Aboulkheyr Es, H, Aref, AR & Warkiani, ME 2022, 'Generation and Culture of Organotypic Breast Carcinoma Spheroids for the Study of Drug Response in a 3D Microfluidic Device', Methods in Molecular Biology, vol. 2535, pp. 49-57.
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Breast cancer (BC) is a leading cause of cancer death among women worldwide. To better understand and predict therapeutic response in BC patient developing a fast, low-cost, and reliable preclinical tumor from patient's tumor specimen is needed. Here, we describe the development of a preclinical model of BC through the generation and ex vivo culture of patient-derived organotypic tumor spheroids (PDOTS) in a 3D microfluidic device. Moreover, the real-time screening of conventional chemotherapy agents on cultured PDOTS is also described.
Agarwal, A, Leslie, WD, Nguyen, TV, Morin, SN, Lix, LM & Eisman, JA 2022, 'Performance of the Garvan Fracture Risk Calculator in Individuals with Diabetes: A Registry-Based Cohort Study', Calcified Tissue International, vol. 110, no. 6, pp. 658-665.
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Diabetes increases fracture and falls risks. We evaluated the performance of the Garvan fracture risk calculator (FRC) in individuals with versus without diabetes. Using the population-based Manitoba bone mineral density (BMD) registry, we identified individuals aged 50-95 years undergoing baseline BMD assessment from 1 September 2012, onwards with diabetes and self-reported falls in the prior 12 months. Five-year Garvan FRC predictions were generated from clinical risk factors, with and without femoral neck BMD. We identified non-traumatic osteoporotic fractures (OF) and hip fractures (HF) from population-based data to 31 March 2018. Fracture risk stratification was assessed from area under the receiver operating characteristic curves (AUROC). Cox regression analysis was performed to examine the effect of diabetes on fractures, adjusted for Garvan FRC predictions. The study population consisted of 2618 women with and 14,064 without diabetes, and 636 and 2201 men with and without the same, respectively. The Garvan FRC provided significant OF and HF risk stratification in women with diabetes, similar to those without diabetes. Analyses of OF in men were limited by smaller numbers; no significant difference was evident by diabetes status. Cox regression showed that OF risk was 23% greater in women with diabetes adjusted for Garvan FRC including BMD (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01-1.49), suggesting it slightly underestimated risk; a non-significant increase in diabetes-related HF risk was noted (HR 1.37, 95% CI 0.88-2.15). Garvan FRC shows similar fracture risk stratification in individuals with versus without diabetes, but may underestimate this risk.
Agarwal, A, Leslie, WD, Nguyen, TV, Morin, SN, Lix, LM & Eisman, JA 2022, 'Predictive performance of the Garvan Fracture Risk Calculator: a registry-based cohort study', Osteoporosis International, vol. 33, no. 3, pp. 541-548.
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UNLABELLED: The G arvan Fracture Risk Calculator predicts risk of osteoporotic fractures. We evaluated its predictive performance in 16,682 women and 2839 men from Manitoba, Canada, and found significant risk stratification, with a strong gradient across scores. The tool outperformed clinical risk factors and bone mineral density for fracture risk stratification. INTRODUCTION: The optimal model for fracture risk estimation to guide treatment decision-making remains controversial. Our objective was to evaluate the predictive performance of the Garvan Fracture Risk Calculator (FRC) in a large clinical registry from Manitoba, Canada. METHODS: Using the population-based Manitoba Bone Mineral Density (BMD) registry, we identified women and men aged 50-95 years undergoing baseline BMD assessment from September 1, 2012, onwards. Five-year Garvan FRC predictions were generated from clinical risk factors (CRFs) with and without femoral neck BMD. We identified incident non-traumatic osteoporotic fractures (OFs) and hip fractures (HFs) from population-based healthcare data sources to March 31, 2018. Fracture risk was assessed from area under the receiver operating characteristic curve (AUROC). Cox regression analysis and calibration ratios (5-year observed/predicted) were assessed for risk quintiles. All analyses were sex stratified. RESULTS: We included 16,682 women (mean age 66.6 + / - SD 8.7 years) and 2839 men (mean age 68.7 + / - SD 10.2 years). During a mean observation time of 2.6 years, incident OFs were identified in 681 women and 140 men and HFs in 199 women and 22 men. AUROC showed significant fracture risk stratification with the Garvan FRC. Tool predictions without BMD were better than from age or decreasing weight, and the tool with BMD performed better than BMD alone. Garvan FRC with BMD performed better than without BMD, especially for HF prediction (AUROC 0.86 in women, 0.82 in men). There was a strong gradient of increasing risk across Garvan FRC...
Araujo, AM, Abaurrea, A, Azcoaga, P, López-Velazco, JI, Manzano, S, Rodriguez, J, Rezola, R, Egia-Mendikute, L, Valdés-Mora, F, Flores, JM, Jenkins, L, Pulido, L, Osorio-Querejeta, I, Fernández-Nogueira, P, Ferrari, N, Viera, C, Martín-Martín, N, Tzankov, A, Eppenberger-Castori, S, Alvarez-Lopez, I, Urruticoechea, A, Bragado, P, Coleman, N, Palazón, A, Carracedo, A, Gallego-Ortega, D, Calvo, F, Isacke, CM, Caffarel, MM & Lawrie, CH 2022, 'Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment', Journal of Clinical Investigation, vol. 132, no. 7, p. e148667.
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The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.
Araujo, AM, Abaurrea, A, Azcoaga, P, López-Velazco, JI, Manzano, S, Rodriguez, J, Rezola, R, Egia-Mendikute, L, Valdés-Mora, F, Flores, JM, Jenkins, L, Pulido, L, Osorio-Querejeta, I, Fernández-Nogueira, P, Ferrari, N, Viera, C, Martín-Martín, N, Tzankov, A, Eppenberger-Castori, S, Alvarez-Lopez, I, Urruticoechea, A, Bragado, P, Coleman, N, Palazón, A, Carracedo, A, Gallego-Ortega, D, Calvo, F, Isacke, CM, Caffarel, MM & Lawrie, CH 2022, 'Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment', Journal of Clinical Investigation, vol. 132, no. 19.
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Asadniaye Fardjahromi, M, Nazari, H, Ahmadi Tafti, SM, Razmjou, A, Mukhopadhyay, S & Warkiani, ME 2022, 'Metal-organic framework-based nanomaterials for bone tissue engineering and wound healing', Materials Today Chemistry, vol. 23, pp. 100670-100670.
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Over the past decade, tremendous growth has been witnessed in the synthesis of scaffolds fabricated by natural or synthetic, composite, or hybrid biomaterials to enhance wound healing, repair of bone fractures, and pathological loss of bones. However, the current limitations of using these scaffolds in tissue engineering are impaired cellular proliferation, poor differentiation, low mechanical stability, and bioactivity. Recent advances in the fabrication of nanoscale metal-organic framework (nano-MOF) scaffolds have provided golden opportunities to enhance the properties of scaffolds in bone and wound tissue engineering. In the past few years, studies have shown that incorporating nano-MOFs into scaffolds can be highly favorable in the regeneration of imperfect tissues owing to their unique properties such as high internal surface areas, high porosity, good mechanical stability, biocompatibility, and tunability. Moreover, the nanoscale structural and topological properties of nano-MOFs enhance the physicochemical properties of scaffolds, enrich them with drug-loading and ion-releasing capacity, and regulate stem cell attachment, proliferation, and differentiation after transplantation. This review initially introduces the various nano-MOFs incorporated into scaffolds for tissue engineering. Recent applications of nanoMOFs for bone and wound healing are comprehensively discussed. The unique properties of nano-MOFs for improving osteoconductivity, osteoinductivity, and wound healing, such as high antibacterial activity, high drug loading capacity (i.e., bioactive molecules and growth factors), and controlled drug release, are discussed. Finally, challenges, clinical barriers, and considerations for implementing these nanomaterials in different scaffolds, tissue-like structures, implants, fillers, and dressers in the orthopedic and wound clinics are comprised.
Augustine, R, S, A, Nayeem, A, Salam, SA, Augustine, P, Dan, P, Maureira, P, Mraiche, F, Gentile, C, Hansbro, PM, McClements, L & Hasan, A 2022, 'Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin–angiotensin-aldosterone system (RAAS) dysregulation', Chemico-Biological Interactions, vol. 351, pp. 109738-109738.
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The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin-converting enzyme (ACE) and the counter regulator, angiotensin-converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role RAAS may direct future research with the potential to improve the prevention and management of COVID-19.
Bao, G, Wang, K, Yang, L, He, J, He, B, Xu, X & Zheng, Y 2022, 'Feasibility evaluation of a Zn-Cu alloy for intrauterine devices: In vitro and in vivo studies', Acta Biomaterialia, vol. 142, pp. 374-387.
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The comprehensively adopted copper-containing intrauterine devices (Cu-IUDs) present typical adverse effects such as bleeding and pain at the initial stage of post-implantation. The replacement of Cu material is demanded. Zinc and its alloys, the emerging biodegradable materials, exhibited contraceptive effects since 1969. In this work, we evaluated the feasibility of bulk Zn alloys as IUD active material. Using pure Cu and pure Zn as control groups, we investigated the contraceptive performance of Zn-0.5Cu and Zn-1Cu alloys via in vitro and in vivo tests. The results showed that the main corrosion product of Zn-Cu alloys is ZnO from both in vitro and in vivo studies. CaZn2(PO4)2·2H2O is formed atop after long-term immersion in simulated uterine fluid, whereas CaCO3 is generally formed atop after implantation in the rat uterine environment. The cytocompatibility of the Zn-1Cu alloy was significantly higher than that of the pure Zn and pure Cu to the human endometrial epithelial cell lines. Furthermore, the in vivo results showed that the Zn-1Cu alloy presented much improved histocompatibility, least damage and the fastest recovery on endometrium structure in comparison to pure Zn, Zn-0.5Cu and pure Cu. The systematic and comparing studies suggest that Zn-1Cu alloy can be considered as a possible candidate for IUD with great biochemical and biocompatible properties as well as high contraceptive effectiveness. STATEMENT OF SIGNIFICANCE: The existing adverse effects with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concerns in their employment. Such as burst release of cupric ions (Cu2+) at the initial stage of the Cu-IUD. Zinc and its alloys which have been emerging as a potential biodegradable material exhibited contraceptive effects since 1969. In this study, Zn-1Cu alloys displayed significantly improved biocompatibility with human uterus cells and a decreased inflammatory response within the u...
Bordhan, P, Razavi Bazaz, S, Jin, D & Ebrahimi Warkiani, M 2022, 'Advances and enabling technologies for phase-specific cell cycle synchronisation', Lab on a Chip, vol. 22, no. 3, pp. 445-462.
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Schematic illustration of conventional (left) and microfluidics-based (right) phase-specific cell cycle synchronization strategies.
Boyd-Moss, M, Firipis, K, Quigley, A, Rifai, A, Cichocki, A, Whitty, S, Ngan, C, Dekiwadia, C, Long, B, Nisbet, DR, Kapsa, R & Williams, RJ 2022, 'Hybrid Self‐Assembling Peptide/Gelatin Methacrylate (GelMA) Bioink Blend for Improved Bioprintability and Primary Myoblast Response', Advanced NanoBiomed Research, vol. 2, no. 2.
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Organ fabrication as the solution to renewable donor demands requires the ability to spatially deposit viable cells into biologically relevant constructs; necessitating reliable and effective cell deposition through bioprinting and the subsequent ability to mature. However, effective bioink development demands advances in both printability and control of cellular response. Effective bioinks are designed to retain shape fidelity, influence cellular behavior, having bioactive morphologies stiffness and highly hydrated environment. Hybrid hydrogels are promising candidates as they reduce the need to re‐engineer materials for tissue‐specific properties, with each component offering beneficial properties. Herein, a multicomponent bioink is developed whereby gelatin methacrylate (GelMA) and fluorenylmethoxycarbonyprotected self‐assembling peptides (Fmoc‐SAPs) undergo coassembly to yield a tuneable bioink. This study shows that the reported fibronectin‐inspired fmoc‐SAPs present cell attachment epitopes RGD and PHSRN in the form of bioactive nanofibers; and that the GelMA enables superior printability, stability in media, and controlled mechanical properties. Importantly, when in the hybrid format, no disruption to either the methacrylate crosslinking of GelMA, or self‐assembled peptide fibril formation is observed. Finally, studies with primary myoblasts show over 98% viability at 72 h and differentiation into fused myotubes at one and two weeks demonstrate the utility of the material as a functional bioink for muscle engineering.
Chandrakanthan, V, Rorimpandey, P, Zanini, F, Chacon, D, Olivier, J, Joshi, S, Kang, YC, Knezevic, K, Huang, Y, Qiao, Q, Oliver, RA, Unnikrishnan, A, Carter, DR, Lee, B, Brownlee, C, Power, C, Brink, R, Mendez-Ferrer, S, Enikolopov, G, Walsh, W, Göttgens, B, Taoudi, S, Beck, D & Pimanda, JE 2022, 'Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta', Nature Cell Biology, vol. 24, no. 8, pp. 1211-1225.
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AbstractMouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition. We investigated whether mesenchymal stem cells, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta–gonad–mesonephros and contribute to the development of the dorsal aorta and endothelial-to-haematopoietic transition. Here we show that mesoderm-derived PDGFRA+ stromal cells (Mesp1der PSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5–E11.5 aorta–gonad–mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1der PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1der PSCs but not Wnt1der PSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT and NOTCH signalling interrupted this reprogramming event. Together, aorta–gonad–mesonephros Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.
Chen, C, Ding, L, Liu, B, Du, Z, Liu, Y, Di, X, Shan, X, Lin, C, Zhang, M, Xu, X, Zhong, X, Wang, J, Chang, L, Halkon, B, Chen, X, Cheng, F & Wang, F 2022, 'Exploiting Dynamic Nonlinearity in Upconversion Nanoparticles for Super-Resolution Imaging', Nano Letters, vol. 22, no. 17, pp. 7136-7143.
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Single-beam super-resolution microscopy, also known as superlinear microscopy, exploits the nonlinear response of fluorescent probes in confocal microscopy. The technique requires no complex purpose-built system, light field modulation, or beam shaping. Here, we present a strategy to enhance this technique's spatial resolution by modulating excitation intensity during image acquisition. This modulation induces dynamic optical nonlinearity in upconversion nanoparticles (UCNPs), resulting in variations of nonlinear fluorescence response in the obtained images. The higher orders of fluorescence response can be extracted with a proposed weighted finite difference imaging algorithm from raw fluorescence images to generate an image with higher resolution than superlinear microscopy images. We apply this approach to resolve single nanoparticles in a large area, improving the resolution to 132 nm. This work suggests a new scope for the development of dynamic nonlinear fluorescent probes in super-resolution nanoscopy.
Chen, X, Chamoli, U, Fogel, H & Diwan, AD 2022, 'Clinicians’ perceptions around discectomy surgery for lumbar disc herniation: a survey of orthopaedic and neuro-surgeons in Australia and New Zealand', Archives of Orthopaedic and Trauma Surgery, vol. 143, no. 1, pp. 189-201.
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INTRODUCTION: Understanding practice-based differences in treatment of lumbar disc herniations (LDHs) is vital for reducing unwarranted variation in the delivery of spine surgical health care. Identifying factors that influence surgeons' decision-making will offer useful insights for developing the most cost-effective and safest surgical strategy as well as developing surgeon education materials for common lumbar pathologies. This study was to capture any variation in techniques used by surgeons in Australia and New Zealand (ANZ) region, and perceived complications of different surgical procedures for primary and recurrent LDH (rLDH). MATERIALS AND METHODS: Web-based survey study was emailed to orthopaedic and neurosurgeons who routinely performed spinal surgery in ANZ from Decmber 20, 2018 to February 20, 2020. The response data were analyzed to assess for differences based on geography, practice setting, speciality, practice experience, practice length, and operative volume. RESULTS: Invitations were sent to 150 surgeons; 96 (64%) responded. Most surgeons reported microdiscectomy as their surgical technique of choice for primary LDH (73%) and the first rLDH (72%). For the second rLDH, the preferred choice for most surgeons was fusion surgery (82%). A surgeon's practice setting (academic/private/hybrid) was a statistically significant factor in what surgical procedure was chosen for the first rLDH (P = 0.014). When stratifying based on surgeon experience, there were statisfically significant differences based on the annual volume of spine surgeries performed (perceived reherniation rates following primary discectomy, P = 0.013; perceived reherniation rates following revision surgeries, P = 0.017; perceived intraoperative complications rates following revision surgeries, P = 0.016) and based on the annual volume of lumbar discectomies performed (perceived reherniation rates following revision surgeries, P = 0.022; perceived intraoperative complications ...
