Publications by authors named "Chamindie Punyadeera"

96 Publications

Determining the utility of a screening program to reduce the incidence of HPV driven oropharyngeal cancer.

Oncoscience 2021 9;8:91-93. Epub 2021 Aug 9.

Translational Research Institute, Queensland, Australia.

The last decade has seen a continued escalation in rates of human papillomavirus related oropharyngeal malignancy (HPV-OPC). This has occurred despite established national vaccination programs. In contrast, HPV associated cervical cancer incidence rates have declined, due in part to effective cervical cancer screening programs, many of which have moved towards the detection of high-risk HPV (hrHPV) as an early marker of malignant potential. This raises questions as to whether similar hrHPV screening methods could be used for early detection of HPV-OPC. Persistent oral hrHPV is a prerequisite for the development of HPV-OPC and can be accurately detected in saliva. Despite this, single point saliva testing for hrHPV lacks sufficient sensitivity and specificity to allow for effective population screening. Recent published literature suggests the use of serial saliva testing in targeted high-risk individuals, with an emphasis on biomarker persistence and intensity patterns, as a potential means of detecting even subclinical microscopic disease. When coupled with serological testing, this has the potential to provide an accurate test for screening at risk individuals. Despite these promising developments, several significant barriers to an effective targeted screening program remain.
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http://dx.doi.org/10.18632/oncoscience.541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351916PMC
August 2021

Salivary High-Risk Human Papillomavirus (HPV) DNA as a Biomarker for HPV-Driven Head and Neck Cancers.

J Mol Diagn 2021 Jul 27. Epub 2021 Jul 27.

Saliva & Liquid Biopsy Translational Laboratory, Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia; Translational Research Institute, Brisbane, Queensland, Australia. Electronic address:

High-risk human papillomavirus (HR-HPV) infection is a major risk factor of head and neck cancers (HNCs). Despite the rising prevalence of HPV-driven HNC (HPV-HNC), biomarkers for detection, prognostication, and disease monitoring are lacking. To evaluate the capacity of salivary HR-HPV DNA as a biomarker of HPV-HNC, the salivary HR-HPV statuses of 491 and 10 patients with primary and recurrent HNC, respectively, were determined at diagnosis, using quantitative real-time PCR and MassARRAY. Tumor cyclin-dependent kinase inhibitor 2A (p16) expression was determined by IHC analysis. Patients with oropharyngeal cancer (OPC) (n = 215) were followed up for ≤5 years. Survival characteristics were evaluated in terms of event-free and cause-specific survival. Of the primary-HNC cohort, 43.2% were positive for salivary HR-HPV DNA, with most having OPC. Salivary HR-HPV DNA was detected in 81.4% of tumor p16-positive OPC patients at diagnosis. Prognosis in salivary HR-HPV-positive OPC patients was favorable compared with that in salivary HR-HPV-negative patients (event-free survival, hazard ratio = 0.42 [95% CI, 0.21-0.81, P = 0.010]; cause-specific survival, hazard ratio = 0.39 [95% CI, 0.18-0.86, P = 0.019]). In the recurrent-HNC cohort, salivary HR-HPV DNA was detected in 83.3% of those who previously had tumor p16-positive HNC. These findings indicate that this liquid biopsy-based, noninvasive biomarker can play an essential role in the detection and management of HPV-HNC.
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http://dx.doi.org/10.1016/j.jmoldx.2021.07.005DOI Listing
July 2021

An exploratory study demonstrating that salivary cytokine profiles are altered in children with small area thermal injury.

J Burn Care Res 2021 Jul 29. Epub 2021 Jul 29.

School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.

Serum can be used to investigate changes in cytokine concentration following burn injury in children, however for children receiving treatment in an outpatient setting, blood is not routinely collected and therefore cannot be used for monitoring. The aim of this study was to investigate the use of saliva as a non-invasive tool for predicting burn outcomes by measuring the concentration of salivary cytokines in children with small area burns. A multiplex cytokine assay was used to measure 17 cytokines in the saliva of paediatric patients with burns (n = 20) and healthy controls (n = 20). After the removal of cytokines that had >30% of samples below the assay lower detection limit, six cytokines including IL-1β, IL-4, IL-7, IL-8, MCP-1 and TNFα were analysed for association with burns. IL-1β and IL-4 were found to be significantly elevated in the paediatric burn patients compared to healthy controls. Interestingly, IL-1β was also significantly elevated in scald burns, compared to contact burns. In addition, biologically meaningful differences in cytokine concentration were identified in patients with different burn characteristics, which warrant further investigation. This exploratory study provides evidence that cytokines can be detected in the saliva of children and that salivary cytokine profiles differ between healthy controls and children with burns. Overall, this study demonstrates the value of saliva for the investigation of cytokines and its potential application in paediatric diagnostics, specifically in situations where blood collection is not appropriate.
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http://dx.doi.org/10.1093/jbcr/irab147DOI Listing
July 2021

Isolation of Circulating Tumour Cells in Patients With Glioblastoma Using Spiral Microfluidic Technology - A Pilot Study.

