vol. 379, no. 2.
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Thoms, J, Truong, P, Subramanian, S, Knezevic, K, Harvey, G, Huang, Y, Seneviratne, J, Carter, D, Joshi, S, Skhinas, J, Chacon, D, Shah, A, de Jong, I, Beck, D, Göttgens, B, Larsson, J, Wong, J, Zanini, F & Pimanda, J 2021, '3034 – DISRUPTION OF A GATA2, TAL1, ERG REGULATORY CIRCUIT PROMOTES ERYTHROID TRANSITION IN HEALTHY AND LEUKEMIC STEM CELLS', Experimental Hematology, vol. 100, pp. S59-S59.
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Thoms, JAI, Truong, P, Subramanian, S, Knezevic, K, Harvey, G, Huang, Y, Seneviratne, JA, Carter, DR, Joshi, S, Skhinas, J, Chacon, D, Shah, A, de Jong, I, Beck, D, Göttgens, B, Larsson, J, Wong, JWH, Zanini, F & Pimanda, JE 2021, 'Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells', Blood, vol. 138, no. 16, pp. 1441-1455.
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Abstract Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other’s, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.

Valdés-Mora, F, Salomon, R, Gloss, BS, Law, AMK, Venhuizen, J, Castillo, L, Murphy, KJ, Magenau, A, Papanicolaou, M, Rodriguez de la Fuente, L, Roden, DL, Colino-Sanguino, Y, Kikhtyak, Z, Farbehi, N, Conway, JRW, Sikta, N, Oakes, SR, Cox, TR, O’Donoghue, SI, Timpson, P, Ormandy, CJ & Gallego-Ortega, D 2021, 'Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype', Cell Reports, vol. 35, no. 2, pp. 108945-108945.
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Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.

Vasilescu, SA, Khorsandi, S, Ding, L, Bazaz, SR, Nosrati, R, Gook, D & Warkiani, ME 2021, 'A microfluidic approach to rapid sperm recovery from heterogeneous cell suspensions', Scientific Reports, vol. 11, no. 1, pp. 1-11.
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AbstractThe isolation of sperm cells from background cell populations and debris is an essential step in all assisted reproductive technologies. Conventional techniques for sperm recovery from testicular sperm extractions stagnate at the sample processing stage, where it can take several hours to identify viable sperm from a background of collateral cells such as white bloods cells (WBCs), red blood cells (RBCs), epithelial cells (ECs) and in some cases cancer cells. Manual identification of sperm from contaminating cells and debris is a tedious and time-consuming operation that can be suitably addressed through inertial microfluidics. Microfluidics has proven an effective technology for high-quality sperm selection based on motility. However, motility-based selection methods cannot cater for viable, non-motile sperm often present in testicular or epididymal sperm extractions and aspirations. This study demonstrates the use of a 3D printed inertial microfluidic device for the separation of sperm cells from a mixed suspension of WBCs, RBCs, ECs, and leukemic cancer cells. This technology presents a 36-fold time improvement for the recovery of sperm cells (> 96%) by separating sperm, RBCS, WBCs, ECs and cancer cells into tight bands in less than 5 min. Furthermore, microfluidic processing of sperm has no impact on sperm parameters; vitality, motility, morphology, or DNA fragmentation of sperm. Applying inertial microfluidics for non-motile sperm recovery can greatly improve the current processing procedure of testicular sperm extractions, simplifying the fertility outcomes for severe forms of male infertility that warrant the surgery.

Wan, B, Entezari, A, Zhang, Z, Wilson, T, Yoda, N, Zheng, K, Wu, C, Sun, G, Sasaki, K, Swain, M & Li, Q 2021, 'On fatigue failure prediction of prosthetic devices through XFEM analysis', International Journal of Fatigue, vol. 147, pp. 106160-106160.
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While prosthetic devices have been extensively used to treat a wide range of human diseases and injuries, failure of these devices due to fatigue under cyclic loading has been recognized as a primary concern on therapeutic longevity. Experimental testing has long been a dominant approach to characterizing the fatigue behavior of prosthetic devices. However, experimental methods could be of multiple shortcomings such as their restrictive nature in-vivo in medical studies and limitations of extrapolating the testing results. This study develops a numerical approach for modeling fatigue failure in some commonly-used osteofixation devices that are implanted to support various major bone defects/trauma and fractures. The eXtended Finite Element Method (XFEM) is employed herein to model fatigue crack formation and propagation as per level set functions to suppress the need for re-meshing. For validation purpose, a benchmark problem involving a modified compact tension structure is first carried out, in which the modeling results are compared with the relevant experimental data to demonstrate the effectiveness of the proposed XFEM approach. Further, two representative orthopedic examples are studied for characterizing the fatigue behavior of a femoral osteofixation plate and a mandibular reconstruction mini-plate, respectively. The results reveal that healing/remodeling of grafted bone as well as tissue ingrowth to the scaffold have significant bearing on fatigue life of fixation plates. This study showcases a valuable approach for predicting fatigue failure of prosthetic devices in-silico, thereby providing an effective tool for design optimization of patient-specific prosthetic devices to ensure their longevity.