Chen, Y, Shimoni, O, Huang, G, Wen, S, Liao, J, Duong, HTT, Maddahfar, M, Su, QP, Ortega, DG, Lu, Y, Campbell, DH, Walsh, BJ & Jin, D 2022, 'Upconversion nanoparticle‐assisted single‐molecule assay for detecting circulating antigens of aggressive prostate cancer', Cytometry Part A, vol. 101, no. 5, pp. 400-410.
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AbstractSensitive and quantitative detection of molecular biomarkers is crucial for the early diagnosis of diseases like metabolic syndrome and cancer. Here we present a single‐molecule sandwich immunoassay by imaging the number of single nanoparticles to diagnose aggressive prostate cancer. Our assay employed the photo‐stable upconversion nanoparticles (UCNPs) as labels to detect the four types of circulating antigens in blood circulation, including glypican‐1 (GPC‐1), leptin, osteopontin (OPN), and vascular endothelial growth factor (VEGF), as their serum concentrations indicate aggressive prostate cancer. Under a wide‐field microscope, a single UCNP doped with thousands of lanthanide ions can emit sufficiently bright anti‐Stokes' luminescence to become quantitatively detectable. By counting every single streptavidin‐functionalized UCNP which specifically labeled on each sandwich immune complex across multiple fields of views, we achieved the Limit of Detection (LOD) of 0.0123 ng/ml, 0.2711 ng/ml, 0.1238 ng/ml, and 0.0158 ng/ml for GPC‐1, leptin, OPN and VEGF, respectively. The serum circulating level of GPC‐1, leptin, OPN, and VEGF in a mixture of 10 healthy normal human serum was 25.17 ng/ml, 18.04 ng/ml, 11.34 ng/ml, and 1.55 ng/ml, which was within the assay dynamic detection range for each analyte. Moreover, a 20% increase of GPC‐1 and OPN was observed by spiking the normal human serum with recombinant antigens to confirm the accuracy of the assay. We observed no cross‐reactivity among the four biomarker analytes, which eliminates the false positives and enhances the detection accuracy. The developed single upconversion nanoparticle‐assisted single‐molecule assay suggests its potential in clinical usage for prostate cancer detection by monitoring tiny concentration differences in a panel of serum biomarkers.
Chepurin, D, Chamoli, U & Diwan, AD 2022, 'Bony Stress and Its Association With Intervertebral Disc Degeneration in the Lumbar Spine: A Systematic Review of Clinical and Basic Science Studies', Global Spine Journal, vol. 12, no. 5, pp. 964-979.
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Study Design: Translational review encompassing basic science and clinical evidence. Objectives: Multiple components of the lumbar spine interact during its normal and pathological function. Bony stress in the lumbar spine is recognized as a factor in the development of pars interarticularis defect and stress fractures, but its relationship with intervertebral disc (IVD) degeneration is not well understood. Therefore, we conducted a systematic review to examine the relationship between bony stress and IVD degeneration. Methods: Online databases Scopus, PubMed and MEDLINE via OVID were searched for relevant studies published between January 1980-February 2020, using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Two authors independently analyzed the data, noting characteristics and biases in various studies. Results: Thirty-two articles were included in the review: 8 clinical studies, 9 finite element modeling studies, 3 in-vivo biomechanical testing studies, and 12 in-vitro biomechanical testing studies. Of the 32 articles, 19 supported, 4 rejected and 9 made no conclusion on the hypothesis that there is a positive associative relationship between IVD degeneration and bony stress. However, sufficient evidence was not available to confirm or reject a causal relationship. Conclusions: Most studies suggest that the prevalence of IVD degeneration increases in the presence of bony stress; whether a causal relationship exists is unclear. The literature recommends early diagnosis and clinical suspicion of IVD degeneration and bony stress. Longitudinal studies are required to explore causal relationships between IVD degeneration a...
Crowther, CA, Samuel, D, McCowan, LME, Edlin, R, Tran, T & McKinlay, CJ 2022, 'Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes', New England Journal of Medicine, vol. 387, no. 7, pp. 587-598.
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BACKGROUND: Treatment of gestational diabetes improves maternal and infant health, although diagnostic criteria remain unclear. METHODS: We randomly assigned women at 24 to 32 weeks' gestation in a 1:1 ratio to be evaluated for gestational diabetes with the use of lower or higher glycemic criteria for diagnosis. The lower glycemic criterion was a fasting plasma glucose level of at least 92 mg per deciliter (≥5.1 mmol per liter), a 1-hour level of at least 180 mg per deciliter (≥10.0 mmol per liter), or a 2-hour level of at least 153 mg per deciliter (≥8.5 mmol per liter). The higher glycemic criterion was a fasting plasma glucose level of at least 99 mg per deciliter (≥5.5 mmol per liter) or a 2-hour level of at least 162 mg per deciliter (≥9.0 mmol per liter). The primary outcome was the birth of an infant who was large for gestational age (defined as a birth weight above the 90th percentile according to Fenton-World Health Organization standards). Secondary outcomes were maternal and infant health. RESULTS: A total of 4061 women underwent randomization. Gestational diabetes was diagnosed in 310 of 2022 women (15.3%) in the lower-glycemic-criteria group and in 124 of 2039 women (6.1%) in the higher-glycemic-criteria group. Among 2019 infants born to women in the lower-glycemic-criteria group, 178 (8.8%) were large for gestational age, and among 2031 infants born to women in the higher-glycemic-criteria group, 181 (8.9%) were large for gestational age (adjusted relative risk, 0.98; 95% confidence interval, 0.80 to 1.19; P = 0.82). Induction of labor, use of health services, use of pharmacologic agents, and neonatal hypoglycemia were more common in the lower-glycemic-criteria group than in the higher-glycemic-criteria group. The results for the other secondary outcomes were similar in the two trial groups, and there were no substantial between-group differences in adverse events. Among the women in both groups who had glucose test results that fell betwe...
Deng, Z, Mu, H, Jiang, L, Xi, W, Xu, X & Zheng, W 2022, 'Preparation and characterization of electrospun PLGA-SF nanofibers as a potential drug delivery system', Materials Chemistry and Physics, vol. 289, pp. 126452-126452.
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Currently drug-controlled release technology has gained a great deal of attention on the field of biomedicine. Nevertheless, most drug-controlled release systems usually require complex modification. Herein, the monolayer and multilayer structure nanofibers for drug delivery of acetylsalicylic acid (ASA), as a model drug, were fabricated using the one-step electrospinning technique for the first time, which was composed with the poly(lactic-co-glycolic acid) (PLGA) and silk fibroin (SF). Meanwhile, the effects of the mass radio of PLGA to SF on the properties of the electrospun monolayer nanofiber membrane was further investigated. The results of the electrospun monolayer PLGA-SF nanofiber membrane with mass radio of 2:1 displayed significant improvement in hydrophilicity as well as mechanical properties compared to the other mass radio of nanofibers membranes. Moreover, drug release studies revealed that nanofiber membrane with multilayer structure was able to promote a much more sustained release of ASA in comparison with monolayer PLGA-SF nanofibers membranes. More remarkable, the nanofiber membrane with multilayer structure presented good biocompatibility. Overall, these results demonstrate the potential of using PLGA-SF nanofibers with multilayer structure as a scaffold for drug-controlled release.
Deng, Z, Wu, H, Mu, H, Jiang, L, Xi, W, Xu, X & Zheng, W 2022, 'Preparation and properties of electrospun NaYF4: Yb3+, Er3+‐PLGA‐gelatin nanofibers', Journal of Applied Polymer Science, vol. 139, no. 26.
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AbstractThe synthesis of composite nanofiber often requires complex reaction conditions and the dimensions of the synthesized composite nanofiber are difficult to control. Electrospinning technique could tackle the issue. In this work, we firstly prepare the NaYF4 up‐conversion material composed of double doped rare earth ions of Er3+ and Yb3+. Then, the up‐conversion luminescent NaYF4: Yb3+, Er3+ nanoparticles (NaYF4 NPs) are encapsulated into poly(lactide‐co‐glycolide)‐gelatin (NaYF4‐PLGA‐gelatin) using one‐step electrospinning process. The effect of NaYF4 NPs on morphology, up‐conversion emission spectra, hydrophilicity, mechanical property and degradation of the electrospun NaYF4‐PLGA‐gelatin nanofiber are studied in detail. The highest luminescent intensity of the electrospun NaYF4‐PLGA‐gelatin nanofiber is achieved when the encapsulated content of NaYF4 NPs is 5 mg/ml. Meanwhile, the mechanical properties of the nanofibers with this encapsulated content are also averagely higher than that of the nanofibers with other concentrations. In addition, the electrospun NaYF4‐PLGA‐gelatin nanofibers with a variety of NaYF4 NPs contents present great hydrophilicity and degradation rates. Therefore, this work provides an effective approach for the design of up‐conversion composite nanofibers and can further exploit the applications in in vivo biological imaging and tissue engineering.
Deng, Z, Zhao, L, Mu, H, Jiang, L, Xi, W, Xu, X & Zheng, W 2022, 'High selective property of gelatin/MWCNTs functionalized carbon fiber microelectrode: Toward real-time monitoring of ascorbate', Journal of Electroanalytical Chemistry, vol. 914, pp. 116315-116315.
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Deng, Z, Zhao, L, Zhou, H, Xu, X & Zheng, W 2022, 'Recent advances in electrochemical analysis of hydrogen peroxide towards in vivo detection', Process Biochemistry, vol. 115, pp. 57-69.
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Di, X, Wang, D, Su, QP, Liu, Y, Liao, J, Maddahfar, M, Zhou, J & Jin, D 2022, 'Spatiotemporally mapping temperature dynamics of lysosomes and mitochondria using cascade organelle-targeting upconversion nanoparticles', Proceedings of the National Academy of Sciences, vol. 119, no. 45, p. e2207402119.
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The intracellular metabolism of organelles, like lysosomes and mitochondria, is highly coordinated spatiotemporally and functionally. The activities of lysosomal enzymes significantly rely on the cytoplasmic temperature, and heat is constantly released by mitochondria as the byproduct of adenosine triphosphate (ATP) generation during active metabolism. Here, we developed temperature-sensitive LysoDots and MitoDots to monitor the in situ thermal dynamics of lysosomes and mitochondria. The design is based on upconversion nanoparticles (UCNPs) with high-density surface modifications to achieve the exceptionally high sensitivity of 2.7% K −1 and low uncertainty of 0.8 K for nanothermometry to be used in living cells. We show the measurement is independent of the ion concentrations and pH values. With Ca 2+ ion shock, the temperatures of both lysosomes and mitochondria increased by ∼2 to 4 °C. Intriguingly, with chloroquine (CQ) treatment, the lysosomal temperature was observed to decrease by up to ∼3 °C, while mitochondria remained relatively stable. Lastly, with oxidative phosphorylation inhibitor treatment, we observed an ∼3 to 7 °C temperature increase and a thermal transition from mitochondria to lysosomes. These observations indicate different metabolic pathways and thermal transitions between lysosomes and mitochondria inside HeLa cells. The nanothermometry probes provide a powerful tool for multimodality functional imaging of subcellular organelles and interactions with high spatial, temporal, and thermal dynamics resolutions.
Ding, L, Razavi Bazaz, S, Asadniaye Fardjahromi, M, McKinnirey, F, Saputro, B, Banerjee, B, Vesey, G & Ebrahimi Warkiani, M 2022, 'A modular 3D printed microfluidic system: a potential solution for continuous cell harvesting in large-scale bioprocessing', Bioresources and Bioprocessing, vol. 9, no. 1.
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AbstractMicrofluidic devices have shown promising applications in the bioprocessing industry. However, the lack of modularity and high cost of testing and error limit their implementation in the industry. Advances in 3D printing technologies have facilitated the conversion of microfluidic devices from research output to applicable industrial systems. Here, for the first time, we presented a 3D printed modular microfluidic system consisting of two micromixers, one spiral microfluidic separator, and one microfluidic concentrator. We showed that this system can detach and separate mesenchymal stem cells (MSCs) from microcarriers (MCs) in a short time while maintaining the cell’s viability and functionality. The system can be multiplexed and scaled up to process large volumes of the industry. Importantly, this system is a closed system with no human intervention and is promising for current good manufacturing practices. Graphical Abstract
Ding, L, Razavi Bazaz, S, Hall, T, Vesey, G & Ebrahimi Warkiani, M 2022, 'Giardia purification from fecal samples using rigid spiral inertial microfluidics', Biomicrofluidics, vol. 16, no. 1, pp. 014105-014105.
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Giardia is one of the most common waterborne pathogens causing around 200 × 106 diarrheal infections annually. It is of great interest to microbiological research as it is among the oldest known eukaryotic cells. Purifying Giardia from fecal samples for both research and diagnostic purposes presents one of the most difficult challenges. Traditional purification methods rely on density gradient centrifugation, membrane-based filtration, and sedimentation methods, which suffer from low recovery rates, high costs, and poor efficiency. Here, we report on the use of microfluidics to purify Giardia cysts from mouse feces. We propose a rigid spiral microfluidic device with a trapezoidal cross section to effectively separate Giardia from surrounding debris. Our characterizations reveal that the recovery rate is concentration-dependent, and our proposed device can achieve recovery rates as high as 75% with 0.75 ml/min throughput. Moreover, this device can purify Giardia from extremely turbid samples to a level where cysts are visually distinguishable with just one round of purification. This highly scalable and versatile 3D printed microfluidic device is then capable of further purifying or enhancing the recovery rate of the samples by recirculation. This device also has the potential to purify other gastrointestinal pathogens of similar size, and throughput can be significantly increased by parallelization.
Ding, L, Razavi Bazaz, S, Shrestha, J, A. Amiri, H, Mas-hafi, S, Banerjee, B, Vesey, G, Miansari, M & Ebrahimi Warkiani, M 2022, 'Rapid and Continuous Cryopreservation of Stem Cells with a 3D Micromixer', Micromachines, vol. 13, no. 9, pp. 1516-1516.
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Cryopreservation is the final step of stem cell production before the cryostorage of the product. Conventional methods of adding cryoprotecting agents (CPA) into the cells can be manual or automated with robotic arms. However, challenging issues with these methods at industrial-scale production are the insufficient mixing of cells and CPA, leading to damage of cells, discontinuous feeding, the batch-to-batch difference in products, and, occasionally, cross-contamination. Therefore, the current study proposes an alternative way to overcome the abovementioned challenges; a highly efficient micromixer for low-cost, continuous, labour-free, and automated mixing of stem cells with CPA solutions. Our results show that our micromixer provides a more homogenous mixing of cells and CPA compared to the manual mixing method, while the cell properties, including surface markers, differentiation potential, proliferation, morphology, and therapeutic potential, are well preserved.
Ding, L, Shan, X, Wang, D, Liu, B, Du, Z, Di, X, Chen, C, Maddahfar, M, Zhang, L, Shi, Y, Reece, P, Halkon, B, Aharonovich, I, Xu, X & Wang, F 2022, 'Lanthanide Ion Resonance‐Driven Rayleigh Scattering of Nanoparticles for Dual‐Modality Interferometric Scattering Microscopy', Advanced Science, vol. 9, no. 32, pp. e2203354-2203354.
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AbstractLight scattering from nanoparticles is significant in nanoscale imaging, photon confinement. and biosensing. However, engineering the scattering spectrum, traditionally by modifying the geometric feature of particles, requires synthesis and fabrication with nanometre accuracy. Here it is reported that doping lanthanide ions can engineer the scattering properties of low‐refractive‐index nanoparticles. When the excitation wavelength matches the ion resonance frequency of lanthanide ions, the polarizability and the resulted scattering cross‐section of nanoparticles are dramatically enhanced. It is demonstrated that these purposely engineered nanoparticles can be used for interferometric scattering (iSCAT) microscopy. Conceptually, a dual‐modality iSCAT microscopy is further developed to identify different nanoparticle types in living HeLa cells. The work provides insight into engineering the scattering features by doping elements in nanomaterials, further inspiring exploration of the geometry‐independent scattering modulation strategy.