Front Oncol 2021 3;11:681130. Epub 2021 Jun 3.

Saliva and Liquid Biopsy Translational Laboratory, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.

Glioblastoma (GBM) is the most common and aggressive type of tumour arising from the central nervous system. GBM remains an incurable disease despite advancement in therapies, with overall survival of approximately 15 months. Recent literature has highlighted that GBM releases tumoural content which crosses the blood-brain barrier (BBB) and is detected in patients' blood, such as circulating tumour cells (CTCs). CTCs carry tumour information and have shown promise as prognostic and predictive biomarkers in different cancer types. Currently, there is limited data for the clinical utility of CTCs in GBM. Here, we report the use of spiral microfluidic technology to isolate CTCs from whole blood of newly diagnosed GBM patients before and after surgery, followed by characterization for GFAP, cell-surface vimentin protein expression and EGFR amplification. CTCs were found in 13 out of 20 patients (9/20 before surgery and 11/19 after surgery). Patients with CTC counts equal to 0 after surgery had a significantly longer recurrence-free survival (p=0.0370). This is the first investigation using the spiral microfluidics technology for the enrichment of CTCs from GBM patients and these results support the use of this technology to better understand the clinical value of CTCs in the management of GBM in future studies.
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http://dx.doi.org/10.3389/fonc.2021.681130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210776PMC
June 2021

Proteomic Alterations in Salivary Exosomes Derived from Human Papillomavirus-Driven Oropharyngeal Cancer.

Mol Diagn Ther 2021 07 2;25(4):505-515. Epub 2021 Jun 2.

Saliva and Liquid Biopsy Translational Laboratory, The Translational Research Institute, The School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Avenue, GPO Box 2434, Brisbane, QLD, 4059, Australia.

Background: Increasing evidence supports the notion that human papillomavirus (HPV) DNA integration onto the human genome can influence and alter the molecular cargo in the exosomes derived from head and neck cancer cells. However, the molecular cargo of salivary exosomes derived from HPV-driven oropharyngeal cancer (HPV-driven OPC) remains unelucidated.

Methods And Materials: Salivary exosomes morphology and molecular characterizations were examined using the nanoparticle tracking (NTA), western blot analysis, transmission electron microscopy (TEM) and mass spectrometry analysis.

Results: We report that HPV16 DNA was detected (80%) in isolated salivary exosomes of HPV-driven OPC patients. Importantly, we demonstrate elevated protein levels of six main glycolytic enzymes [i.e., aldolase (ALDOA), glyceraldehye-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A/B (LDHA and LDHB), phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M1/2 (PKM)] in isolated salivary exosomes of HPV-driven OPC patients, suggesting a novel mechanism underlying the potential role of salivary exosomes in mediating the reciprocal interplay between glucose metabolism and HPV-driven OPC.

Conclusion: Our data demonstrate the potential diagnostic value of HPV16 DNA and glycolytic enzymes in salivary exosomes in discriminating healthy controls from HPV-driven OPC patients, thereby opening new avenues in the future for clinical translation studies.
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http://dx.doi.org/10.1007/s40291-021-00538-2DOI Listing
July 2021

Overexpression of miRNA-9 enhances galectin-3 levels in oral cavity cancers.

Mol Biol Rep 2021 May 21;48(5):3979-3989. Epub 2021 May 21.

Saliva & Liquid Biopsy Translational Laboratory, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Room 603D, 60 Musk Avenue, Brisbane, QLD, 4059, Australia.

Oral cavity cancer (OCC) is the predominant subtype of head and neck cancer (HNC) and has up to 50% mortality. Genome-wide microRNA (miR) sequencing data indicates overexpression of miR-9-5p in HNC tumours, however, the biological role of miR-9-5p in OCC is complex; it can either act as a tumour suppressor or an oncomir, regulating many target genes at the post-transcriptional level. We have investigated the overexpression of miR-9-5p in three OCC cell lines. We have evaluated its expression levels and Galectin-3 as potential biomarkers in saliva samples collected from controls and OCC patients. We found that over expression of miR-9-5p in OCC cell lines resulted in a significant reduction in cell proliferation and migration, and an increase in apoptosis, which was paralleled by an increase in Galectin-3 secretion and export of Galectin-3 protein. Our data are consistent with miR-9-5p being a modulator of Galectin-3 via the AKT/γ-catenin pathway. In addition, the positive correlation between the levels of miR-9-5p expression and secreted Galectin-3 in saliva reflects a similar relationship in vivo, and supports the utility of their integrative evaluation in OCC. Our findings indicate that both miR-9-5p and Galectin-3 are critical biomolecules in the progression of OCC.
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http://dx.doi.org/10.1007/s11033-021-06398-7DOI Listing
May 2021

Exosomes in cancer.