Wang, H, Roche, CD & Gentile, C 2021, 'Reply to Yurekli et al.', European Journal of Cardio-Thoracic Surgery.
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Wang, L, Zhang, T, Ye, L, Li, JJ & Su, SW 2021, 'An Efficient Calibration Method for Triaxial Gyroscope', IEEE Sensors Journal, vol. 21, no. 18, pp. 19896-19903.
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This paper presents an efficient servomotor-aided calibration method for the triaxial gyroscope. The entire calibration process only requires approximately one minute, and does not require high-precision equipment. This method is based on the idea that the measurement of the gyroscope should be equal to the rotation speed of the servomotor. A six-observation experimental design is proposed to minimize the maximum variance of the estimated scale factors and biases. In addition, a fast converging recursive linear least square estimation method is presented to reduce computational complexity. The simulation results reflect the robustness of the calibration method under normal and extreme conditions. We experimentally demonstrate the feasibility of the proposed method on a robot arm, and implement the method on a microcontroller. We verify the calibration results of the proposed method by comparing with a traditional turntable approach, and the experiment indicates that the results of these two methods are comparable. By comparing the calibrated low-cost gyroscope reading with the reading from a high-precision gyroscope, we can conclude that our method significantly increases the gyroscope's accuracy.

Winston Zhao, Z, Peter Su, Q, Xie, XS & Sun, Y 2021, 'Super-Resolution Imaging Reveals Spatio-Temporal Propagation of Human Replication Foci Mediated by CTCF-Organized Chromatin Structures', Biophysical Journal, vol. 120, no. 3, pp. 278a-278a.
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Wu, C, Entezari, A, Zheng, K, Fang, J, Zreiqat, H, Steven, GP, Swain, MV & Li, Q 2021, 'A machine learning-based multiscale model to predict bone formation in scaffolds', Nature Computational Science, vol. 1, no. 8, pp. 532-541.
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Wu, C, Fang, J, Entezari, A, Sun, G, Swain, MV, Xu, Y, Steven, GP & Li, Q 2021, 'A time-dependent mechanobiology-based topology optimization to enhance bone growth in tissue scaffolds', Journal of Biomechanics, vol. 117, pp. 110233-110233.
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Scaffold-based bone tissue engineering has been extensively developed as a potential means to treatment of large bone defects. To enhance the biomechanical performance of porous tissue scaffolds, computational design techniques have gained growing popularity attributable to their compelling efficiency and strong predictive features compared with time-consuming trial-and-error experiments. Nevertheless, the mechanical stimulus necessary for bone regeneration, which characterizes dynamic nature due to continuous variation in the bone-scaffold construct system as a result of bone-ingrowth and scaffold biodegradation, is often neglected. Thus, this study proposes a time-dependent mechanobiology-based topology optimization framework for design of tissue scaffolds, thereby developing an ongoing favorable microenvironment and ensuring a long-term outcome for bone regeneration. For the first time, a level-set based topology optimization algorithm and a time-dependent shape derivative are developed to optimize the scaffold architecture. In this study, a large bone defect in a simulated 2D femur model and a partial defect in a 3D femur model are considered to demonstrate the effectiveness of the proposed design method. The results are compared with those obtained from stiffness-based topology optimization, time-independent design and typical scaffold constructs, showing significant advantages in continuing bone ingrowth outcomes.

Xiao, L, Somers, K, Murray, J, Pandher, R, Karsa, M, Ronca, E, Bongers, A, Terry, R, Ehteda, A, Gamble, LD, Issaeva, N, Leonova, KI, O'Connor, A, Mayoh, C, Venkat, P, Quek, H, Brand, J, Kusuma, FK, Pettitt, JA, Mosmann, E, Kearns, A, Eden, G, Alfred, S, Allan, S, Zhai, L, Kamili, A, Gifford, AJ, Carter, DR, Henderson, MJ, Fletcher, JI, Marshall, G, Johnstone, RW, Cesare, AJ, Ziegler, DS, Gudkov, AV, Gurova, KV, Norris, MD & Haber, M 2021, 'Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma', Clinical Cancer Research, vol. 27, no. 15, pp. 4338-4352.
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Abstract Purpose: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. Experimental Design: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. Results: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. ...

Xing, D, Wang, K, Wu, J, Zhao, Y, Liu, W, Li, JJ, Gao, T, Yan, D, Wang, L, Hao, J & Lin, J 2021, 'Clinical-Grade Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Ameliorate the Progression of Osteoarthritis in a Rat Model', Molecules, vol. 26, no. 3, pp. 604-604.
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Mesenchymalstem cell (MSC)-based therapy is being increasingly explored in preclinical and clinical studies as a regenerative method for treating osteoarthritis (OA). However, the use of primary MSCs is hampered by a number of limitations, including donor heterogeneity and inconsistent cell quality. Here, we tested the therapeutic potential of embryonic stem cell-derived MSCs (ES-MSCs) in anOA rat model. ES-MSCs were generated and identified by morphology, trilineage differentiation and flow cytometry. Sprague Dawley rats were treated with either a single dose (106 cells/rat) of ES-MSCs or with three doses spaced one week apart for each dose, starting at four weeks after anterior cruciate ligament transectionto induce OA. Cartilage quality was evaluated at 6 and 10 weeks after treatment with behavioral analysis, macroscopic examination, and histology. At sixweeks after treatment, the groups treated with both single and repeated doses of ES-MSCs had significantly better modified Mankin scores and International Cartilage Repair Society (ICRS) macroscopic scores in the femoral condyle compared to the control group. At 10 weeks after treatment, the repeated doses group had a significantly better ICRS macroscopic scores in the femoral condyle compared to the single dose and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, along with lower Mankin scores in the repeated doses group. In conclusion, treatment with multiple injections of ES-MSCs can ameliorate OA in a rat model. TheES-MSCs have potential to be considered as a regenerative therapy for OA, and can provide an infinite cellular source.