Elsemary, MT, Maritz, MF, Smith, LE, Warkiani, M, Bandara, V, Napoli, S, Barry, SC, Coombs, JT & Thierry, B 2022, 'Inertial Microfluidic Purification of CAR‐T‐Cell Products', Advanced Biology, vol. 6, no. 1, pp. e2101018-e2101018.
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AbstractChimeric antigen receptor T (CAR‐T) cell therapy is rapidly becoming a frontline cancer therapy. However, the manufacturing process is time‐, labor‐ and cost‐intensive, and it suffers from significant bottlenecks. Many CAR‐T products fail to reach the viability release criteria set by regulators for commercial cell therapy products. This results in non‐recoupable costs for the manufacturer and is detrimental to patients who may not receive their scheduled treatment or receive out‐of‐specification suboptimal formulation. It is demonstrated here that inertial microfluidics can, within minutes, efficiently deplete nonviable cells from low‐viability CAR‐T cell products. The percentage of viable cells increases from 40% (SD ± 0.12) to 71% (SD ± 0.09) for untransduced T cells and from 51% (SD ± 0.12) to 71% (SD ± 0.09) for CAR‐T cells, which meets the clinical trials’ release parameters. In addition, the processing of CAR‐T cells formulated in CryStor yields a 91% reduction in the amount of the cryoprotectant dimethyl sulfoxide. Inertial microfluidic processing has no detrimental effects on the proliferation and cytotoxicity of CAR‐T cells. Interestingly, ≈50% of T‐regulatory and T‐suppressor cells are depleted, suggesting the potential for inertial microfluidic processing to tune the phenotypical composition of T‐cell products.
Fatemi, N, Tierling, S, Es, HA, Varkiani, M, Mojarad, EN, Aghdaei, HA, Walter, J & Totonchi, M 2022, 'DNA methylation biomarkers in colorectal cancer: Clinical applications for precision medicine', International Journal of Cancer, vol. 151, no. 12, pp. 2068-2081.
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AbstractColorectal cancer (CRC) is the second leading cause of cancer death worldwide that is attributed to gradual long‐term accumulation of both genetic and epigenetic changes. To reduce the mortality rate of CRC and to improve treatment efficacy, it will be important to develop accurate noninvasive diagnostic tests for screening, acute and personalized diagnosis. Epigenetic changes such as DNA methylation play an important role in the development and progression of CRC. Over the last decade, a panel of DNA methylation markers has been reported showing a high accuracy and reproducibility in various semi‐invasive or noninvasive biosamples. Research to obtain comprehensive panels of markers allowing a highly sensitive and differentiating diagnosis of CRC is ongoing. Moreover, the epigenetic alterations for cancer therapy, as a precision medicine strategy will increase their therapeutic potential over time. Here, we discuss the current state of DNA methylation‐based biomarkers and their impact on CRC diagnosis. We emphasize the need to further identify and stratify methylation‐biomarkers and to develop robust and effective detection methods that are applicable for a routine clinical setting of CRC diagnostics particularly at the early stage of the disease.
Ferguson, BM, Entezari, A, Fang, J & Li, Q 2022, 'Optimal placement of fixation system for scaffold-based mandibular reconstruction', Journal of the Mechanical Behavior of Biomedical Materials, vol. 126, pp. 104855-104855.
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A current challenge in bone tissue engineering is to create favourable biomechanical conditions conducive to tissue regeneration for a scaffold implanted in a segmental defect. This is particularly the case immediately following surgical implantation when a firm mechanical union between the scaffold and host bone is yet to be established via osseointegration. For mandibular reconstruction of a large segmental defect, the position of the fixation system is shown here to have a profound effect on the mechanical stimulus (for tissue regeneration within the scaffold), structural strength, and structural stiffness of the tissue scaffold-host bone construct under physiological load. This research combines computer tomography (CT)-based finite element (FE) modelling with multiobjective optimisation to determine the optimal height and angle to place a titanium fixation plate on a reconstructed mandible so as to enhance tissue ingrowth, structural strength and structural stiffness of the scaffold-host bone construct. To this end, the respective design criteria for fixation plate placement are to: (i) maximise the volume of the tissue scaffold experiencing levels of mechanical stimulus sufficient to initiate bone apposition, (ii) minimise peak stress in the scaffold so that it remains intact with a diminished risk of failure and, (iii) minimise scaffold ridge displacement so that the reconstructed jawbone resists deformation under physiological load. First, a CT-based FE model of a reconstructed human mandible implanted with a bioceramic tissue scaffold is developed to visualise and quantify changes in the biomechanical responses as the fixation plate's height and/or angle are varied. The volume of the scaffold experiencing appositional mechanical stimulus is observed to increase with the height of the fixation plate. Also, as the principal load-transfer mechanism to the scaffold is via the fixation system, there is a significant ingress of appositional stimulus ...
Francis, I, Shrestha, J, Paudel, KR, Hansbro, PM, Warkiani, ME & Saha, SC 2022, 'Recent advances in lung-on-a-chip models', Drug Discovery Today, vol. 27, no. 9, pp. 2593-2602.
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Gao, L, Li, S, Xu, X, Zou, C & Zhang, G 2022, 'Highly Sensitive H2 Sensors Based on Co3O4/PEI-CNTs at Room Temperature', Journal of Nanomaterials, vol. 2022, pp. 1-8.
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The highly dispersed Co3O4 on the surface of CNTs modified with polyethylenimine (PEI) was synthesized using the hydrothermal method. In the CNT-Co3O4 composite materials, CNTs not only provide the substrate for the Co3O4 nanoparticles but also prevent their aggregation. Furthermore, the interaction between Co3O4 and CNTs modified with polyethylenimine (PEI) helps to improve the gas sensing performance. In particular, the CNT-Co3O4 composite synthesized at 190°C shows the outstanding sensitive characteristics to H2 with a lower detection limit of 30 ppm at room temperature. The obtained CNT-Co3O4 sensor displays excellent selectivity and stability to H2. The energy band model of the conductive mechanism has been built to explain the resistance change when the gas sensor is exposed to the H2. Hence, the CNT-Co3O4 composite material presents highly promising applications in H2 gas sensing.
Ghalehno, AD, Saeedi, M, Bazaz, SR, Asadi, P, EbrahimiWarkiani, M & Yazdian-Robati, R 2022, 'Nano aptasensors for detection of streptomycin: A review', Nanomedicine Journal, vol. 9, no. 1, pp. 24-33.
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This review provides a literature update of the progress in optical and electrochemical aptasensors for the detection of streptomycin in human sera and animal-derived foods. The uncontrolled use of antibiotics and rising resistance to them, has created a global problem. Therefore, the detection and quantitation of antibiotics, i.e., streptomycin by robust, easy, and sensitive methods is in great demand. Among different strategies, new analytical methods for the efficient detection and quantitative determination of streptomycin have been developed. Aptasensors or aptamer-based biosensors have attracted more attention due to their unique recognition, simple fabrication, and significant selectivity, sensitivity, and specificity. Advantages of aptasensors will be highlighted in this review, with emphasis on methodological technique and specific properties of aptasensors developed for STR determination. In this review paper, we will focus on the recent development of aptasensors for streptomycin detection, considering the papers summarized in the data bases scopus and google scholar covering the period of time from 2013 till 2021.
Ghalehno, AD, Saeedi, M, Bazaz, SR, Asadi, P, EbrahimiWarkiani, M & Yazdian-Robati, R 2022, 'Nano aptasensors for detection of streptomycin: A review', NANOMEDICINE JOURNAL, vol. 9, no. 1, pp. 24-33.
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This review provides a literature update of the progress in optical and electrochemical aptasensors for the detection of streptomycin in human sera and animal-derived foods. The uncontrolled use of antibiotics and rising resistance to them, has created a global problem. Therefore, the detection and quantitation of antibiotics, i.e., streptomycin by robust, easy, and sensitive methods is in great demand. Among different strategies, new analytical methods for the efficient detection and quantitative determination of streptomycin have been developed. Aptasensors or aptamer-based biosensors have attracted more attention due to their unique recognition, simple fabrication, and significant selectivity, sensitivity, and specificity. Advantages of aptasensors will be highlighted in this review, with emphasis on methodological technique and specific properties of aptasensors developed for STR determination. In this review paper, we will focus on the recent development of aptasensors for streptomycin detection, considering the papers summarized in the data bases scopus and google scholar covering the period of time from 2013 till 2021.
Gonzalez de Vega, R, Lockwood, TE, Xu, X, Gonzalez de Vega, C, Scholz, J, Horstmann, M, Doble, PA & Clases, D 2022, 'Analysis of Ti- and Pb-based particles in the aqueous environment of Melbourne (Australia) via single particle ICP-MS', Analytical and Bioanalytical Chemistry, vol. 414, no. 18, pp. 5671-5681.
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AbstractThe analysis of natural and anthropogenic nanomaterials (NMs) in the environment is challenging and requires methods capable to identify and characterise structures on the nanoscale regarding particle number concentrations (PNCs), elemental composition, size, and mass distributions. In this study, we employed single particle inductively coupled plasma-mass spectrometry (SP ICP-MS) to investigate the occurrence of NMs in the Melbourne area (Australia) across 63 locations. Poisson statistics were used to discriminate between signals from nanoparticulate matter and ionic background. TiO2-based NMs were frequently detected and corresponding NM signals were calibated with an automated data processing platform. Additionally, a method utilising a larger mass bandpass was developed to screen for particulate high-mass elements. This procedure identified Pb-based NMs in various samples. The effects of different environmental matrices consisting of fresh, brackish, or seawater were mitigated with an aerosol dilution method reducing the introduction of salt into the plasma and avoiding signal drift. Signals from TiO2- and Pb-based NMs were counted, integrated, and subsequently calibrated to determine PNCs as well as mass and size distributions. PNCs, mean sizes, particulate masses, and ionic background levels were compared across different locations and environments. Graphical abstract
Hanaei, S, Takian, A, Majdzadeh, R, Maboloc, CR, Grossmann, I, Gomes, O, Milosevic, M, Gupta, M, Shamshirsaz, AA, Harbi, A, Burhan, AM, Uddin, LQ, Kulasinghe, A, Lam, C-M, Ramakrishna, S, Alavi, A, Nouwen, JL, Dorigo, T, Schreiber, M, Abraham, A, Shelkovaya, N, Krysztofiak, W, Ebrahimi Warkiani, M, Sellke, F, Ogino, S, Barba, FJ, Brand, S, Vasconcelos, C, Salunke, DB & Rezaei, N 2022, 'Emerging Standards and the Hybrid Model for Organizing Scientific Events During and After the COVID-19 Pandemic', Disaster Medicine and Public Health Preparedness, vol. 16, no. 3, pp. 1172-1177.
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AbstractSince the beginning of 2020, the coronavirus disease (COVID-19) pandemic has dramatically influenced almost every aspect of human life. Activities requiring human gatherings have either been postponed, canceled, or held completely virtually. To supplement lack of in-person contact, people have increasingly turned to virtual settings online, advantages of which include increased inclusivity and accessibility and a reduced carbon footprint. However, emerging online technologies cannot fully replace in-person scientific events. In-person meetings are not susceptible to poor Internet connectivity problems, and they provide novel opportunities for socialization, creating new collaborations and sharing ideas. To continue such activities, a hybrid model for scientific events could be a solution offering both in-person and virtual components. While participants can freely choose the mode of their participation, virtual meetings would most benefit those who cannot attend in-person due to the limitations. In-person portions of meetings should be organized with full consideration of prevention and safety strategies, including risk assessment and mitigation, venue and environmental sanitation, participant protection and disease prevention, and promoting the hybrid model. This new way of interaction between scholars can be considered as a part of a resilience system, which was neglected previously and should become a part of routine practice in the scientific community.
Ho, W-HJ, Law, AMK, Masle-Farquhar, E, Castillo, LE, Mawson, A, O’Bryan, MK, Goodnow, CC, Gallego-Ortega, D, Oakes, SR & Ormandy, CJ 2022, 'Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases', Breast Cancer Research, vol. 24, no. 1.
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AbstractBackgroundThe interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. UsingN-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice.MethodsTo determine if sole activation ofOas2could alter the course of mammary cancer, we combined theOas2mutation with theMMTV-PyMToncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan–Meier survival analysis with immunohistochemistry and flow cytometry.ResultsOas2mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when theOas2mutation was present.ConclusionsThese data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.
Houshyar, S, Rifai, A, Zizhou, R, Dekiwadia, C, Booth, MA, John, S, Fox, K & Truong, VK 2022, 'Liquid metal polymer composite: Flexible, conductive, biocompatible, and antimicrobial scaffold', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 110, no. 5, pp. 1131-1139.
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AbstractGallium and its alloys, such as eutectic gallium indium alloy (EGaIn), a form of liquid metal, have recently attracted the attention of researchers due to their low toxicity and electrical and thermal conductivity for biomedical application. However, further research is required to harness EGaIn‐composites advantages and address their application as a biomedical scaffold. In this research, EGaIn‐polylactic acid/polycaprolactone composites with and without a second conductive filler, MXene, were prepared and characterized. The addition of MXene, into the EGaIn‐composite, can improve the composite's electrochemical properties by connecting the liquid metal droplets resulting in electrically conductive continuous pathways within the polymeric matrix. The results showed that the composite with 50% EGaIn and 4% MXene, displayed optimal electrochemical properties and enhanced mechanical and radiopacity properties. Furthermore, the composite showed good biocompatibility, examined through interactions with fibroblast cells, and antibacterial properties against methicillin‐resistant Staphylococcus aureus. Therefore, the liquid metal (EGaIn) polymer composite with MXene provides a first proof‐of‐concept engineering scaffold strategy with low toxicity, functional electrochemical properties, and promising antimicrobial properties.
Hu, B, Bao, G, Xu, X & Yang, K 2022, 'Topical hemostatic materials for coagulopathy', Journal of Materials Chemistry B, vol. 10, no. 12, pp. 1946-1959.
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We present a thorough analysis on the hemostatic mechanisms and the design principles of hemostatic materials for coagulopathy, survey their remarkable success, and briefly discuss the challenges and perspectives for their clinical translation.
Huang, G, Zhu, Y, Wen, S, Mei, H, Liu, Y, Wang, D, Maddahfar, M, Su, QP, Lin, G, Chen, Y & Jin, D 2022, 'Single Small Extracellular Vesicle (sEV) Quantification by Upconversion Nanoparticles', Nano Letters, vol. 22, no. 9, pp. 3761-3769.
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Cancer-derived small extracellular vesicles (sEVs) are potential circulating biomarkers in liquid biopsies. However, their small sizes, low abundance, and heterogeneity in molecular makeups pose major technical challenges for detecting and characterizing them quantitatively. Here, we demonstrate a single-sEV enumeration platform using lanthanide-doped upconversion nanoparticles (UCNPs). Taking advantage of the unique optical properties of UCNPs and the background-eliminating property of total internal reflection fluorescence (TIRF) imaging technique, a single-sEV assay recorded a limit of detection 1.8 × 106 EVs/mL, which was nearly 3 orders of magnitude lower than the standard enzyme-linked immunosorbent assay (ELISA). Its specificity was validated by the difference between EpCAM-positive and EpCAM-negative sEVs. The accuracy of the UCNP-based single-sEV assay was benchmarked with immunomagnetic-beads flow cytometry, showing a high correlation (R2> 0.99). The platform is suitable for evaluating the heterogeneous antigen expression of sEV and can be easily adapted for biomarker discoveries and disease diagnosis.
Johansen, MD, Mahbub, RM, Idrees, S, Nguyen, DH, Miemczyk, S, Pathinayake, P, Nichol, K, Hansbro, NG, Gearing, LJ, Hertzog, PJ, Gallego-Ortega, D, Britton, WJ, Saunders, BM, Wark, PA, Faiz, A & Hansbro, PM 2022, 'Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing', American Journal of Respiratory and Critical Care Medicine, vol. 206, no. 6, pp. 712-729.