Adv Clin Chem 2021 18;101:1-40. Epub 2020 Aug 18.

Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia; Translational Research Institute, Woolloongabba, QLD, Australia. Electronic address:

Exosomes are small extracellular vesicles released by cells under physiological and pathological conditions. There is emerging evidence associating exosomes with tumorigenesis. They carry cargo (DNA, RNA, miRNA and protein) pertaining to the cell of origin and play a key role in intercellular communication, influencing several cellular processes. Moreover, exosomes can be shed and found in almost all body fluids, providing a source of biomarkers for tumor diagnosis and prognosis. In addition, the use of exosomes for cancer therapeutics is another research area that is gaining attention. This book chapter aims to explore the role of exosomes in tumor biogenesis, progression and clinical applications, comprehensively compiling the research for three tumor types, namely head and neck cancer, lung cancer and glioblastoma.
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http://dx.doi.org/10.1016/bs.acc.2020.06.006DOI Listing
July 2021

A review of potential biomarkers for assessing physical and psychological trauma in paediatric burns.

Burns Trauma 2021 Jan 9;9:tkaa049. Epub 2021 Feb 9.

Queensland University of Technology (QUT), Centre for Children's Burn and Trauma Research, Centre for Children's Health Research, South Brisbane, Queensland, Australia.

Biological markers that evaluate physical healing as well as psychological impact of a burn are essential for effective treatment of paediatric burns. The objective of this review is to summarize the evidence supporting the use of biomarkers in children with burns. An extensive review of the literature was performed using PubMed. A total of 59 biomarkers were identified relating to burn presence, specifically relating to processes involved in inflammation, wound healing, growth and metabolism. In addition, biomarkers involved in the stress response cascade following a burn trauma were also identified. Although many biomarkers have been identified that are potentially associated with burn-related physical and psychological trauma, an understanding of burn biology is still lacking in children. We propose that future research in the field of children's burns should be conducted using broad screening methods for identifying potential biomarkers, examine the biological interactions of different biomarkers, utilize child-appropriate biological fluids such as urine or saliva, and include a range of different severity burns. Through further research, the biological response to burn injury may be fully realized and clinically relevant diagnostic tests and treatment therapies utilizing these biomarkers could be developed, for the improvement of healing outcomes in paediatric burn patients.
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http://dx.doi.org/10.1093/burnst/tkaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901707PMC
January 2021

Diagnostics for SARS-CoV-2 infections.

Nat Mater 2021 05 15;20(5):593-605. Epub 2021 Feb 15.

Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every corner of the globe, causing societal instability. The resultant coronavirus disease 2019 (COVID-19) leads to fever, sore throat, cough, chest and muscle pain, dyspnoea, confusion, anosmia, ageusia and headache. These can progress to life-threatening respiratory insufficiency, also affecting the heart, kidney, liver and nervous systems. The diagnosis of SARS-CoV-2 infection is often confused with that of influenza and seasonal upper respiratory tract viral infections. Due to available treatment strategies and required containments, rapid diagnosis is mandated. This Review brings clarity to the rapidly growing body of available and in-development diagnostic tests, including nanomaterial-based tools. It serves as a resource guide for scientists, physicians, students and the public at large.
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http://dx.doi.org/10.1038/s41563-020-00906-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264308PMC
May 2021

Highly Multiplexed Digital Spatial Profiling of the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma Patients.

Front Oncol 2020 19;10:607349. Epub 2021 Jan 19.

The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia.

Background: Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture.

Methods: In this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy.

Results: Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1.

Conclusion: This study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings.
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http://dx.doi.org/10.3389/fonc.2020.607349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851078PMC
January 2021

Chemoradiation therapy changes oral microbiome and metabolomic profiles in patients with oral cavity cancer and oropharyngeal cancer.

Head Neck 2021 05 2;43(5):1521-1534. Epub 2021 Feb 2.

The Saliva and Liquid Biopsy Translational Research Team, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

Background: Patients with oral cavity cancer (OCC) and oropharyngeal cancer (OPC) are often seen with locoregionally advanced disease requiring complex multimodality treatments. These treatments may have detrimental effects on the oral microbiome, which is critical to maintaining physiological balance and health.