Xu, X, Jia, Z, Zheng, Y & Wang, Y 2021, 'Bioadaptability of biomaterials: Aiming at precision medicine', Matter, vol. 4, no. 8, pp. 2648-2650.
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Xu, Z, Xia, Y, Zhou, P, Li, JJ, Yang, M, Zhang, Y, Zhang, Y, Xie, Y, Li, L, Pan, H, Xu, S & Wang, G 2021, 'Silicon incorporation into hydroxyapatite nanocarrier counteracts the side effects of vancomycin for efficient chronic osteomyelitis treatment', Chemical Engineering Journal, vol. 406, pp. 126821-126821.
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Local administration of antibiotics is a primary approach for treating chronic osteomyelitis (CO). However, clinically used antibiotic delivery systems exhibit suboptimal osteoinductivity, ascribed to the carrier material itself and the cytotoxicity of the loaded antibiotic, often leading to unsatisfactory treatment efficiency. To overcome this problem, we introduced Si into hydroxyapatite (HAp) nanocarriers by surface wrapping with a certain thickness of mesoporous bioactive glass (MBG). This facilitates controlled and sustained antibiotic release, while more importantly, silicon (Si) released from MBG counteracts the side effects of having a high antibiotic concentration at the defect site. Vancomycin-loaded HAp nanocarriers wrapped with MBG were shown to have a higher loading efficiency and more sustained antibiotic release behaviour. In vitro experiments using MC3T3-E1 cells showed that Si ions were effective in counteracting the negative effects of vancomycin on cell proliferation and osteogenic differentiation. In vivo implantation into a CO rat model showed that vancomycin-loaded MBG-wrapped HAp nanocarriers efficiently eliminated the infection and promoted superior bone healing at the fracture site compared to the control that did not release Si. This study highlights the important role of Si in neutralising the side effects of antibiotics, thus opening up a new design concept for biomaterials as antibiotic carriers for treating infection.

Xue, B, Zhou, C, Qin, Y, Li, Y, Sun, Y, Chang, L, Shao, S, Li, Y, Zhang, M, Sun, C, He, R, Peter Su, Q & Sun, Y 2021, 'PN-ImTLSM facilitates high-throughput low background single-molecule localization microscopy deep in the cell', Biophysics Reports, vol. 7, no. 4, pp. 313-313.
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When imaging the nucleus structure of a cell, the out-of-focus fluorescence acts as background and hinders the detection of weak signals. Light-sheet fluorescence microscopy (LSFM) is a wide-field imaging approach which has the best of both background removal and imaging speed. However, the commonly adopted orthogonal excitation/detection scheme is hard to be applied to single-cell imaging due to steric hindrance. For LSFMs capable of high spatiotemporal single-cell imaging, the complex instrument design and operation largely limit their throughput of data collection. Here, we propose an approach for high-throughput background-free fluorescence imaging of single cells facilitated by the Immersion Tilted Light Sheet Microscopy (ImTLSM). ImTLSM is based on a light-sheet projected off the optical axis of a water immersion objective. With the illumination objective and the detection objective placed opposingly, ImTLSM can rapidly patrol and optically section multiple individual cells while maintaining single-molecule detection sensitivity and resolution. Further, the simplicity and robustness of ImTLSM in operation and maintenance enables high-throughput image collection to establish background removal datasets for deep learning. Using a deep learning model to train the mapping from epi-illumination images to ImTLSM illumination images, namely PN-ImTLSM, we demonstrated cross-modality fluorescence imaging, transforming the epi-illumination image to approach the background removal performance obtained with ImTLSM. We demonstrated that PN-ImTLSM can be generalized to large-field homogeneous illumination imaging, thereby further improving the imaging throughput. In addition, compared to commonly used background removal methods, PN-ImTLSM showed much better performance for areas where the background intensity changes sharply in space, facilitating high-density single-molecule localization microscopy. In summary, PN-ImTLSM paves the way for background-free fluor...