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Rationale: Patients with chronic obstructive pulmonary disease (COPD) develop more severe coronavirus disease (COVID-19); however, it is unclear whether they are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and what mechanisms are responsible for severe disease. Objectives: To determine whether SARS-CoV-2 inoculated primary bronchial epithelial cells (pBECs) from patients with COPD support greater infection and elucidate the effects and mechanisms involved. Methods: We performed single-cell RNA sequencing analysis on differentiated pBECs from healthy subjects and patients with COPD 7 days after SARS-CoV-2 inoculation. We correlated changes with viral titers, proinflammatory responses, and IFN production. Measurements and Main Results: Single-cell RNA sequencing revealed that COPD pBECs had 24-fold greater infection than healthy cells, which was supported by plaque assays. Club/goblet and basal cells were the predominant populations infected and expressed mRNAs involved in viral replication. Proteases involved in SARS-CoV-2 entry/infection (TMPRSS2 and CTSB) were increased, and protease inhibitors (serpins) were downregulated more so in COPD. Inflammatory cytokines linked to COPD exacerbations and severe COVID-19 were increased, whereas IFN responses were blunted. Coexpression analysis revealed a prominent population of club/goblet cells with high type 1/2 IFN responses that were important drivers of immune responses to infection in both healthy and COPD pBECs. Therapeutic inhibition of proteases and inflammatory imbalances reduced viral titers and cytokine responses, particularly in COPD pBECs. Conclusions: COPD pBECs are more susceptible to SARS-CoV-2 infection because of increases in coreceptor expression and protease imbalances and have greater inflammatory responses. A prominent cluster of IFN-responsive club/goblet cells emerges during infection, which may be important drivers of immunity. Therapeutic i...
Kapeleris, J, Ebrahimi Warkiani, M, Kulasinghe, A, Vela, I, Kenny, L, Ladwa, R, O’Byrne, K & Punyadeera, C 2022, 'Clinical Applications of Circulating Tumour Cells and Circulating Tumour DNA in Non-Small Cell Lung Cancer—An Update', Frontiers in Oncology, vol. 12, p. 859152.
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Despite efforts to improve earlier diagnosis of non-small cell lung cancer (NSCLC), most patients present with advanced stage disease, which is often associated with poor survival outcomes with only 15% surviving for 5 years from their diagnosis. Tumour tissue biopsy is the current mainstream for cancer diagnosis and prognosis in many parts of the world. However, due to tumour heterogeneity and accessibility issues, liquid biopsy is emerging as a game changer for both cancer diagnosis and prognosis. Liquid biopsy is the analysis of tumour-derived biomarkers in body fluids, which has remarkable advantages over the use of traditional tumour biopsy. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are two main derivatives of liquid biopsy. CTC enumeration and molecular analysis enable monitoring of cancer progression, recurrence, and treatment response earlier than traditional biopsy through a minimally invasive liquid biopsy approach. CTC-derived ex-vivo cultures are essential to understanding CTC biology and their role in metastasis, provide a means for personalized drug testing, and guide treatment selection. Just like CTCs, ctDNA provides opportunity for screening, monitoring, treatment evaluation, and disease surveillance. We present an updated review highlighting the prognostic and therapeutic significance of CTCs and ctDNA in NSCLC.
Kapeleris, J, Müller Bark, J, Ranjit, S, Irwin, D, Hartel, G, Warkiani, ME, Leo, P, O'Leary, C, Ladwa, R, O'Byrne, K, Hughes, BGM & Punyadeera, C 2022, 'Prognostic value of integrating circulating tumour cells and cell-free DNA in non-small cell lung cancer', Heliyon, vol. 8, no. 7, pp. e09971-e09971.
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BACKGROUND: Non-small cell lung cancer (NSCLC) often presents at an incurable stage, and majority of patients will be considered for palliative treatment at some point in their disease. Despite recent advances, the prognosis remains poor, with a median overall survival of 12-18 months. Liquid biopsy-based biomarkers have emerged as potential candidates for predicting prognosis and response to therapy in NSCLC patients. This pilot study evaluated whether combining circulating tumour cells and clusters (CTCs) and cell-free DNA (cfDNA) can predict progression-free survival (PFS) in NSCLC patients. METHODS: CTC and cfDNA/ctDNA from advanced stage NSCLC patients were measured at study entry (T0) and 3-months post-treatment (T1). CTCs were enriched using a spiral microfluidic chip and characterised by immunofluorescence. ctDNA was assessed using an UltraSEEK® Lung Panel. Kaplan-Meier plots were generated to investigate the contribution of the presence of CTC/CTC clusters and cfDNA for PFS. Cox proportional hazards analysis compared time to progression versus CTC/CTC cluster counts and cfDNA levels. RESULTS: Single CTCs were found in 14 out of 25 patients, while CTC clusters were found in 8 out of the 25 patients at T0. At T1, CTCs were found in 7 out of 18 patients, and CTC clusters in 1 out of the 18 patients. At T0, CTC presence and the combination of CTC cluster counts with cfDNA levels were associated with shorter PFS, p = 0.0261, p = 0.0022, respectively. CONCLUSIONS: Combining CTC cluster counts and cfDNA levels could improve PFS assessment in NSCLC patients. Our results encourage further investigation on the combined effect of CTC/cfDNA as a prognostic biomarker in a large cohort of advanced stage NSCLC patients.
Lan, T, Hutvagner, G, Zhang, X, Liu, T, Wong, L & Li, J 2022, 'Density-based detection of cell transition states to construct disparate and bifurcating trajectories', Nucleic Acids Research, vol. 50, no. 21, pp. e122-e122.
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Abstract Tree- and linear-shaped cell differentiation trajectories have been widely observed in developmental biologies and can be also inferred through computational methods from single-cell RNA-sequencing datasets. However, trajectories with complicated topologies such as loops, disparate lineages and bifurcating hierarchy remain difficult to infer accurately. Here, we introduce a density-based trajectory inference method capable of constructing diverse shapes of topological patterns including the most intriguing bifurcations. The novelty of our method is a step to exploit overlapping probability distributions to identify transition states of cells for determining connectability between cell clusters, and another step to infer a stable trajectory through a base-topology guided iterative fitting. Our method precisely re-constructed various benchmark reference trajectories. As a case study to demonstrate practical usefulness, our method was tested on single-cell RNA sequencing profiles of blood cells of SARS-CoV-2-infected patients. We not only re-discovered the linear trajectory bridging the transition from IgM plasmablast cells to developing neutrophils, and also found a previously-undiscovered lineage which can be rigorously supported by differentially expressed gene analysis.
Law, AMK, Chen, J, Colino‐Sanguino, Y, Fuente, LRDL, Fang, G, Grimes, SM, Lu, H, Huang, RJ, Boyle, ST, Venhuizen, J, Castillo, L, Tavakoli, J, Skhinas, JN, Millar, EKA, Beretov, J, Rossello, FJ, Tipper, JL, Ormandy, CJ, Samuel, MS, Cox, TR, Martelotto, L, Jin, D, Valdes‐Mora, F, Ji, HP & Gallego‐Ortega, D 2022, 'ALTEN: A High‐Fidelity Primary Tissue‐Engineering Platform to Assess Cellular Responses Ex Vivo', Advanced Science, vol. 9, no. 21, pp. e2103332-2103332.
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AbstractTo fully investigate cellular responses to stimuli and perturbations within tissues, it is essential to replicate the complex molecular interactions within the local microenvironment of cellular niches. Here, the authors introduce Alginate‐based tissue engineering (ALTEN), a biomimetic tissue platform that allows ex vivo analysis of explanted tissue biopsies. This method preserves the original characteristics of the source tissue's cellular milieu, allowing multiple and diverse cell types to be maintained over an extended period of time. As a result, ALTEN enables rapid and faithful characterization of perturbations across specific cell types within a tissue. Importantly, using single‐cell genomics, this approach provides integrated cellular responses at the resolution of individual cells. ALTEN is a powerful tool for the analysis of cellular responses upon exposure to cytotoxic agents and immunomodulators. Additionally, ALTEN's scalability using automated microfluidic devices for tissue encapsulation and subsequent transport, to enable centralized high‐throughput analysis of samples gathered by large‐scale multicenter studies, is shown.
Li, H, He, Z, Li, W, Li, JJ, Lin, J & Xing, D 2022, 'Self-assembled microtissues loaded with osteogenic MSCs for in vivo bone regeneration', Frontiers in Bioengineering and Biotechnology, vol. 10, p. 1069804.
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Bone regeneration strategies based on mesenchymal stem cell (MSC) therapy have received widespread attention. Although MSC incorporation into bone scaffolds can help with the repair process, a large number of studies demonstrate variable effects of MSCs with some noting that the inclusion of MSCs does not provide better outcomes compared to unseeded scaffolds. This may in part be related to low cell survival following implantation and/or limited ability to continue with osteogenic differentiation for pre-differentiated cells. In this study, we incorporated MSCs into gelatin microcryogels to form microtissues, and subjected these microtissues to osteogenic induction. We then mixed as-formed microtissues with those subjected to 6 days of osteogenic induction in different ratios, and investigated their ability to induce in vitro and in vivo osteogenesis during self-assembly. Using a full-thickness rat calvarial defect model, we found that undifferentiated and osteogenically induced microtissues mixed in a ratio of 2:1 produced the best outcomes of bone regeneration. This provides a new, customizable cell-based therapeutic strategy for in vivo repair of bone defects.
Li, JJ, Liu, H, Zhu, Y, Yan, L, Liu, R, Wang, G, Wang, B & Zhao, B 2022, 'Animal Models for Treating Spinal Cord Injury Using Biomaterials-Based Tissue Engineering Strategies', Tissue Engineering Part B: Reviews, vol. 28, no. 1, pp. 79-100.
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The aim of the study is to provide an up-to-date review of studies that used preclinical animal models for the evaluation of tissue engineering treatments for spinal cord injury (SCI), which involved the use of biomaterials with or without the addition of cells or biomolecules. Electronic search of the PubMed, Web of Science, and Embase databases was performed for relevant studies published between January 2009 and December 2019. In total, 1579 articles were retrieved, of which 58 studies were included for analysis. Among the included studies, rats were the most common species used for animal models of SCI, while complete transection was the most commonly used injury pattern. Immediate intervention after injury was conducted in the majority of studies, and 8 weeks was the most common final time point of outcome assessment. A wide range of natural and synthetic biomaterials with different morphologies were used as a part of tissue engineering treatments for SCI, including scaffolds, hydrogels, and particles. Experimental parameters in studies using SCI animal models to evaluate tissue engineering treatments should be carefully considered to match the purpose of the study. Biomaterials that have functional modifications or are applied in combination with cells and biomolecules can be effective in creating a permissive environment for SCI repair in preclinical animal models. Impact statement This review provides an up-to-date summary of the preclinical landscape where tissue engineering treatments involving biomaterials were tested in animal models of spinal cord injury (SCI). Using studies published within the last 10 years, novel perspectives were presented on the animal species used, injury pattern, timing of intervention and outcome measurement, and biomaterials selection, as well as a summary of the individual findings of each study. This review provides unique insight into biomaterials-based tissue engineering strategies that have progressed to testi...
Lukomskyj, AO, Rao, N, Yan, L, Pye, JS, Li, H, Wang, B & Li, JJ 2022, 'Stem Cell-Based Tissue Engineering for the Treatment of Burn Wounds: A Systematic Review of Preclinical Studies', Stem Cell Reviews and Reports, vol. 18, no. 6, pp. 1926-1955.
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AbstractBurn wounds are a devastating type of skin injury leading to severe impacts on both patients and the healthcare system. Current treatment methods are far from ideal, driving the need for tissue engineered solutions. Among various approaches, stem cell-based strategies are promising candidates for improving the treatment of burn wounds. A thorough search of the Embase, Medline, Scopus, and Web of Science databases was conducted to retrieve original research studies on stem cell-based tissue engineering treatments tested in preclinical models of burn wounds, published between January 2009 and June 2021. Of the 347 articles retrieved from the initial database search, 33 were eligible for inclusion in this review. The majority of studies used murine models with a xenogeneic graft, while a few used the porcine model. Thermal burn was the most commonly induced injury type, followed by surgical wound, and less commonly radiation burn. Most studies applied stem cell treatment immediately post-burn, with final endpoints ranging from 7 to 90 days. Mesenchymal stromal cells (MSCs) were the most common stem cell type used in the included studies. Stem cells from a variety of sources were used, most commonly from adipose tissue, bone marrow or umbilical cord, in conjunction with an extensive range of biomaterial scaffolds to treat the skin wounds. Overall, the studies showed favourable results of skin wound repair in animal models when stem cell-based tissue engineering treatments were applied, suggesting that such strategies hold promise as an improved therapy for burn wounds.Graphical abstract
Mahmud, MAP, Bazaz, SR, Dabiri, S, Mehrizi, AA, Asadnia, M, Warkiani, ME & Wang, ZL 2022, 'Advances in MEMS and Microfluidics‐Based Energy Harvesting Technologies', Advanced Materials Technologies, vol. 7, no. 7, pp. 2101347-2101347.
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AbstractEnergy harvesting from mechanical vibrations, thermal gradients, electromagnetic radiations, and solar radiations has experienced rapid progress in recent times not only to develop an alternative power source that can replace conventional batteries to energize portable and personal electronics smartly but also to achieve sustainable self‐sufficient micro/nanosystems. Utilizing micro‐electromechanical system (MEMS) and microfluidics technologies through selective designs and fabrications effectively, those energy harvesters can be considerably downsized while ensuring a stable, portable, and consistent power supply. Although ambient energy sources such as solar radiation are harvested for decades, recent developments have enabled ambient vibrations, electromagnetic radiation, and heat to be harvested wirelessly, independently, and sustainably. Developments in the field of microfluidics have also led to the design and fabrication of novel energy harvesting devices. This paper reviews the recent advancements in energy harvesting technologies such as piezoelectric, electromagnetic, electrostatic, thermoelectric, radio frequency, and solar to drive self‐powered portable electronics. Moreover, the potential application of MEMS and microfluidics as well as MEMS‐based structures and fabrication techniques for energy harvesting are summarized and presented. Finally, a few crucial challenges affecting the performance of energy harvesters are addressed.
Mathew, M, Rad, MA, Mata, JP, Mahmodi, H, Kabakova, IV, Raston, CL, Tang, Y, Tipper, JL & Tavakoli, J 2022, 'Hyperbranched polymers tune the physicochemical, mechanical, and biomedical properties of alginate hydrogels', Materials Today Chemistry, vol. 23, pp. 100656-100656.
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The current research aimed to fabricate an alginate-hyperbranched polymer (HBP) complex, using a vortex fluidic device (VFD), to control the physicochemical, structural, and mechanical properties of alginate hydrogel; thus, providing a dominant biomaterial system for different biomedical applications. Samples were prepared by mixing alginate (6%w/w) with HBP (0.85 μM) before cross-linking with Ca2+ (100 mM). Magnet stirrer (600 rpm) and VFD (6000 rpm) were used to prepare experimental samples, and alginate was used as control. Comprehensive evaluations of bulk and surface morphology, microstructural analysis, swelling kinetics, mechanical characteristics, cytotoxicity, and formation of hydrogen bonds were conducted. The findings from this study revealed that the addition of HBP to alginate structure led to a higher swelling capability (86%), increased diffusion coefficient (66-fold), and enhanced failure mechanical properties (160% and 20% increases for failure stress and elongation at break, respectively) than control. Traditional mixing affected the surface morphology, while the bulk structure remained unchanged. Moreover, the rate of degradation was not significantly different between alginate and alginate-HBP samples. When VFD was incorporated, a higher swelling ratio (30%) was observed than the control sample and the coefficient of diffusion increased (34-fold). The associated degradation rate increased 30-fold, and the failure stress and elongation at break were increased 310% and 83%, respectively, compared to the control sample. The micromixing of alginate with HBP under high shear stress using a VFD created a micro-hybrid composite formed by alginate microparticles embedded in an alginate sheet.
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 2022, 'Author Correction: Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization', Nature Immunology, vol. 23, no. 6, pp. 985-985.
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Mei, F, Li, J, Zhang, L, Gao, J, Li, H, Zhou, D, Xing, D & Lin, J 2022, 'Posterior-Stabilized Versus Cruciate-Retaining Prostheses for Total Knee Arthroplasty: An Overview of Systematic Reviews and Risk of Bias Considerations', Indian Journal of Orthopaedics, vol. 56, no. 11, pp. 1858-1870.
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BACKGROUND: Numerous systematic reviews have been published comparing the outcomes of patients undergoing posterior stabilized (PS) versus cruciate-retaining (CR) procedures in total knee arthroplasty (TKA), but with some overlaps and contradictions. The objectives of this study were (1) to perform an overview of current systematic reviews comparing PS versus CR in TKA, by evaluating their methodological quality and risk of bias, and (2) to provide recommendations through the best evidence. METHODS: A systematic search of systematic reviews comparing PS and CR in TKA, published until June 2021 was conducted using the MEDLINE, EMBASE, and Cochrane Library databases. Included systematic reviews were assessed for methodological quality and risk of bias by the AMSTAR2 instrument and ROBIS tool, respectively. The choice of best evidence was conducted according to the Jadad decision algorithm. RESULTS: A total of eight systematic reviews were eligible for inclusion in this study. The Jadad decision algorithm suggested that reviews with the highest AMSTAR2 scores should be selected. According to the ROBIS tool, there were three reviews with a low risk of bias and five with a high risk of bias. Consequently, one systematic review conducted by Verra et al. with the highest AMSTAR2 score and low risk of bias was selected as the best evidence. CONCLUSIONS: Although current systematic reviews demonstrated some statistical differences in clinical presentation and functional outcomes between PS and CR, the current outcome indicators cannot be taken to provide recommendations for undergoing PS or CR. The decision for prosthesis selection could be made mostly based on the surgeon's preference, indications and other indicators.
Mei, F, Li, J, Zhang, L, Gao, J, Wang, B, Zhou, Q, Xu, Y, Zhou, C, Zhao, J, Li, P, Zhao, Y, Yuan, T, Fu, W, Li, C, Jin, Y, Yang, P, Xing, D & Lin, J 2022, 'Preference of Orthopedic Practitioners Toward the Use of Topical Medicine for Musculoskeletal Pain Management in China: A National Survey', Orthopaedic Surgery, vol. 14, no. 10, pp. 2470-2479.
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ObjectiveMusculoskeletal pain is having growing impacts worldwide with clinical challenge in pain management. The purpose of the present study is to investigate the preferences of orthopedic surgeons of China for using medicine in musculoskeletal pain.MethodsA questionnaire was developed, including the following domains, personal information, medication preference for pain treatment, and perceptions of topical medicine. Ten participants were selected to confirm the consistency of questionnaire. A cross‐sectional survey was conducted in orthopedic physicians with different specialties in different regions of China via the online survey platform. The participants' survey results were analyzed one‐way and multi‐way using chi‐square test and logistic regression.ResultsThe pre‐survey analysis results of 10 randomly selected investigators were a mean weighted kappa coefficient of 0.76 (range 0.61–0.89), which indicated the substantial consistency of the present questionnaire. A total of 1099 orthopedic surgeons (mean age, 41.67 ± 8.31 years) responded to our survey, most of whom were male (90.72%), and most of whom worked in level III hospitals (63.24%) and trained in modern medicine (71.43%). Most surgeons who participated in the survey had used topical analgesics in their clinical work (95.81%), and most preferred to use topical analgesics (39.50%) or a combination of oral analgesics (28.87%). Primary reasons for preferring topical analgesics were as follows: less adverse reactions (68.01%); ease of use (60.90%); and not interfering with other oral medications (49.60%). The preference for prescribing topical analgesics increased with the education level of the respondent, where statistically significant differences were seen (P < 0.05)...
Miri-Lavasani, Z, Torabi, S, Solhi, R, Shokouhian, B, Afsharian, P, Heydari, Z, Piryaei, A, Farzaneh, Z, Hossein-khannazer, N, Es, HA, Zahmatkesh, E, Nussler, A, Hassan, M, Najimi, M & Vosough, M 2022, 'Conjugated Linoleic Acid Treatment Attenuates Cancerous features in Hepatocellular Carcinoma Cells', Stem Cells International, vol. 2022, pp. 1-14.
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Background. A growing number of hepatocellular carcinoma (HCC), and recurrence frequency recently have drawn researchers’ attention to alternative approaches. The concept of differentiation therapies (DT) relies on inducing differentiation in HCC cells in order to inhibit recurrence and metastasis. Hepatocyte nuclear factor 4 alpha (HNF4α) is the key hepatogenesis transcription factor and its upregulation may decrease the invasiveness of cancerous cells by suppressing epithelial-mesenchymal transition (EMT). This study aimed to evaluate the effect of conjugated linoleic acid (CLA) treatment, natural ligand of HNF4α, on the proliferation, migration, and invasion capacities of HCC cells in vitro. Materials and Method. Sk-Hep-1 and Hep-3B cells were treated with different doses of CLA or BIM5078 [1-(2 -chloro-5 -nitrobenzenesulfonyl)−2-methylbenzimidazole], an HNF4α antagonist. The expression levels of HNF4a and EMT related genes were evaluated and associated to hepatocytic functionalities, migration, and colony formation capacities, as well as to viability and proliferation rate of HCC cells. Results. In both HCC lines, CLA treatment induced HNF4α expression in parallel to significantly decreased EMT marker levels, migration, colony formation capacity, and proliferation rate, whereas BIM5078 treatment resulted in the opposite effects. Moreover, CLA supplementation also upregulated ALB, ZO1, and HNF4α proteins as well as glycogen storage capacity in the treated HCC cells. Conclusion. CLA treatment can induce a remarkable hepatocytic differentiation...
Moradi, S, Kamal, A, Aboulkheyr Es, H, Farhadi, F, Ebrahimi, M, Chitsaz, H, Sharifi-Zarchi, A & Baharvand, H 2022, 'Pan-cancer analysis of microRNA expression profiles highlights microRNAs enriched in normal body cells as effective suppressors of multiple tumor types: A study based on TCGA database', PLOS ONE, vol. 17, no. 4, pp. e0267291-e0267291.
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BackgroundMicroRNAs (miRNAs) are frequently deregulated in various types of cancer. While antisense oligonucleotides are used to block oncomiRs, delivery of tumour-suppressive miRNAs holds great potential as a potent anti-cancer strategy. Here, we aim to determine, and functionally analyse, miRNAs that are lowly expressed in various types of tumour but abundantly expressed in multiple normal tissues.MethodsThe miRNA sequencing data of 14 cancer types were downloaded from the TCGA dataset. Significant differences in miRNA expression between tumor and normal samples were calculated using limma package (R programming). An adjusted p value < 0.05 was used to compare normal versus tumor miRNA expression profiles. The predicted gene targets were obtained using TargetScan, miRanda, and miRDB and then subjected to gene ontology analysis using Enrichr. Only GO terms with an adjusted p < 0.05 were considered statistically significant. All data from wet-lab experiments (cell viability assays and flow cytometry) were expressed as means ± SEM, and their differences were analyzed using GraphPad Prism software (Student’s t test, p < 0.05).ResultsBy compiling all publicly available miRNA profiling data from The Cancer Genome Atlas (TCGA) Pan-Cancer Project, we reveal a small set of tumour-suppressing miRNAs (which we designate as ’normomiRs’) that are highly expressed in 14 types of normal tissues but poorly expressed in corresponding tumour tissues. Interestingly, muscle-enriched miRNAs (e.g. miR-133a/b and miR-206) and miRNAs from DLK1-DIO3 locus (e...
Morshedi Rad, D, Rezaei, M, Radfar, P & Ebrahimi Warkiani, M 2022, 'Microengineered filters for efficient delivery of nanomaterials into mammalian cells', Scientific Reports, vol. 12, no. 1, p. 4383.
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AbstractIntracellular delivery of nanomaterials into the cells of interest has enabled cell manipulation for numerous applications ranging from cell-based therapies to biomedical research. To date, different carriers or membrane poration-based techniques have been developed to load nanomaterials to the cell interior. These biotools have shown promise to surpass the membrane barrier and provide access to the intracellular space followed by passive diffusion of exogenous cargoes. However, most of them suffer from inconsistent delivery, cytotoxicity, and expensive protocols, somewhat limiting their utility in a variety of delivery applications. Here, by leveraging the benefits of microengineered porous membranes with a suitable porosity, we demonstrated an efficient intracellular loading of diverse nanomaterials to different cell types based on inducing mechanical disruption to the cell membrane. In this work, for the first time, we used ultra-thin silicon nitride (SiN) filter membranes with uniform micropores smaller than the cell diameter to load impermeable nanomaterials into adherent and non-adherent cell types. The delivery performance using SiN microsieves has been validated through the loading of functional nanomaterials from a few nanometers to hundreds of nanometers into mammalian cells with minimal undesired impacts. Besides the high delivery efficiency and improved cell viability, this simple and low-cost approach offers less clogging and higher throughput (107 cell min−1). Therefore, it yields to the efficient introduction of exogenous nanomaterials into the large population of cells, illustrating the potential of these microengineered filters to be widely used in the microfiltroporation (MFP) setup.
Nazari, H, Heirani-Tabasi, A, Esmaeili, E, Kajbafzadeh, A-M, Hassannejad, Z, Boroomand, S, Shahsavari Alavijeh, MH, Mishan, MA, Ahmadi Tafti, SH, Warkiani, ME & Dadgar, N 2022, 'Decellularized human amniotic membrane reinforced by MoS2-Polycaprolactone nanofibers, a novel conductive scaffold for cardiac tissue engineering', Journal of Biomaterials Applications, vol. 36, no. 9, pp. 1527-1539.
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In order to regenerate myocardial tissues with functional characteristics, we need to copy some properties of the myocardium, such as its extracellular matrix and electrical conductivity. In this study, we synthesized nanosheets of Molybdenum disulfide (MoS2), and integrated them into polycaprolactone (PCL) and electrospun on the surface of decellularized human amniotic membrane (DHAM) with the purpose of improving the scaffolds mechanical properties and electrical conductivity. For in vitro studies, we seeded the mouse embryonic cardiac cells, mouse Embryonic Cardiac Cells (mECCs), on the scaffolds and then studied the MoS2nanocomposites by scanning electron microscopy and Raman spectroscopy. In addition, we characterized the DHAM/PCL and DHAM/PCL-MoS2by SEM, transmission electron microscopy, water contact angle measurement, electrical conductivity, and tensile test. Besides, we confirmed the scaffolds are biocompatible by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT assay. Furthermore, by means of SEM images, it was shown that mECCs attached to the DHAM/PCL-MoS2scaffold have more cell aggregations and elongated morphology. Furthermore, through the Real-Time PCR and immunostaining studies, we found out cardiac genes were maturated and upregulated, and they also included GATA-4, c-TnT, NKX 2.5, and alpha-myosin heavy chain in cells cultured on DHAM/PCL-MoS2scaffold in comparison to DHAM/PCL and DHAM. Therefore, in terms of cardiac tissue engineering, DHAM nanofibrous scaffolds reinforced by PCL-MoS2can be suggested as a proper candidate.
Nazari, H, Heirani-Tabasi, A, Ghorbani, S, Eyni, H, Razavi Bazaz, S, Khayati, M, Gheidari, F, Moradpour, K, Kehtari, M, Ahmadi Tafti, SM, Ahmadi Tafti, SH & Ebrahimi Warkiani, M 2022, 'Microfluidic-Based Droplets for Advanced Regenerative Medicine: Current Challenges and Future Trends', Biosensors, vol. 12, no. 1, pp. 20-20.
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Microfluidics is a promising approach for the facile and large-scale fabrication of monodispersed droplets for various applications in biomedicine. This technology has demonstrated great potential to address the limitations of regenerative medicine. Microfluidics provides safe, accurate, reliable, and cost-effective methods for encapsulating different stem cells, gametes, biomaterials, biomolecules, reagents, genes, and nanoparticles inside picoliter-sized droplets or droplet-derived microgels for different applications. Moreover, microenvironments made using such droplets can mimic niches of stem cells for cell therapy purposes, simulate native extracellular matrix (ECM) for tissue engineering applications, and remove challenges in cell encapsulation and three-dimensional (3D) culture methods. The fabrication of droplets using microfluidics also provides controllable microenvironments for manipulating gametes, fertilization, and embryo cultures for reproductive medicine. This review focuses on the relevant studies, and the latest progress in applying droplets in stem cell therapy, tissue engineering, reproductive biology, and gene therapy are separately evaluated. In the end, we discuss the challenges ahead in the field of microfluidics-based droplets for advanced regenerative medicine.
Nguyen, TV 2022, 'Personalised assessment of fracture risk: Which tool to use?', Australian Journal of General Practice, vol. 51, no. 3, pp. 189-190.
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Papanicolaou, M, Parker, AL, Yam, M, Filipe, EC, Wu, SZ, Chitty, JL, Wyllie, K, Tran, E, Mok, E, Nadalini, A, Skhinas, JN, Lucas, MC, Herrmann, D, Nobis, M, Pereira, BA, Law, AMK, Castillo, L, Murphy, KJ, Zaratzian, A, Hastings, JF, Croucher, DR, Lim, E, Oliver, BG, Mora, FV, Parker, BL, Gallego-Ortega, D, Swarbrick, A, O’Toole, S, Timpson, P & Cox, TR 2022, 'Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis', Nature Communications, vol. 13, no. 1, p. 4587.
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AbstractThe tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.
Paudel, KR, Patel, V, Vishwas, S, Gupta, S, Sharma, S, Chan, Y, Jha, NK, Shrestha, J, Imran, M, Panth, N, Shukla, SD, Jha, SK, Devkota, HP, Warkiani, ME, Singh, SK, Ali, MK, Gupta, G, Chellappan, DK, Hansbro, PM & Dua, K 2022, 'Nutraceuticals and COVID‐19: A mechanistic approach toward attenuating the disease complications', Journal of Food Biochemistry, vol. 46, no. 12, p. e14445.
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Nutraceuticals have emerged as potential compounds to attenuate the COVID-19 complications. Precisely, these food additives strengthen the overall COVID treatment and enhance the immunity of a person. Such compounds have been used at a large scale, in almost every household due to their better affordability and easy access. Therefore, current research is focused on developing newer advanced formulations from potential drug candidates including nutraceuticals with desirable properties viz, affordability, ease of availability, ease of administration, stability under room temperature, and potentially longer shelf-lives. As such, various nutraceutical-based products such as compounds could be promising agents for effectively managing COVID-19 symptoms and complications. Most importantly, regular consumption of such nutraceuticals has been shown to boost the immune system and prevent viral infections. Nutraceuticals such as vitamins, amino acids, flavonoids like curcumin, and probiotics have been studied for their role in the prevention of COVID-19 symptoms such as fever, pain, malaise, and dry cough. In this review, we have critically reviewed the potential of various nutraceutical-based therapeutics for the management of COVID-19. We searched the information relevant to our topic from search engines such as PubMed and Scopus using COVID-19, nutraceuticals, probiotics, and vitamins as a keyword. Any scientific literature published in a language other than English was excluded. PRACTICAL APPLICATIONS: Nutraceuticals possess both nutritional values and medicinal properties. They can aid in the prevention and treatment of diseases, as well as promote physical health and the immune system, normalizing body functions, and improving longevity. Recently, nutraceuticals such as probiotics, vitamins, polyunsaturated fatty acids, trace minerals, and medicinal plants have attracted considerable attention and are widely regarded as potential alternatives to current the...
Pham, DX, Phung, AHT, Nguyen, HD, Bui, TD, Mai, LD, Tran, BNH, Tran, TS, Nguyen, TV & Ho-Pham, LT 2022, 'Trends in colorectal cancer incidence in Ho Chi Minh City, Vietnam (1996–2015): Joinpoint regression and age–period–cohort analyses', Cancer Epidemiology, vol. 77, pp. 102113-102113.
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BACKGROUND: Little is known about the trends in colorectal cancer (CRC) in Vietnam. We aimed to investigate the trends in epidemiology and anatomical subsites of CRC in Ho Chi Minh City, Vietnam. METHODS: Based on the Ho Chi Minh City Cancer Registry data during 1996-2015, we calculated the average annual percent changes (AAPCs) of the age-standardized incidence rates (ASRs) by sex, age groups, and anatomical subsites, using joinpoint regressions analysis. We further performed age-period-cohort (APC) analysis using the United States National Cancer Institute's web-based statistical tool to explore the underlying reason for the incidence trend. RESULTS: Over 20 years the overall ASR of CRC increased from 10.5 to 17.9 per 100,000, a 1.7-fold increase. CRC incidence elevated more rapidly in men (AAPC 4.7, 95%CI 2.2-7.3) than in women (AAPC 2.6, 95%CI 0.6-4.8). The highest and lowest increasing rates of ASRs were observed in the 50-64-year-old age group (AAPC 5.3, 95%CI 2.8-7.9) and < 50-year-old age group (AAPC 1.1, 95%CI -0.7 to 2.9), respectively. Regarding subsites, rectal cancer had the highest rate of increase (AAPC 3.3, 95%CI 1.0-5.7). Furthermore, the APC analysis indicated significant increases in CRC incidence in birth cohorts after 1975 in both genders. CONCLUSIONS: The CRC incidence in Ho Chi Minh City increased, with the more prominent rates being among men and older populations, in rectal subsites, and in people born after 1975. The upward trend of CRC incidence in Ho Chi Minh City may be due to the adoption of a westernized lifestyle.