Yan, L, Li, JJ, Zhu, Y, Liu, H, Liu, R, Zhao, B & Wang, B 2021, 'Interference screws are more likely to perform better than cortical button and cross-pin fixation for hamstring autograft in ACL reconstruction: a Bayesian network meta-analysis', Knee Surgery, Sports Traumatology, Arthroscopy, vol. 29, no. 6, pp. 1850-1861.
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PURPOSE:Anterior cruciate ligament (ACL) reconstruction is widely accepted as the first choice of treatment for ACL injury, but there is disagreement in the literature regarding the optimal femoral fixation method. This meta-analysis assesses the evidence surrounding three common femoral fixation methods: cortical button (CB), cross-pin (CP) and interference screws (IS). METHODS:A systematic search was conducted in Medline, EMBASE and the Cochrane Library to identify studies with evidence level I or II that compared at least two femoral fixation methods with hamstring autograft for ACL reconstruction. Ten primary outcomes were collected. Risk of bias was assessed following the Cochrane Handbook for Systematic Reviews of Interventions. Standardized mean differences (SMD) were estimated using random-effects network meta-analysis in a Bayesian framework. Probability of ranking best (ProBest) and surface under the cumulative ranking curve (SUCRA) were used to rank all treatments. Funnel plots were used to identify publication bias and small-study effects. RESULTS:Sixteen clinical trials were included for analysis out of 2536 retrieved studies. Bayesian network meta-analysis showed no significant differences among the three fixation methods for the ten primary outcome measures. Based on the 10 outcome measures, the IS, CB and CP had the highest ProBest in 5, 5 and 0 outcomes, and the highest SUCRA values in 5, 4 and 1 outcomes, respectively. No substantial inconsistency between direct and indirect evidence, or publication bias was detected in the outcomes. CONCLUSION:There were no statistical differences in performance among the CP, CB and IS femoral fixation methods with hamstring autograft in ACL reconstruction, although the IS was more likely to perform better than CB and CP based on the analysis of outcome measures from the included studies. LEVEL OF EVIDENCE:1.

Yang, B, Song, B-P, Shankar, S, Guller, A & Deng, W 2021, 'Recent advances in liposome formulations for breast cancer therapeutics', Cellular and Molecular Life Sciences, vol. 78, no. 13, pp. 5225-5243.
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Among many nanoparticle-based delivery platforms, liposomes have been particularly successful with many formulations passed into clinical applications. They are well-established and effective gene and/or drug delivery systems, widely used in cancer therapy including breast cancer. In this review we discuss liposome design with the targeting feature and triggering functions. We also summarise the recent progress (since 2014) in liposome-based therapeutics for breast cancer including chemotherapy and gene therapy. We finally identify some challenges on the liposome technology development for the future clinical translation.

Yang, Y, Wang, Y, Jia, H, Li, B, Xing, D & Li, JJ 2021, 'MicroRNA-1 Modulates Chondrocyte Phenotype by Regulating FZD7 of Wnt/ β-Catenin Signaling Pathway', CARTILAGE, vol. 13, no. 2_suppl, pp. 1019S-1029S.
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Objective Osteoarthritis (OA) is an incurable joint disease characterized by pronounced pain. MicroRNAs constitute epigenetic mechanisms that may affect OA progression by contributing to changes in chondrocyte phenotype. This study investigates for the first time whether there is a link between miRNA-1 (miR-1) and OA pathogenesis, and the molecular mechanisms involved. Design OA-associated gene expression, including MMP-13, ADAMTS5, and COL2A1 was compared in chondrocytes from non-OA and OA cartilage, and in SW1353 cells over- and underexpressing miR-1. Bioinformatics and luciferase reporter assay were conducted to confirm whether FZD7 was a target of miR-1. The effects of miR-1 on FZD7 expression and downstream Wnt/β-catenin signalling were investigated. Results Non-OA and OA chondrocytes differed significantly in the expression of miR-1 and OA-associated genes. MiR-1 over- and underexpression in SW1353 cells, respectively, reduced and enhanced gene expression associated with cartilage catabolism. FZD7, which has an important role in the Wnt/β-catenin signaling pathway, was shown to be a potential target of miR-1. MiR-1 binding to FZD7 increased the levels of phosphorylated (inactivated) β-catenin, thereby preventing downstream β-catenin signaling. Conclusions Inhibition of Wnt/β-catenin signaling by miR-1 in chondrocytes may attenuate the expression of genes that regulate the activity of catabolic enzymes. This finding may be useful for future investigations of molecular targets for OA treatment.

Yeola, A, Subramanian, S, Oliver, RA, Lucas, CA, Thoms, JAI, Yan, F, Olivier, J, Chacon, D, Tursky, ML, Srivastava, P, Potas, JR, Hung, T, Power, C, Hardy, P, Ma, DD, Kilian, KA, McCarroll, J, Kavallaris, M, Hesson, LB, Beck, D, Curtis, DJ, Wong, JWH, Hardeman, EC, Walsh, WR, Mobbs, R, Chandrakanthan, V & Pimanda, JE 2021, 'Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine', Science Advances, vol. 7, no. 3, pp. 1-12.
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Human adipocytes are a source of tissue-regenerative multipotent stem cells.

Yin, L, Au, WY, Yu, CC, Kwon, T, Lai, Z, Shang, M, Warkiani, ME, Rosche, R, Lim, CT & Han, J 2021, 'Miniature auto‐perfusion bioreactor system with spiral microfluidic cell retention device', Biotechnology and Bioengineering, vol. 118, no. 5, pp. 1951-1961.
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AbstractMedium perfusion is critical in maintaining high cell concentration in cultures. The conventional membrane filtration method for medium exchange has been challenged by the fouling and clogging of the membrane filters in long‐term cultures. In this study, we present a miniature auto‐perfusion system that can be operated inside a common‐size laboratory incubator. The system is equipped with a spiral microfluidic chip for cell retention to replace conventional membrane filters, which fundamentally overcomes the clogging and fouling problem. We showed that the system supported continuous perfusion culture of Chinese hamster ovary (CHO) cells in suspension up to 14 days without cell retention chip replacement. Compared to daily manual medium change, 25% higher CHO cell concentration can be maintained at an average auto‐perfusion rate of 196 ml/day in spinner flask at 70 ml working volume (2.8 VVD). The auto‐perfusion system also resulted in better cell quality at high concentrations, in terms of higher viability, more uniform and regular morphology, and fewer aggregates. We also demonstrated the potential application of the system for culturing mesenchymal stem cells on microcarriers. This miniature auto‐perfusion system provides an excellent solution to maintain cell‐favorable conditions and high cell concentration in small‐scale cultures for research and clinical uses.