Rad, HS, Shiravand, Y, Radfar, P, Ladwa, R, Perry, C, Han, X, Warkiani, ME, Adams, MN, Hughes, BGM, O'Byrne, K & Kulasinghe, A 2022, 'Understanding the tumor microenvironment in head and neck squamous cell carcinoma', Clinical & Translational Immunology, vol. 11, no. 6, p. e1397.
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AbstractHead and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5‐year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease. However, not all HNSCC tumors respond to immune checkpoint blockade therapy. Understanding the complex cellular composition and interactions of the tumor microenvironment is likely to lead to new knowledge for effective therapies and treatment resistance. In this review, we discuss HNSCC characteristics, predictive biomarkers, factors influencing immunotherapy response, with a focus on the tumor microenvironment.
Rad, MA, Mahmodi, H, Filipe, EC, Cox, TR, Kabakova, I & Tipper, JL 2022, 'Micromechanical characterisation of 3D bioprinted neural cell models using Brillouin microspectroscopy', Bioprinting, vol. 25, pp. e00179-e00179.
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Biofabrication of three-dimensional (3D) in vitro neural cell models that closely mimic the central nervous system (CNS) is an emerging field of research with applications from fundamental biology to regenerative medicine, and far reaching benefits for the economy, healthcare and the ethical use of animals. The micromechanical properties of such models are an important factor dictating the success of modelling outcomes in relation to accurate reproduction of the processes in native tissues. Characterising the micromechanical properties of such models non-destructively and over a prolonged span of time, however, are key challenges. Brillouin microspectroscopy (BM) could provide a solution to this problem since this technology is non-invasive, label-free and is capable of micro-scale 3D imaging. In this work, the micromechanical properties of 3D bioprinted neural cell models consisting of NG 108-15 neuronal cells and Gelatin methacryloyl (GelMA) hydrogels of various concentrations were investigated using BM. We demonstrate changes in the volume-averaged (VA) and local micro-scale mechanical properties of these models over a 7 day period, in which the hydrogel component of the model are found to soften as the cells grow, multiply and form stiffer spheroid-type structures. These findings signify the necessity to resolve in microscopic detail the mechanics of in vitro 3D tissue models and suggest Brillouin microspectroscopy to be a suitable technology to bridge this gap.
Radfar, P, Aboulkheyr Es, H, Salomon, R, Kulasinghe, A, Ramalingam, N, Sarafraz-Yazdi, E, Thiery, JP & Warkiani, ME 2022, 'Single-cell analysis of circulating tumour cells: enabling technologies and clinical applications', Trends in Biotechnology, vol. 40, no. 9, pp. 1041-1060.
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Multimodal analysis of circulating tumour cells (CTCs) has the potential to provide remarkable insight for cancer development and metastasis. CTCs and CTC clusters investigation using single-cell analysis, enables researchers to gain crucial information on metastatic mechanisms and the genomic alterations responsible for drug resistance, empowering treatment, and management of cancer. Despite a plethora of CTC isolation technologies, careful attention to the strengths and weaknesses of each method should be considered in order to isolate these rare cells. Here, we provide an overview of cutting-edge technologies used for single-cell isolation and analysis of CTCs. Additionally, we highlight the biological features, clinical application, and the therapeutic potential of CTCs and CTC clusters using single-cell analysis platforms for cancer management.
Ramakrishna, VAS, Chamoli, U, Larosa, AG, Mukhopadhyay, SC, Prusty, BG & Diwan, AD 2022, 'Finite element modeling of temporal bone graft changes in XLIF: Quantifying biomechanical effects at adjacent levels', Journal of Orthopaedic Research, vol. 40, no. 6, pp. 1420-1435.
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AbstractExtreme lateral interbody fusion allows for the insertion of a large‐footprint interbody cage while maintaining the presence of natural stabilizing ligaments and the facets. It is unclear how the load‐distribution mechanisms through these structures alter with temporal changes in the bone graft. The aim of this study was to examine the effects of temporal bone graft changes on load distribution among the cage, graft, and surrounding spinal structures using finite element analysis. Thoracolumbosacral spine computed tomography data from an asymptomatic male subject were segmented into anatomical regions of interest and digitally stitched to generate a surface mesh of the lumbar spine (L1‐S1). The interbody cage was inserted into the L4‐L5 region during surface meshing. A volumetric mesh was generated and imported into finite element software for pre‐processing, running nonlinear static solves, and post‐processing. Temporal stiffening was simulated in the graft region with unbonded (Soft Callus, Temporal Stages 1–3, Solid Graft) and bonded (Partial Fusion, Full Fusion) contact. In flexion and extension, cage stress reduced by 20% from the soft callus to solid graft state. Force on the graft was directly related to its stiffness, and load‐share between the cage and graft improved with increasing graft stiffness, regardless of whether contact was fused with the endplates. Fused contact between the cage‐graft complex and the adjacent endplates shifted load‐distribution pathways from the ligaments and facets to the implant, however, these changes did not extend to adjacent levels. These results suggest that once complete fusion is achieved, the existing load paths are seemingly diminished.
Rao, A, Elder, E, Center, JR, Tran, T, Pocock, N & Elder, GJ 2022, 'Improving Bone Mineral Density Screening by Using Digital X‐Radiogrammetry Combined With Mammography', JBMR Plus, vol. 6, no. 5.
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ABSTRACTFracture risk evaluation of postmenopausal women is suboptimal, but most women undergo screening mammography. Digital X‐radiogrammetry (DXR) determines bone mineral density (BMD) at the metacarpal shaft and can be performed on mammography equipment. This study examined correlations between DXR and dual‐energy X‐ray absorptiometry (DXA) in women undergoing mammography, to identify optimal DXR thresholds for triage to osteoporosis screening by central DXA. Postmenopausal women over age 50 years, recruited from Westmead Hospital's Breast Cancer Institute, underwent mammography, DXR and DXA. Agreements were determined using the area under the receiver operator characteristic (AUC ROC) curve and Lin's concordance correlation coefficient. Optimal DXR T‐scores to exclude osteoporosis by DXA were determined using the Youden's method. Of 200 women aged 64 ± 7 years (mean ± standard deviation [SD]), 82% had been diagnosed with breast cancer and 37% reported prior fracture. DXA T‐scores were ≤ −1 at the spine, hip or forearm in 77.5% and accorded with DXR T‐scores in 77%. For DXR and DXA T‐scores ≤ −2.5, the AUC ROC was 0.87 (95% confidence interval [CI], 0.81–0.94) at the 1/3 radius, and 0.74 (95% CI, 0.64–0.84) for hip or spine. DXR T‐scores > −1.98 provided a negative predictive value of 94% (range, 88%, 98%) for osteoporosis by central DXA. In response to a questionnaire, radiography staff responded that DXR added 5 minutes to patient throughput with minimal workflow impact. In the mammography setting, triaging women with a screening DXR T‐score < −1.98 for DXA evaluation would capture a significant proportion of at‐risk women who may not otherwise be identified and improve current low rates of osteoporosis screening. © 2022 The Authors. JBMR...
Razavi Bazaz, S, Mihandust, A, Salomon, R, Joushani, HAN, Li, W, A. Amiri, H, Mirakhorli, F, Zhand, S, Shrestha, J, Miansari, M, Thierry, B, Jin, D & Ebrahimi Warkiani, M 2022, 'Zigzag microchannel for rigid inertial separation and enrichment (Z-RISE) of cells and particles', Lab on a Chip, vol. 22, no. 21, pp. 4093-4109.
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Overview of the zigzag microchannel for rigid inertial separation and enrichment (Z-RISE). The proposed device has superior performance for particle focusing and separation.
Rzhevskiy, AS, Kapitannikova, AY, Butnaru, DV, Shpot, EV, Joosse, SA, Zvyagin, AV & Ebrahimi Warkiani, M 2022, 'Liquid Biopsy in Diagnosis and Prognosis of Non-Metastatic Prostate Cancer', Biomedicines, vol. 10, no. 12, pp. 3115-3115.
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Currently, sensitive and specific methods for the detection and prognosis of early stage PCa are lacking. To establish the diagnosis and further identify an appropriate treatment strategy, prostate specific antigen (PSA) blood test followed by tissue biopsy have to be performed. The combination of tests is justified by the lack of a highly sensitive, specific, and safe single test. Tissue biopsy is specific but invasive and may have severe side effects, and therefore is inappropriate for screening of the disease. At the same time, the PSA blood test, which is conventionally used for PCa screening, has low specificity and may be elevated in the case of noncancerous prostate tumors and inflammatory conditions, including benign prostatic hyperplasia and prostatitis. Thus, diverse techniques of liquid biopsy have been investigated to supplement or replace the existing tests of prostate cancer early diagnosis and prognostics. Here, we provide a review on the advances in diagnosis and prognostics of non-metastatic prostate cancer by means of various biomarkers extracted via liquid biopsy, including circulating tumor cells, exosomal miRNAs, and circulating DNAs.
Rzhevskiy, AS, Kapitannikova, AY, Vasilescu, SA, Karashaeva, TA, Razavi Bazaz, S, Taratkin, MS, Enikeev, DV, Lekarev, VY, Shpot, EV, Butnaru, DV, Deyev, SM, Thiery, JP, Zvyagin, AV & Ebrahimi Warkiani, M 2022, 'Isolation of Circulating Tumor Cells from Seminal Fluid of Patients with Prostate Cancer Using Inertial Microfluidics', Cancers, vol. 14, no. 14, pp. 3364-3364.
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Prostate cancer (PCa) diagnosis is primarily based on prostate-specific antigen (PSA) testing and prostate tissue biopsies. However, PSA testing has relatively low specificity, while tissue biopsies are highly invasive and have relatively low sensitivity at early stages of PCa. As an alternative, we developed a technique of liquid biopsy, based on isolation of circulating tumor cells (CTCs) from seminal fluid (SF). The recovery of PCa cells from SF was demonstrated using PCa cell lines, achieving an efficiency and throughput as high as 89% (±3.8%) and 1.7 mL min−1, respectively, while 99% (±0.7%) of sperm cells were disposed of. The introduced approach was further tested in a clinical setting by collecting and processing SF samples of PCa patients. The yield of isolated CTCs measured as high as 613 cells per SF sample in comparison with that of 6 cells from SF of healthy donors, holding significant promise for PCa diagnosis. The correlation analysis of the isolated CTC numbers with the standard prognostic parameters such as Gleason score and PSA serum level showed correlation coefficient values at 0.40 and 0.73, respectively. Taken together, our results show promise in the developed liquid biopsy technique to augment the existing diagnosis and prognosis of PCa.
Salis, Z, Keen, H, Gallego, B, Nguyen, TV & Sainsbury-Salis, A 2022, 'OP0227 WEIGHT LOSS IS ASSOCIATED WITH REDUCED INCIDENCE AND PROGRESSION OF STRUCTURAL DEFECTS IN KNEE OSTEOARTHRITIS, AS ASSESSED BY RADIOGRAPHY OVER 4 TO 5 YEARS: A PROSPECTIVE MULTI-COHORT STUDY', Annals of the Rheumatic Diseases, vol. 81, no. Suppl 1, pp. 149.2-150.
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BackgroundOverweight and obesity are associated with greater incidence and progression of the structural defects of knee osteoarthritis, but it is unknown if weight loss is of benefit.ObjectivesTo describe the association between change in body mass index (BMI) and the incidence and progression of structural defects in knee osteoarthritis.MethodsScores from radiographic analyses of knees at baseline and at 4 to 5 years’ follow up were obtained from three independent data sets (the OAI and MOST data sets from the United States from America, and the CHECK data set from the Netherlands). The exposure of interest was change in BMI from baseline to 4 to 5 years’ follow up. To investigate the incidence of structural defects of knee osteoarthritis, we selected a total of 9732 knees (from 5802 participants) that had a Kellgren-Lawrence (KL) grade of knee osteoarthritis at baseline of ‘none’ (0) or ‘doubtful’ (1) (the ‘incidence cohort’), and determined the odds of having a KL grade at follow-up of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4). To investigate progression, we selected a total of 6084 knees (from 3996 participants) that had a KL grade at baseline of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4) (the ‘progression cohort’), and determined the odds of increasing by 1 or more KL grades by follow up. The degradation of three individual structural features of knee osteoarthritis (i.e., joint space narrowing, osteophytes on the femoral surface, and osteophytes on the tibial surface), on both the medial and lateral sides of the knee, were also investigated in both the incidence and progression cohorts. Here, degradation was defined as an increase by 1 or more Osteoarthritis Research Society International (OARSI) grades.Results
Sharma, P, Beck, D, Murtha, LA, Figtree, G, Boyle, A & Gentile, C 2022, 'Fibulin-3 Deficiency Protects Against Myocardial Injury Following Ischaemia/ Reperfusion in in vitro Cardiac Spheroids', Frontiers in Cardiovascular Medicine, vol. 9, p. 913156.
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Myocardial infarction (MI, or heart attack) is a leading cause of death worldwide. Myocardial ischaemia reperfusion (I/R) injury typical of MI events is also associated with the development of cardiac fibrosis and heart failure in patients. Fibulin-3 is an extracellular matrix component that plays a role in regulating MI response in the heart. In this study, we generated and compared in vitro cardiac spheroids (CSs) from wild type (WT) and fibulin-3 knockout (Fib-3 KO) mice. These were then exposed to pathophysiological changes in oxygen (O2) concentrations to mimic an MI event. We finally measured changes in contractile function, cell death, and mRNA expression levels of cardiovascular disease genes between WT and Fib-3 KO CSs. Our results demonstrated that there are significant differences in growth kinetics and endothelial network formation between WT and Fib-3 KO CSs, however, they respond similarly to changes in O2 concentrations. Fib-3 deficiency resulted in an increase in viability of cells and improvement in contraction frequency and fractional shortening compared to WT I/R CSs. Gene expression analyses demonstrated that Fib-3 deficiency inhibits I/R injury and cardiac fibrosis and promotes angiogenesis in CSs. Altogether, our findings suggest that Fib-3 deficiency makes CSs resistant to I/R injury and associated cardiac fibrosis and helps to improve the vascular network in CSs.
Sharma, P, Liu Chung Ming, C & Gentile, C 2022, 'In vitro modeling of myocardial ischemia/reperfusion injury with murine or human 3D cardiac spheroids', STAR Protocols, vol. 3, no. 4, pp. 101751-101751.
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Myocardial infarction (MI) is the primary cause of death worldwide, but there are no clinically relevant models to study MI. Here, we describe an ischemia/reperfusion (I/R) injury model typical of MI using mouse or human 3D in vitro cardiac spheroids (CSs). First, we demonstrated the culture and maintenance of CSs. Then, we detailed how to expose CSs to pathophysiological oxygen concentrations to induce I/R injury. The protocol can be used in combination with viability, contractility, and mRNA expression level measurements. For complete details on the use and execution of this protocol, please refer to Sharma et al. (2022).
Sharma, P, Liu Chung Ming, C, Wang, X, Bienvenu, LA, Beck, D, Figtree, G, Boyle, A & Gentile, C 2022, 'Biofabrication of advanced in vitro 3D models to study ischaemic and doxorubicin-induced myocardial damage', Biofabrication, vol. 14, no. 2, pp. 025003-025003.
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Abstract Current preclinical in vitro and in vivo models of cardiac injury typical of myocardial infarction (MI, or heart attack) and drug induced cardiotoxicity mimic only a few aspects of these complex scenarios. This leads to a poor translation of findings from the bench to the bedside. In this study, we biofabricated for the first time advanced in vitro models of MI and doxorubicin (DOX) induced injury by exposing cardiac spheroids (CSs) to pathophysiological changes in oxygen (O2) levels or DOX treatment. Then, contractile function and cell death was analyzed in CSs in control verses I/R and DOX CSs. For a deeper dig into cell death analysis, 3D rendering analyses and mRNA level changes of cardiac damage-related genes were compared in control verses I/R and DOX CSs. Overall, in vitro CSs recapitulated major features typical of the in vivo MI and drug induced cardiac damages, such as adapting intracellular alterations to O2 concentration changes and incubation with cardiotoxic drug, mimicking the contraction frequency and fractional shortening and changes in mRNA expression levels for genes regulating sarcomere structure, calcium transport, cell cycle, cardiac remodelling and signal transduction. Taken together, our study supports the use of I/R and DOX CSs as advanced in vitro models to study MI and DOX-induced cardiac damge by recapitulating their complex in vivo scenario.
Sheu, A, Bliuc, D, Tran, T, White, CP & Center, JR 2022, 'Fractures in type 2 diabetes confer excess mortality: The Dubbo osteoporosis epidemiology study', Bone, vol. 159, pp. 116373-116373.
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PURPOSE: Diabetes and fractures are both associated with increased mortality, however the effect of the combination is not well-established. We examined the mortality risk following all types of fractures in type 2 diabetes (T2D). METHODS: In the Dubbo Osteoporosis Epidemiology Study (1989-2017), participants were grouped according to T2D and/or incident fracture. Study outcome was all-cause mortality. First incident radiological fragility fracture and incident T2D diagnosis were time-dependent variables. Cox's proportional hazards models quantified mortality risk associated with T2D and incident fracture overall, as well as by fracture site, T2D duration and T2D medication type. RESULTS: In 3618 participants (62% women), 272 had baseline and 179 developed T2D over median 13.0 years (IQR 8.2-19.6). 796 women (56 with T2D) and 240 men (25 with T2D) sustained a fracture. Compared to those without T2D or fracture, mortality risk increased progressively, in T2D without fracture, then no T2D with fracture, and was highest in those with T2D with fracture (adjusted hazard ratio (aHR) (95% CI) for women 2.62 (1.75-3.93) and men 2.61 (1.42-4.81)). Within T2D participants, incident fracture was associated with increased mortality (aHR for women 1.87 (1.10-3.16) and men 2.83 (1.41-5.68)), especially following hip/vertebral fractures in men (aHR 2.97 (1.29-6.83)) and non-hip non-vertebral fractures in women (aHR 2.42 (1.24-4.75)), and in T2D duration >5 years. CONCLUSION: Any fracture in T2D conferred significant excess mortality. Individuals with T2D should be carefully monitored post-fracture, especially if T2D >5 years. Optimising fracture prevention and post-fracture management in T2D is critical and warrants further studies.
Shi, J, Fan, K, Yan, L, Fan, Z, Li, F, Wang, G, Liu, H, Liu, P, Yu, H, Li, JJ & Wang, B 2022, 'Cost Effectiveness of Pharmacological Management for Osteoarthritis: A Systematic Review', Applied Health Economics and Health Policy, vol. 20, no. 3, pp. 351-370.
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BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a highly prevalent, disabling disease requiring chronic management that is associated with an enormous individual and societal burden. This systematic review provides a global cost-effectiveness evaluation of pharmacological therapy for the management of OA. METHODS: Following Center for Reviews and Dissemination (CRD) guidance, a literature search strategy was undertaken using PubMed, EMBASE, Cochrane Library, Health Technology Assessment (HTA) database, and National Health Service Economic Evaluation database (NHS EED) to identify original articles containing cost-effectiveness evaluation of OA pharmacological treatment published before 4 November 2021. Risk of bias was assessed by two independent reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for economic evaluations. The Quality of Health Economic Studies (QHES) instrument was used to assess the reporting quality of included articles. RESULTS: Database searches identified 43 cost-effectiveness analysis studies (CEAs) on pharmacological management of OA that were conducted in 18 countries and four continents, with one study containing multiple continents. A total of four classes of drugs were assessed, including non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), and intra-articular (IA) injections. The methodological approaches of these studies showed substantial heterogeneity. The incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) were (in 2021 US dollars) US$44.40 to US$307,013.56 for NSAIDS, US$11,984.84 to US$128,028.74 for opioids, US$10,930.17 to US$27,799.73 for SYSADOAs, and US$258.36 to US$58,447.97 for IA injections in different continents. The key drivers of cost effectiveness included medical resources, productivity, relative risks, and selected comparators. CONCLUSION: This review showed substantial ...
Shojaei, M, Shamshirian, A, Monkman, J, Grice, L, Tran, M, Tan, CW, Teo, SM, Rodrigues Rossi, G, McCulloch, TR, Nalos, M, Raei, M, Razavi, A, Ghasemian, R, Gheibi, M, Roozbeh, F, Sly, PD, Spann, KM, Chew, KY, Zhu, Y, Xia, Y, Wells, TJ, Senegaglia, AC, Kuniyoshi, CL, Franck, CL, dos Santos, AFR, Noronha, LD, 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, GT, Warkiani, ME, Gallo, CS, Souza-Fonseca-Guimaraes, F, Nguyen, Q, Mclean, A, Kulasinghe, A, Short, KR & Tang, B 2022, 'IFI27 transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study', Frontiers in Immunology, vol. 13, p. 1060438.
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PurposeRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.ResultsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.ConclusionThese data suggest that prognostic biomarkers targeting the family of IFI27
Shokouhian, B, Aboulkheyr Es, H, Negahdari, B, Tamimi, A, Shahdoust, M, Shpichka, A, Timashev, P, Hassan, M & Vosough, M 2022, 'Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways', Journal of Cellular Physiology, vol. 237, no. 11, pp. 3984-4000.
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AbstractDevelopment is a symphony of cells differentiation in which different signaling pathways are orchestrated at specific times and periods to form mature and functional cells from undifferentiated cells. The similarity of the gene expression profile in malignant and undifferentiated cells is an interesting topic that has been proposed for many years and gave rise to the differentiation‐therapy concept, which appears a rational insight and should be reconsidered. Hepatocellular carcinoma (HCC), as the sixth common cancer and the third leading cause of cancer death worldwide, is one of the health‐threatening complications in communities where hepatotropic viruses are endemic. Sedentary lifestyle and high intake of calories are other risk factors. HCC is a complex condition in which various dimensions must be addressed, including heterogeneity of cells in the tumor mass, high invasiveness, and underlying diseases that limit the treatment options. Under these restrictions, recognizing, and targeting common signaling pathways during liver development and HCC could expedite to a rational therapeutic approach, reprograming malignant cells to well‐differentiated ones in a functional state. Accordingly, in this review, we highlighted the commonalities of signaling pathways in hepatogenesis and hepatocarcinogenesis, and comprised an update on the current status of targeting these pathways in laboratory studies and clinical trials.
Shrestha, J, Razavi Bazaz, S, Ding, L, Vasilescu, S, Idrees, S, Söderström, B, Hansbro, PM, Ghadiri, M & Ebrahimi Warkiani, M 2022, 'Rapid separation of bacteria from primary nasal samples using inertial microfluidics', Lab on a Chip, vol. 23, no. 1, pp. 146-156.
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Development of an inertial microfluidic device based on a zigzag configuration for rapid separation of bacteria from primary nasal samples.
Skjöldebrand, C, Tipper, JL, Hatto, P, Bryant, M, Hall, RM & Persson, C 2022, 'Current status and future potential of wear-resistant coatings and articulating surfaces for hip and knee implants', Materials Today Bio, vol. 15, pp. 100270-100270.
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Hip and knee joint replacements are common and largely successful procedures that utilise implants to restore mobility and relieve pain for patients suffering from e.g. osteoarthritis. However, metallic ions and particles released from both the bearing surfaces and non-articulating interfaces, as in modular components, can cause hypersensitivity and local tissue necrosis, while particles originating from a polymer component have been associated with aseptic loosening and osteolysis. Implant coatings have the potential to improve properties compared to both bulk metal and ceramic alternatives. Ceramic coatings have the potential to increase scratch resistance, enhance wettability and reduce wear of the articulating surfaces compared to the metallic substrate, whilst maintaining overall toughness of the implant ensuring a lower risk of catastrophic failure of the device compared to use of a bulk ceramic. Coatings can also act as barriers to inhibit ion release from the underlying material caused by corrosion. This review aims to provide a comprehensive overview of wear-resistant coatings for joint replacements - both those that are in current clinical use as well as those under investigation for future use. While the majority of coatings belong predominantly in the latter group, a few coated implants have been successfully marketed and are available for clinical use in specific applications. Commercially available coatings for implants include titanium nitride (TiN), titanium niobium nitride (TiNbN), oxidized zirconium (OxZr) and zirconium nitride (ZrN) based coatings, whereas current research is focused not only on these, but also on diamond-like-carbon (DLC), silicon nitride (SiN), chromium nitride (CrN) and tantalum-based coatings (TaN and TaO). The coating materials referred to above that are still at the research stage have been shown to be non-cytotoxic and to reduce wear in a laboratory setting. However, the adhesion of implant coatings remains a m...
Smith, CM & Hutvagner, G 2022, 'A comparative analysis of single cell small RNA sequencing data reveals heterogeneous isomiR expression and regulation', Scientific Reports, vol. 12, no. 1.
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AbstractMicroRNAs (miRNAs) are non-coding small RNAs which play a critical role in the regulation of gene expression in cells. It is known that miRNAs are often expressed as multiple isoforms, called isomiRs, which may have alternative regulatory functions. Despite the recent development of several single cell small RNA sequencing protocols, these methods have not been leveraged to investigate isomiR expression and regulation to better understand their role on a single cell level. Here we integrate sequencing data from three independent studies and find substantial differences in isomiR composition that suggest that cell autonomous mechanisms may drive isomiR processing. We also find evidence of altered regulatory functions of different classes of isomiRs, when compared to their respective wild-type miRNA, which supports a biological role for many of the isomiRs that are expressed.
Stratton‐Powell, AA, Williams, S, Tipper, JL, Redmond, AC & Brockett, CL 2022, 'Mixed material wear particle isolation from periprosthetic tissue surrounding total joint replacements', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 110, no. 10, pp. 2276-2289.
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AbstractSubmicron‐sized wear particles are generally accepted as a potential cause of aseptic loosening when produced in sufficient volumes. With the accelerating use of increasingly wear‐resistant biomaterials, identifying such particles and evaluating their biological response is becoming more challenging. Highly sensitive wear particle isolation methods have been developed but these methods cannot isolate the complete spectrum of particle types present in individual tissue samples. Two established techniques were modified to create one novel method to isolate both high‐ and low‐density materials from periprosthetic tissue samples. Ten total hip replacement and eight total knee replacement tissue samples were processed. All particle types were characterized using high resolution scanning electron microscopy. UHMWPE and a range of high‐density materials were isolated from all tissue samples, including: polymethylmethacrylate, zirconium dioxide, titanium alloy, cobalt chromium alloy and stainless steel. This feasibility study demonstrates the coexistence of mixed particle types in periprosthetic tissues and provides researchers with high‐resolution images of clinically relevant wear particles that could be used as a reference for future in vitro biological response studies.
Tang, T, Hutvagner, G, Wang, W & Li, J 2022, 'Simultaneous compression of multiple error-corrected short-read sets for faster data transmission and betterde novoassemblies', Briefings in Functional Genomics, vol. 21, no. 5, pp. 387-398.
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AbstractNext-Generation Sequencing has produced incredible amounts of short-reads sequence data for de novo genome assembly over the last decades. For efficient transmission of these huge datasets, high-performance compression algorithms have been intensively studied. As both the de novo assembly and error correction methods utilize the overlaps between reads data, a concern is that the will the sequencing errors bring up negative effects on genome assemblies also affect the compression of the NGS data. This work addresses two problems: how current error correction algorithms can enable the compression algorithms to make the sequence data much more compact, and whether the sequence-modified reads by the error-correction algorithms will lead to quality improvement for de novo contig assembly. As multiple sets of short reads are often produced by a single biomedical project in practice, we propose a graph-based method to reorder the files in the collection of multiple sets and then compress them simultaneously for a further compression improvement after error correction. We use examples to illustrate that accurate error correction algorithms can significantly reduce the number of mismatched nucleotides in the reference-free compression, hence can greatly improve the compression performance. Extensive test on practical collections of multiple short-read sets does confirm that the compression performance on the error-corrected data (with unchanged size) significantly outperforms that on the original data, and that the file reordering idea contributes furthermore. The error correction on the original reads has also resulted in quality improvements of the genome assemblies, sometimes remarkably. However, it is still an open question that how to combine appropriate error correction methods with an assembly algorithm so that the assembly performance can be always significantly improved.
Tavakoli, J & Tipper, JL 2022, 'Detailed mechanical characterization of the transition zone: New insight into the integration between the annulus and nucleus of the intervertebral disc', Acta Biomaterialia, vol. 143, pp. 87-99.
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The Nucleus Pulposus (NP) and Annulus Fibrous (AF) are two primary regions of the intervertebral disc (IVD). The interface between the AF and NP, where the gradual transition in structure and type of fibers are observed, is known as the Transition Zone (TZ). Recent structural studies have shown that the TZ contains organized fibers that appear to connect the NP to the AF. However, the mechanical characteristics of the TZ are yet to be explored. The current study aimed to investigate the mechanical properties of the TZ at the anterolateral (AL) and posterolateral (PL) regions in both radial and circumferential directions of loading using ovine IVDs (N = 28). Young's and toe moduli, maximum stress, failure strain, strain at maximum stress, and toughness were calculated mechanical parameters. The findings from this study revealed that the mechanical properties of the TZ, including young's modulus (p = 0.001), failure strain (p < 0.001), strain at maximum stress (p = 0.002), toughness (p = 0.027), and toe modulus (p = 0.005), were significantly lower for the PL compared to the AL region. Maximum stress was not significantly different between the PL and AL regions (p = 0.164). We found that maximum stress (p = 0.002), failure strain (p < 0.001), and toughness (p = 0.001) were significantly different in different loading directions. No significant differences for modulus (young's; p = 0.169 and toe; p = 0.352) and strain at maximum stress (p = 0.727) were found between the radial and circumferential loading directions. STATEMENT OF SIGNIFICANCE: To date there has not been a study that has investigated the mechanical characterization of the annulus (AF)-nucleus (NP) interface (transition zone; TZ) in the intervertebral disc (IVD), nor is it known whether the posterolateral (PL) and anterolateral (AL) regions of the TZ exhibit different mechanical properties. Accordingly, the TZ mechanical properties have been rarely used in the development of computational IVD...
Thomas, SR, Yang, W, Morgan, DJ, Davies, TE, Li, JJ, Fischer, RA, Huang, J, Dimitratos, N & Casini, A 2022, 'Bottom‐up Synthesis of Water‐Soluble Gold Nanoparticles Stabilized by N‐Heterocyclic Carbenes: From Structural Characterization to Applications', Chemistry – A European Journal, vol. 28, no. 56, p. e202201575.
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AbstractN‐heterocyclic carbenes (NHCs) have become attractive ligands for functionalizing gold nanoparticle surfaces with applications ranging from catalysis to biomedicine. Despite their great potential, NHC stabilized gold colloids (NHC@AuNPs) are still scarcely explored and further efforts should be conducted to improve their design and functionalization. Here, the ‘bottom‐up’ synthesis of two water‐soluble gold nanoparticles (AuNP‐1 and AuNP‐2) stabilized by hydrophilic mono‐ and bidentate NHC ligands is reported together with their characterization by various spectroscopic and analytical methods. The NPs showed key differences likely to be due to the selected NHC ligand systems. Transmission electron microscopy (TEM) images showed small quasi‐spherical and faceted NHC@AuNPs of similar particle size (ca. 2.3–2.6 nm) and narrow particle size distribution, but the colloids featured different ratios of Au(I)/Au(0) by X‐ray photoelectron spectroscopy (XPS). Furthermore, the NHC@AuNPs were supported on titania and fully characterized. The new NPs were studied for their catalytic activity towards the reduction of nitrophenol substrates, the reduction of resazurin and for their photothermal efficiency. Initial results on their application in photothermal therapy (PTT) were obtained in human cancer cells in vitro. The aforementioned reactions represent important model reactions towards wastewater remediation, bioorthogonal transformations and cancer treatment.
Tran, T, Bliuc, D, Ho-Le, T, Abrahamsen, B, van den Bergh, JP, Chen, W, Eisman, JA, Geusens, P, Hansen, L, Vestergaard, P, Nguyen, TV, Blank, RD & Center, JR 2022, 'Association of Multimorbidity and Excess Mortality After Fractures Among Danish Adults', JAMA Network Open, vol. 5, no. 10, pp. e2235856-e2235856.