Zhand, S, Xiao, K, Razavi Bazaz, S, Zhu, Y, Bordhan, P, Jin, D & Warkiani, ME 2021, 'Improving capture efficiency of human cancer cell derived exosomes with nanostructured metal organic framework functionalized beads', Applied Materials Today, vol. 23, pp. 100994-100994.
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Extracellular vesicles (EVs) have emerged as an invaluable tool for analyzing the physiological processes and an alternative source of disease diagnostic and prognostic biomarkers in liquid biopsies. Exosomes are a subset of EVs offer a window into altered cellular or tissue states, and their detection potentially offers a multicomponent early-stage diagnostic readout. Immunocapture and flow cytometry analysis of exosomes using micron-sized beads has been reported to be a reproducible technique for analysis of exosome surface markers. Nevertheless, the capture capacity remains poor due to limited available surface area. In this study, we have proposed a nanocoating strategy using metal-organic framework (MOF) materials, in particular, Zeolitic Imidazolate Framework-8 (ZIF-8), for highly efficient capturing of low concentration of exosomes from minimally processed samples. In this method, a ZIF-8 thin film was formed on polydopamine-polyethyleneimine (PDA-PEI) coated polystyrene microbeads to improve antibody immobilization due to the larger surface area provided by the MOF microstructures. This novel coating enabled us to detect as little as 50 exosomes per 10 µm polystyrene bead functionalized with ZIF-8/PDA-PEI, which is 180 times higher than the previously reported methods using naked microbeads. This coating requires a lower concentration of antibody to capture exosomes on the surface of microbeads compared to the standard protocols. More importantly, the higher concentration of exosomes on each bead surface provides the opportunity (i.e., higher signal intensity) to sort the beads using fluorescence-activated cell sorting, facilitating molecular analysis of post fractionation exosomes. Additionally, the exosomes can easily be detached from the coated microbeads using EDTA, limiting the usage of harsh chemicals. The procedure described here can be easily reproduced and employed regardless of the biological sample used to obtain exosomes.

Zhang, H, Li, Y, Zhang, P, Ren, C, Xu, X, Sun, B & Yang, Z 2021, 'A Flexible Implantable Polyimide Catheter Device for Targeted Treatment of Cardiovascular Diseases by Aggregating Magnetic Nanoparticles', IEEE Transactions on Components, Packaging and Manufacturing Technology, vol. 11, no. 6, pp. 911-917.
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Zhang, X, Liu, Y, Yu, Z, Blumenstein, M, Hutvagner, G & Li, J 2021, 'Instance-based error correction for short reads of disease-associated genes', BMC Bioinformatics, vol. 22, no. S6, pp. 1-17.
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Abstract Background Genomic reads from sequencing platforms contain random errors. Global correction algorithms have been developed, aiming to rectify all possible errors in the reads using generic genome-wide patterns. However, the non-uniform sequencing depths hinder the global approach to conduct effective error removal. As some genes may get under-corrected or over-corrected by the global approach, we conduct instance-based error correction for short reads of disease-associated genes or pathways. The paramount requirement is to ensure the relevant reads, instead of the whole genome, are error-free to provide significant benefits for single-nucleotide polymorphism (SNP) or variant calling studies on the specific genes. Results To rectify possible errors in the short reads of disease-associated genes, our novel idea is to exploit local sequence features and statistics directly related to these genes. Extensive experiments are conducted in comparison with state-of-the-art methods on both simulated and real datasets of lung cancer associated genes (including single-end and paired-end reads). The results demonstrated the superiority of our method with the best performance on precision, recall and gain rate, as well as on sequence assembly results (e.g., N50, the length of contig and contig quality). Conclusion Instance-based strategy makes it possible to explore fine-grained patterns focusing on specific genes, providing high precision error correction and convincing gene sequence assembly. SNP case studies show that errors occurring at some traditional SNP areas can be accurately corrected, providing high precision and sensitivity for inve...

Zhang, X, Ping, P, Hutvagner, G, Blumenstein, M & Li, J 2021, 'Aberration-corrected ultrafine analysis of miRNA reads at single-base resolution: a k-mer lattice approach', Nucleic Acids Research, vol. 49, no. 18, pp. e106-e106.
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Abstract Raw sequencing reads of miRNAs contain machine-made substitution errors, or even insertions and deletions (indels). Although the error rate can be low at 0.1%, precise rectification of these errors is critically important because isoform variation analysis at single-base resolution such as novel isomiR discovery, editing events understanding, differential expression analysis, or tissue-specific isoform identification is very sensitive to base positions and copy counts of the reads. Existing error correction methods do not work for miRNA sequencing data attributed to miRNAs’ length and per-read-coverage properties distinct from DNA or mRNA sequencing reads. We present a novel lattice structure combining kmers, (k – 1)mers and (k + 1)mers to address this problem. The method is particularly effective for the correction of indel errors. Extensive tests on datasets having known ground truth of errors demonstrate that the method is able to remove almost all of the errors, without introducing any new error, to improve the data quality from every-50-reads containing one error to every-1300-reads containing one error. Studies on experimental miRNA sequencing datasets show that the errors are often rectified at the 5′ ends and the seed regions of the reads, and that there are remarkable changes after the correction in miRNA isoform abundance, volume of singleton reads, overall entropy, isomiR families, tissue-specific miRNAs, and rare-miRNA quantities.