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ImportanceLimited knowledge about interactions among health disorders impedes optimal patient care. Because comorbidities are common among patients 50 years and older with fractures, these fractures provide a useful setting for studying interactions among disorders.ObjectiveTo define multimorbidity clusters at the time of fracture and quantify the interaction between multimorbidity and fracture in association with postfracture excess mortality.Design, Setting, and ParticipantsThis nationwide cohort study included 307 870 adults in Denmark born on or before January 1, 1951, who had an incident low-trauma fracture between January 1, 2001, and December 31, 2014, and were followed up through December 31, 2016. Data were analyzed from February 1 to March 31, 2022.Main Outcomes and MeasuresFracture and 32 predefined chronic diseases recorded within 5 years before the index fracture were identified from the Danish National Hospital Discharge Register. Death was ascertained from the Danish Register on Causes of Death. Latent class analysis was conducted to identify multimorbidity clusters. Relative survival analysis was used to quantify excess mortality associated with the combination of multimorbidity and fractures at specific sites.ResultsAmong the 307 870 participants identified with incident fractures, 95 372 were men (31.0%; mean [SD] age at fracture, 72.3 [11.2] years) and 212 498 were women (69.0%; mean [SD] age at fracture, 74.9 [11.2] years). During a median of 6.5 (IQR, 3.0-11.0) years of follow-up, 41 017 men (43.0%) and 81 727 women (38.5%) died. Almost half of ...
Vranken, L, Wyers, CE, Van der Velde, RY, Janzing, HMJ, Kaarsemakers, S, Driessen, J, Eisman, J, Center, JR, Nguyen, TV, Tran, T, Bliuc, D, Geusens, P & van den Bergh, JP 2022, 'Association between incident falls and subsequent fractures in patients attending the fracture liaison service after an index fracture: a 3-year prospective observational cohort study', BMJ Open, vol. 12, no. 7, pp. e058983-e058983.
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ObjectivesTo evaluate the risk of subsequent fractures in patients who attended the Fracture Liaison Service (FLS), with and without incident falls after the index fracture.DesignA 3-year prospective observational cohort study.SettingAn outpatient FLS in the Netherlands.ParticipantsPatients aged 50+ years with a recent clinical fracture.Outcome measuresIncident falls and subsequent fractures.ResultsThe study included 488 patients (71.9% women, mean age: 64.6±8.6 years). During the 3-year follow-up, 959 falls had been ascertained in 296 patients (60.7%) (ie, fallers), and 60 subsequent fractures were ascertained in 53 patients (10.9%). Of the fractures, 47 (78.3%) were fall related, of which 25 (53.2%) were sustained at the first fall incident at a median of 34 weeks. An incident fall was associated with an approximately 9-fold (HR: 8.6, 95% CI 3.1 to 23.8) increase in the risk of subsequent fractures.ConclusionThese data suggest that subsequent fractures among patients on treatment prescribed in an FLS setting are common, and that an incident fall is a strong predictor of subsequent fracture risk. Immediate attention for fall risk could be beneficial in an FLS model of care.Trial registration numberNL45707.072.13.
Wang, B, Liu, W, Li, JJ, Chai, S, Xing, D, Yu, H, Zhang, Y, Yan, W, Xu, Z, Zhao, B, Du, Y & Jiang, Q 2022, 'A low dose cell therapy system for treating osteoarthritis: In vivo study and in vitro mechanistic investigations', Bioactive Materials, vol. 7, pp. 478-490.
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Mesenchymal stem cells (MSCs) can be effective in alleviating the progression of osteoarthritis (OA). However, low MSC retention and survival at the injection site frequently require high doses of cells and/or repeated injections, which are not economically viable and create additional risks of complications. In this study, we produced MSC-laden microcarriers in spinner flask culture as cell delivery vehicles. These microcarriers containing a low initial dose of MSCs administered through a single injection in a rat anterior cruciate ligament (ACL) transection model of OA achieved similar reparative effects as repeated high doses of MSCs, as evaluated through imaging and histological analyses. Mechanistic investigations were conducted using a co-culture model involving human primary chondrocytes grown in monolayer, together with MSCs grown either within 3D constructs or as a monolayer. Co-culture supernatants subjected to secretome analysis showed significant decrease of inflammatory factors in the 3D group. RNA-seq of co-cultured MSCs and chondrocytes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed processes relating to early chondrogenesis and increased extracellular matrix interactions in MSCs of the 3D group, as well as phenotypic maintenance in the co-cultured chondrocytes. The cell delivery platform we investigated may be effective in reducing the cell dose and injection frequency required for therapeutic applications.
Wang, G, Xing, D, Liu, W, Zhu, Y, Liu, H, Yan, L, Fan, K, Liu, P, Yu, B, Li, JJ & Wang, B 2022, 'Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses', International Journal of Rheumatic Diseases, vol. 25, no. 5, pp. 532-562.
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AbstractAimTo provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA.MethodA systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009‐2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA.ResultsIn total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1 × 106 to 200 × 106 cells with an average of 37.91 × 106 cells.ConclusionMesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high‐quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.
Wang, H, Obeidy, P, Wang, Z, Zhao, Y, Wang, Y, Su, QP, Cox, CD & Ju, LA 2022, 'Fluorescence-coupled micropipette aspiration assay to examine calcium mobilization caused by red blood cell mechanosensing', European Biophysics Journal, vol. 51, no. 2, pp. 135-146.
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AbstractMechanical stimuli such as tension, compression, and shear stress play critical roles in the physiological functions of red blood cells (RBCs) and their homeostasis, ATP release, and rheological properties. Intracellular calcium (Ca2+) mobilization reflects RBC mechanosensing as they transverse the complex vasculature. Emerging studies have demonstrated the presence of mechanosensitive Ca2+ permeable ion channels and their function has been implicated in the regulation of RBC volume and deformability. However, how these mechanoreceptors trigger Ca2+ influx and subsequent cellular responses are still unclear. Here, we introduce a fluorescence-coupled micropipette aspiration assay to examine RBC mechanosensing at the single-cell level. To achieve a wide range of cell aspirations, we implemented and compared two negative pressure adjusting apparatuses: a homemade water manometer (− 2.94 to 0 mmH2O) and a pneumatic high-speed pressure clamp (− 25 to 0 mmHg). To visualize Ca2+ influx, RBCs were pre-loaded with an intensiometric probe Cal-520 AM, then imaged under a confocal microscope with concurrent bright-field and fluorescent imaging at acquisition rates of 10 frames per second. Remarkably, we observed the related changes in intracellular Ca2+ levels immediately after aspirating individual RBCs in a pressure-dependent manner. The RBC aspirated by the water manometer only displayed 1.1-fold increase in fluorescence intensity, whereas the RBC aspirated by the pneumatic clamp showed up to threefold increase. These results demonstrated the water manometer as a gentle tool for cell manipulation with minimal pre-activation, while the high-speed pneumatic clamp as a much stronger pressure actuator to examine cell mechanosensing directly. Together, this multimodal platform enables us to precisely co...
Wang, K, Bao, G, Fan, Q, Zhu, L, Yang, L, Liu, T, Zhang, Z, Li, G, Chen, X, Xu, X, Xu, X, He, B & Zheng, Y 2022, 'Feasibility evaluation of a Cu-38 Zn alloy for intrauterine devices: In vitro and in vivo studies', Acta Biomaterialia, vol. 138, pp. 561-575.
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The existing adverse effects of copper in copper-containing intrauterine devices (Cu-IUDs) have raised concerns regarding their use. These adverse effects include burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUDs. In this study, we investigated the use of two copper alloys, Cu-38 Zn and H62 as the new upgrading or alternative material for IUDs. Their corrosive properties were studied in simulated uterine fluid (SUF) by using electrochemical methods, with pure Cu as a control. We studied the in vitro long-term corrosion behaviors in SUF, cytotoxicity to uterine cells (human endometrial epithelial cells and human endometrial stromal cells), in vivo biocompatibility and contraceptive efficacy of pure Cu, H62, and Cu-38 Zn. In the first month, the burst release rate of Cu2+ in the Cu-38 Zn group was significantly lower than those in the pure Cu and H62 groups. The in vitro cytocompatibility Cu-38 Zn was better than that of pure Cu and H62. Moreover, Cu-38 Zn showed improved tissue biocompatibility in vivo experiments. Therefore, the contraceptive efficacy of the Cu-38 Zn is still maintained as high as the pure Cu while the adverse effects are significantly eased, suggesting that Cu-38 Zn can be a suitable potential candidate material for IUDs. STATEMENT OF SIGNIFICANCE: The existing adverse effects associated with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concern in their employment. Such as, burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUD. In this work, Cu alloyed with a high amount of bioactive Zn was used for a Cu-IUD. The Cu-38 Zn alloy exhibited reduced burst release of Cu2+ within the first month compared with the pure Cu and H62. Furthermore, the Cu-38 Zn alloy displayed significantly improved biocompatibility and a much smoother surface. Therefore, high antifertility efficacy o...
Xing, D, Li, R, Li, JJ, Tao, K, Lin, J, Yan, T & Zhou, D 2022, 'Catastrophic Periprosthetic Osteolysis in Total Hip Arthroplasty at 20 Years: A Case Report and Literature Review', Orthopaedic Surgery, vol. 14, no. 8, pp. 1918-1926.
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BackgroundPeriprosthetic osteolysis is a serious complication following total hip arthroplasty (THA). However, most orthopedic surgeons only focus on bone loss and hip reconstruction. Thus, it was required to understand the treatment algorithm for periprosthetic osteolysis integrally.Case PresentationA 52‐year‐old Asian male presented with chronic hip pain. A mass appeared on the medial side of the proximal left thigh at more than 20 years after bilateral THA. Radiographs revealed catastrophic periprosthetic osteolysis, especially on the acetabular side. Large amounts of necrotic tissue and bloody fluids were thoroughly debrided during revision THA. A modular hemipelvic prosthesis was used for revision of the left hip. Four years later, the patient presented with right hip pain, where a mass appeared on the medial side of the proximal right thigh. A primary acetabular implant with augment was used for revision of the right hip. Laboratory evaluation of bloody fluid retrieved from surgery revealed elevated levels of inflammatory markers.ConclusionInflammatory responses to polyethylene wear debris can lead to severe bone resorption and aseptic loosening in the long‐term following THA. Therefore, in spite of revision THA, interrupting the cascade inflammatory might be the treatment principle for periprosthetic osteolysis.
Yang, Z, Liu, X, Cribbin, EM, Kim, AM, Li, JJ & Yong, K-T 2022, 'Liver-on-a-chip: Considerations, advances, and beyond', Biomicrofluidics, vol. 16, no. 6, pp. 061502-061502.
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The liver is the largest internal organ in the human body with largest mass of glandular tissue. Modeling the liver has been challenging due to its variety of major functions, including processing nutrients and vitamins, detoxification, and regulating body metabolism. The intrinsic shortfalls of conventional two-dimensional (2D) cell culture methods for studying pharmacokinetics in parenchymal cells (hepatocytes) have contributed to suboptimal outcomes in clinical trials and drug development. This prompts the development of highly automated, biomimetic liver-on-a-chip (LOC) devices to simulate native liver structure and function, with the aid of recent progress in microfluidics. LOC offers a cost-effective and accurate model for pharmacokinetics, pharmacodynamics, and toxicity studies. This review provides a critical update on recent developments in designing LOCs and fabrication strategies. We highlight biomimetic design approaches for LOCs, including mimicking liver structure and function, and their diverse applications in areas such as drug screening, toxicity assessment, and real-time biosensing. We capture the newest ideas in the field to advance the field of LOCs and address current challenges.
Yuan, X, Seneviratne, JA, Du, S, Xu, Y, Chen, Y, Jin, Q, Jin, X, Balachandran, A, Huang, S, Xu, Y, Zhai, Y, Lu, L, Tang, M, Dong, Y, Cheung, BB, Marshall, GM, Shi, W, Carter, DR & Zhang, C 2022, 'Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory', Cell Reports, vol. 41, no. 1, pp. 111455-111455.
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Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term 'transitional.' Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets.
Zandavi, SM, Koch, FC, Vijayan, A, Zanini, F, Mora, FV, Ortega, DG & Vafaee, F 2022, 'Disentangling single-cell omics representation with a power spectral density-based feature extraction', Nucleic Acids Research, vol. 50, no. 10, pp. 5482-5492.
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Abstract Emerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and diverse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired by power spectral density analysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.
Zhang, F, Zhang, X, Li, Z, Yi, R, Li, Z, Wang, N, Xu, X, Azimi, Z, Li, L, Lysevych, M, Gan, X, Lu, Y, Tan, HH, Jagadish, C & Fu, L 2022, 'A New Strategy for Selective Area Growth of Highly Uniform InGaAs/InP Multiple Quantum Well Nanowire Arrays for Optoelectronic Device Applications', Advanced Functional Materials, vol. 32, no. 3, pp. 2103057-2103057.
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AbstractIII‐V semiconductor nanowires with quantum wells (QWs) are promising for ultra‐compact light sources and photodetectors from visible to infrared spectral region. However, most of the reported InGaAs/InP QW nanowires are based on the wurtzite phase and exhibit non‐uniform morphology due to the complex heterostructure growth, making it challenging to incorporate multiple‐QWs (MQW) for optoelectronic applications. Here, a new strategy for the growth of InGaAs/InP MQW nanowire arrays by selective area metalorganic vapor phase epitaxy is reported. It is revealed that {110} faceted InP nanowires with mixed zincblende and wurtzite phases can be achieved, forming a critical base for the subsequent growth of highly‐uniform, taper‐free, hexagonal‐shaped MQW nanowire arrays with excellent optical properties. Room‐temperature lasing at the wavelength of ≈1 µm under optical pumping is achieved with a low threshold. By incorporating dopants to form an n+‐i‐n+ structure, InGaAs/InP 40‐QW nanowire array photodetectors are demonstrated with the broadband response (400–1600 nm) and high responsivities of 2175 A W−1 at 980 nm outperforming those of conventional planar InGaAs photodetectors. The results show that the new growth strategy is highly feasible to achieve high‐quality InGaAs/InP MQW nanowires for the development of future optoelectronic devices and integrated photonic systems.
Zhang, F, Zhang, X, Li, Z, Yi, R, Li, Z, Wang, N, Xu, X, Azimi, Z, Li, L, Lysevych, M, Gan, X, Lu, Y, Tan, HH, Jagadish, C & Fu, L 2022, 'A New Strategy for Selective Area Growth of Highly Uniform InGaAs/InP Multiple Quantum Well Nanowire Arrays for Optoelectronic Device Applications (Adv. Funct. Mater. 3/2022)', Advanced Functional Materials, vol. 32, no. 3, pp. 2270018-2270018.
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Zhang, X, Ekanayake Weeramange, C, Hughes, BGM, Vasani, S, Liu, ZY, Warkiani, ME, Hartel, G, Ladwa, R, Thiery, JP, Kenny, L & Punyadeera, C 2022, 'Application of circulating tumour cells to predict response to treatment in head and neck cancer', Cellular Oncology, vol. 45, no. 4, pp. 543-555.
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Abstract Background Local recurrence and metastasis remain the major causes of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) are shed from primary and metastatic sites into the circulation system and have been reported to play critical roles in the metastasis and recurrence of HNC. Here, we explored the use of CTCs to predict the response to treatment and disease progression in HNC patients. Methods Blood samples were collected at diagnosis from HNC patients (n = 119). CTCs were isolated using a spiral microfluidic device and were identified using immunofluorescence staining. Correlation of baseline CTC numbers to 13-week PET-CT data and multidisciplinary team consensus data were conducted. Results CTCs were detected in 60/119 (50.4%) of treatment naïve HNC patients at diagnosis. Baseline CTC numbers were higher in stage III vs. stage I-II p16-positive oropharyngeal cancers (OPCs) and other HNCs (p = 0.0143 and 0.032, respectively). In addition, we found that baseline CTC numbers may serve as independent predictors of treatment response, even after adjusting for other conventional prognostic factors. CTCs were detected in 10 out of 11 patients exhibiting incomplete treatment responses. Conclusions We found that baseline CTC numbers are correlated with treatment response in patients with HNC. The expression level of cell-surface vimentin (CSV) on CTCs was significantly higher in patients with persistent or progressive disease, thus providing additional prognostic information...