Zhao, Y, You, Z, Xing, D, Li, JJ, Zhang, Q, Huang, H, Li, Z, Jiang, S, Wu, Z, Zhang, Y, Li, W, Zhang, L, Du, Y & Lin, J 2021, 'Comparison of Chondrocytes in Knee Osteoarthritis and Regulation by Scaffold Pore Size and Stiffness', Tissue Engineering Part A, vol. 27, no. 3-4, pp. 223-236.
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BACKGROUND:In knee osteoarthritis (OA), there is more pronounced cartilage damage in the medial compartment ('lesion zone') than the lateral compartment ('remote zone'). This study fills a gap in the literature by conducting a systematic comparison of cartilage and chondrocyte characteristics from these two zones. It also investigates whether chondrocytes from the different zones respond distinctly to changes in the physical and mechanical microenvironment using 3D porous scaffolds by changing stiffness and pore size. METHODS:Cartilage was harvested from patients with end-stage varus knee OA. Cartilage from the lesion and remote zones were compared through histological and biomechanical assessments, as well as proteomic and gene transcription analyses of chondrocytes. Gelatin scaffolds with varied pore sizes and stiffness were used to investigate in vitro microenvironmental regulation of chondrocytes from the two zones. RESULTS:Cartilage from the lesion and remote zones differed significantly (P<0.05) in histological and biomechanical characteristics, as well as phenotype, protein and gene expression of chondrocytes. Chondrocytes from both zones were sensitive to changes in the structural and mechanical properties of gelatin scaffolds. Interestingly, while all chondrocytes better retained chondrocyte phenotype in stiffer scaffolds, those from the lesion and remote zones respectively preferred scaffolds with larger and smaller pores. CONCLUSIONS:Distinct variations exist in cartilage and chondrocyte characteristics in the lesion and remote zones of knee OA. Cells in these two zones respond differently to variations in the physical and mechanical microenvironment. Understanding and manipulating these differences will facilitate the development of more efficient and precise diagnostic and therapeutic approaches for knee OA.

Zhao, Z, Wang, Z, Tavakoli, J, Shan, G, Zhang, J, Peng, C, Xiong, Y, Zhang, X, Cheung, TS, Tang, Y, Huang, B, Yu, Z, Lam, JWY & Tang, BZ 2021, 'Revisiting an ancient inorganic aggregation‐induced emission system: An enlightenment to clusteroluminescence', Aggregate, vol. 2, no. 2.
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AbstractOrganic and inorganic clusteroluminescence have attracted great attention while the underlying mechanisms is still not well understood. Here, we employed a series of ancient inorganic complexes platinocyanides with aggregation‐induced emission property to elucidate the mechanism of clusteroluminescence including how does the chromophore form and how does the solid structures influence the luminescence behaviors. The results indicate that the isolated platinocyanide cannot work as a chromophore to emit visible light, while their clusterization at aggregate state can trigger the d‐orbitals coupling of the platinum atoms to facilitate the electron exchange and delocalization to form a new chromophore to emit visible light. Furthermore, the counter ions and H2O ligands help to rigidify the three‐dimensional network structure of the platinocyanides to suppress the excited state nonradiative decay, resulting in the high quantum yield of up to 96%. This work fundamentally helps understanding both the organic and inorganic clusteroluminescence phenomenon.

Zhu, G, Wang, G & Li, JJ 2021, 'Advances in implant surface modifications to improve osseointegration', Materials Advances, vol. 2, no. 21, pp. 6901-6927.
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Presenting the latest advances in surface modification of titanium and titanium alloy implants by physical, chemical and biological methods.

Zhu, Y & Reece, PJ 2021, 'Differential Interference Contrast-Based Interrogation of Plasmonic Gold Nanohole Arrays for Label-Free Imaging Sensing', ACS Applied Nano Materials, vol. 4, no. 10, pp. 10657-10664.
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Plasmonic nanostructures provide a robust platform for label-free, refractive-index-based optical sensing. Most readout strategies for plasmonic sensing rely on the measurement of angle, wavelength, or intensity changes. The phase response, though it changes much more abruptly at plasmonic resonances, has been rarely investigated because of the requirement of a more sophisticated optical arrangement. Here, we present a phase-based imaging approach using differential interference contrast (DIC) as means of label-free optical sensing with plasmonic nanohole arrays. We develop a colorimetric-based imaging readout and evaluate the refractive-index sensing capability using a layer-by-layer polyelectrolyte deposition model. We cross-validate the DIC imaging approach using the corresponding DIC intensity and reflectance spectrum as well as numerical simulation and show good agreement among different measurements. Our platform opens an avenue for exploiting the phase response of nanoplasmonic structures for rapid and multiplexed sensing application.

Bark, JM, Kulasinghe, A, Leo, P, Hartel, G, Warkiani, ME, Jeffree, RL, Chua, B, Day, BW & Punyadeera, C 1970, 'Circulating tumor cells as prognostic biomarkers in glioblastoma.', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, PA, Philadelphia.

Bazaz, SR & Warkiani, ME 1970, 'Design and characterization of an inertial microfluidic channel to enhance the process of CAR-T cell therapy', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 1215-1216.
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Chimeric Antigen Receptor T (CAR-T) cell therapy is a novel approach that reprograms and strengthens the patients' T cells to attack cancer cells. During the process of CAR-T cell manufacturing, a significant number of cells should be discarded as their viability become compromised. Here, we have demonstrated that inertial microfluidics can assist in the rapid and high throughput separation of viable CAR-T cells from non-viable ones.

Elsemary, MT, Maritz, MF, Smith, L, Warkiani, M & Thierry, B 1970, 'Microfluidic purification of T lymphocytes separated from blood for chimeric antigen receptor T-cell manufacturing.', CANCER IMMUNOLOGY RESEARCH, AMER ASSOC CANCER RESEARCH.

Elsemary, MT, Maritz, MF, Smith, L, Warkiani, M & Thierry, B 1970, 'Microfluidic purification of T lymphocytes separated from blood for chimeric antigen receptor T-cell manufacturing.', CANCER IMMUNOLOGY RESEARCH, AMER ASSOC CANCER RESEARCH.

Kulasinghe, A, Monkman, J, Taheri, T, Warkiani, M, O'leary, C, Ladwa, R, Richard, D & O'Byrne, K 1970, 'High-Plex Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)', JOURNAL OF THORACIC ONCOLOGY, ELSEVIER SCIENCE INC, pp. S50-S50.

Lei, Q, Phan, TH, Le Thi, P, Poon, C, Pansani, TN, Kabakowa, I, Kalionis, B, Park, KD & Chrzanowski, W 1970, 'HydroGEV: Extracellular Vesicle-Laden Hydrogel for Wound Healing Applications', Springer International Publishing, pp. 81-89.
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Ni Chroinin, D, Wilson, C, Marov, L, Kelly, A, Gaudin, J, El Haddad, C, Center, J, Eisman, JA, Nguyen, TV, Hassett, G & Frost, SA 1970, 'The slippery slope of breaking a bone: Recent prior fracture common amongst hip fracture patients (a retrospective observational study)', AUSTRALASIAN JOURNAL ON AGEING, WILEY, pp. 70-71.

Rad, DM, Zhang, Z & Warkiani, ME 1970, 'Engineering of the mammalian cells with hand-held microfiltroporation platform', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 607-608.
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Recent breakthroughs have focused on reinvigorating conventional delivery methods as they critically suffer from low cell viability, expensive protocols, and inconsistent material delivery. Thus, we developed a hand-held microfiltroporation (MFP) platform to overcome these issues and achieve instant cargo delivery into the cells of interest without requiring a complex setup.

Radfar, P, Ding, L, Rezaei, M & Warkiani, ME 1970, 'RETRIEVAL OF STATIC DROPLETS: A STEP TOWARDS SINGLE-CELL ANALYSIS OF RARE CELLS', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 555-556.
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Single-cell Analysis (SA) of rare cells has shed new lights in diagnosis and management of patients. Yet, majority of SA workflows face difficulties to analyse low-input samples in a cost- and time-effective manner. Static Droplet Arrays offer a handheld and affordable solution for SA of low-input samples; however, they are limited in downstream applications due to the inability of recovering the droplets. To overcome this limitation, we have developed droplet retrieval methods for different rare cell analysis at single-cell resolution. The entire methods are operated manually using a handheld pipette, without relying on specialised equipment.

Thoms, J, Truong, P, Subramanian, S, Knezevic, K, Harvey, G, Huang, Y, Seneviratne, J, Carter, D, Joshi, S, Skhinas, J, Chacon, D, Shah, A, de Jong, I, Beck, D, Gottgens, B, Larsson, J, Wong, J, Zanini, F & Pimanda, J 1970, 'DISRUPTION OF A GATA2, TAL1, ERG REGULATORY CIRCUIT PROMOTES ERYTHROID TRANSITION IN HEALTHY AND LEUKEMIC STEM CELLS', EXPERIMENTAL HEMATOLOGY, ELSEVIER SCIENCE INC, pp. S59-S59.

Xiao, L, Karsa, M, Ronca, E, Bongers, A, Gao, W, Kosciolek, A, El-Ayoubi, A, Norris, M, Haber, M & Somers, K 1970, 'Targeting chromatin potently inhibits leukemia progression in MLL-rearranged leukemia models', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, WILEY, pp. 15-15.

Zhand, S, Bazaz, SR, Sayyadi, N & Warkiani, ME 1970, 'Affibody functionalized microbeads: A novel and facile platform for ultra-sensitive detection of exosomes', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 1427-1428.
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Exosomes regarded as a promising source of cancer biomarkers in liquid biopsy. Thus, accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affibody biomolecules are a type of engineered protein scaffold with small size, high thermal stability, affinity, and specificity. For the first time, we have proposed a novel strategy by using Anti-EGFR-Affibody functionalized microbeads (AffiBeads) for the detection of A549 cancer cell-derived exosomes. Results illustrate that the affibody probe can detect 15.6 ng exosomes/mL (~12 exosomes per AffiBead). This approach could be used for sensitive detection of low expressed cancer markers, providing a basis for early-stage cancer diagnosis.

Zhang, X, Tang, K, Hughes, B, Vasani, S, Liu, Z, Warkiani, M, Hartel, G, Ladwa, R, Kenny, L & Punyadeera, C 1970, 'Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers.', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, PA, Philadelphia.

Zhao, ZW, Su, QP, Xie, SX & Sun, Y 1970, 'Super-resolution imaging reveals spatio-temporal propagation of human replication foci mediated by CTCF-organized chromatin structures', Single Molecule Spectroscopy and Superresolution Imaging XIV, Single Molecule Spectroscopy and Superresolution Imaging XIV, SPIE.
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Zhao, ZW, Su, QP, Xie, XS & Sun, Y 1970, 'Super-resolution imaging reveals spatio-temporal propagation of human replication foci mediated by CTCF-organized chromatin structures', EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, SPRINGER, pp. 192-192.

Chandrakanthan, V, Rorimpandey, P, Zanini, F, Chacon, D, Kang, YC, Knezevic, K, Huang, Y, Qiao, Q, Oliver, RA, Unnikrishnan, A, Carter, DR, Lee, B, Brownlee, C, Power, C, Mendez-Ferrer, S, Enikolopov, G, Walsh, W, Göttgens, B, Taoudi, S, Beck, D & Pimanda, JE 2021, 'Mesoderm-Derived PDGFRA⁺Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta', Cold Spring Harbor Laboratory.
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Chen, Y, Xu, X, Li, C, Bendavid, A, Westerhausen, MT, Bradac, C, Toth, M, Aharonovich, I & Tran, TT 2021, 'Bottom-Up Synthesis of Hexagonal Boron Nitride Nanoparticles with Intensity-Stabilized Quantum Emitters'.

Iranpour, H, Shahsavarani, H, Hosseini, SN, Far, HH, Zhand, S, Ghanbarlou, MM, Bouzari, S & Shokrgozar, MA 2021, 'WITHDRAWN: Self-assembling of Chimeric Mussel-inspired Bio-adhesives Originated from Mytilus Californianus and Anabaena Flos-aquae: A New Approach to Develop Underwater Adhesion', Research Square Platform LLC.
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Liu Chung Ming, C, Sesperez, K, Ben-Sefer, E, Arpon, D, McGrath, K, McClements, L & Gentile, C 2021, 'Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease', MDPI AG.
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Pham, D, Nguyen, H, Phung, A, Bui, T, Tran, T, Tran, B, Ho-Pham, L & Nguyen, T 2021, 'Trends in Incidence and Histological Pattern of Thyroid Cancer in Ho Chi Minh City, Vietnam (1996-2015): A Population-Based Study', Research Square Platform LLC.
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Pham, DX, Phung, AHT, Bui, TD, Mai, LD, Tran, TS, Ho-Pham, LT, Nguyen, TV & Nguyen, HD 2021, 'An Age-Period-Cohort And Joinpoint Analysis Of Colorectal Cancer Incidence Trends in Ho Chi Minh City, Vietnam(1996-2015)', Research Square Platform LLC.
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Rad, MA, Mahmodi, H, Filipe, EC, Cox, TR, Kabakova, I & Tipper, JL 2021, 'Micromechanical Characterisation of 3D Bioprinted neural cell models using Brillouin Microscopy', Cold Spring Harbor Laboratory.
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Roche, CD, Iyer, GR, Nguyen, MH, Mabroora, S, Dome, A, Sakr, K, Pawar, RP, Lee, V, Wilson, CC & Gentile, C 2021, 'Cardiac patch transplantation instruments for robotic minimally invasive cardiac surgery: initial proof-of-concept designs and surgery in a porcine cadaver [preprint]', Center for Open Science.
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Shojaei, M, Shamshirian, A, Monkman, J, Grice, L, Tran, M, Tan, CW, Rossi, GR, McCulloch, TR, Nalos, M, Chew, KY, Zhu, Y, Xia, Y, Wells, TJ, Senegaglia, AC, Rebelatto, CLK, Franck, CL, dos Santos, AFR, de Noronha, L, Motamen, S, Valadan, R, Amjadi, O, Gogna, R, Madan, E, Alizadeh-Navaei, R, Lamperti, L, Zuñiga, F, Nova-Lamperti, E, Labarca, G, Knippenberg, B, Herwanto, V, Wang, Y, Phu, A, Chew, T, Kwan, T, Kim, K, Teoh, S, Pelaia, TM, Kuan, WS, Jee, Y, Iredell, J, O’Byrne, K, Fraser, JF, Davis, MJ, Belz, G, Warkiani, M, Gallo, CS, Souza-Fonseca-Guimaraes, F, Nguyen, Q, Mclean, A, Kulasinghe, A, Short, KR & Tang, B 2021, 'IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study', Cold Spring Harbor Laboratory.
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Zandavi, SM, Koch, F, Vijayan, A, Zanini, F, Mora, FV, Ortega, DG & Vafaee, F 2021, 'Disentangling single-cell omics representation with a power spectral density-based feature extraction', Cold Spring Harbor Laboratory.
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