Methods: The effects of different OCC and OPC treatment types on the oral microbiome and metabolomic profiles for 24-month post-treatment in patients with OCC and OPC were investigated using 16S rRNA gene amplicon next-generation sequencing and gas chromatography-mass spectrometry (GC-MS), respectively.

Results: Chemoradiation resulted in oral dysbiosis with specific depletion of genera which regulate the enterosalivary nitrate-nitrite-nitric oxide pathway. These data also correlate with the oral metabolomic profiles with nitric oxide-related precursor, modulator, or catalyst significantly downregulated in saliva samples from patients' postchemoradiation.

Conclusions: Together, we have shown that oral dysbiosis due to the effects of chemoradiation could potentially have an impact on OCC and OPC patient's quality of life post-treatment.
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http://dx.doi.org/10.1002/hed.26619DOI Listing
May 2021

Pharmacotherapeutics of SARS-CoV-2 Infections.

J Neuroimmune Pharmacol 2021 03 6;16(1):12-37. Epub 2021 Jan 6.

Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

The COVID-19 pandemic has affected more than 38 million people world-wide by person to person transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therapeutic and preventative strategies for SARS-CoV-2 remains a significant challenge. Within the past several months, effective treatment options have emerged and now include repurposed antivirals, corticosteroids and virus-specific antibodies. The latter has included convalescence plasma and monoclonal antibodies. Complete viral eradication will be achieved through an effective, safe and preventative vaccine. To now provide a comprehensive summary for each of the pharmacotherapeutics and preventative strategies being offered or soon to be developed for SARS-CoV-2.
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http://dx.doi.org/10.1007/s11481-020-09968-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785334PMC
March 2021

culture of circulating tumour cells derived from non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):1795-1809

Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.

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

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

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

Conclusions: We were able to detect CTCs in >50% of NSCLC patients. NSCLC patients with >2 CTCs had a poor prognosis. The short-term CTC culture success rate was 12.9%. Further optimization of this culture methodology may provide a means by which to expand CTCs derived from NSCLC patient's bloods. CTC cultures allow for expansion of cells to a critical mass, allowing for functional characterization of CTCs with the goal of drug sensitivity testing and the creation of CTC cell lines.
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http://dx.doi.org/10.21037/tlcr-20-521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653113PMC
October 2020

The use of minimally invasive biomarkers for the diagnosis and prognosis of hepatocellular carcinoma.

Biochim Biophys Acta Rev Cancer 2020 12 14;1874(2):188451. Epub 2020 Oct 14.

Institute of Health & Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove Campus, QLD, Australia. Electronic address:

Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Despite advances in systemic therapies, patient survival remains low due to late diagnosis and frequent underlying liver diseases. HCC diagnosis generally relies on imaging and liver tissue biopsy. Liver biopsy presents limitations because it is invasive, potentially risky for patients and it frequently misrepresents tumour heterogeneity. Recently, liquid biopsy has emerged as a way to monitor cancer progression in a non-invasive manner. Tumours shed content into the bloodstream, such as circulating tumour cells (CTCs), circulating nucleic acids, extracellular vesicles and proteins, that can be isolated from biological fluids of patients with HCC. These biomarkers provide knowledge regarding the genetic landscape of tumours and might be used for diagnostic or prognostic purposes. In this review, we summarize recent literature on circulating biomarkers for HCC, namely CTCs, circulating tumour DNA (ctDNA), RNA, extracellular vesicles and proteins, and their clinical relevance in HCC.
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http://dx.doi.org/10.1016/j.bbcan.2020.188451DOI Listing
December 2020

Should patients with heart failure listen to their gut?

Med J Aust 2020 10 29;213(8):357-358. Epub 2020 Sep 29.

Queensland University of Technology, Brisbane, QLD.

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http://dx.doi.org/10.5694/mja2.50797DOI Listing
October 2020

Protein glycosylation in head and neck cancers: From diagnosis to treatment.

Biochim Biophys Acta Rev Cancer 2020 12 25;1874(2):188422. Epub 2020 Aug 25.

Saliva and Liquid Biopsy Translational Laboratory, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia; Translational Research Institute, Woolloongabba, QLD, Australia.. Electronic address:

Glycosylation is the most common post-translational modification (PTM) of proteins. Malignant tumour cells frequently undergo an alteration in surface protein glycosylation. This phenomenon is also common in cancers of the head and neck, most of which are squamous cell carcinomas (HNSCC). It affects cell functions, including proliferation, motility and invasiveness, thus increasing the propensity to metastasise. HNSCC represents the sixth most frequent malignancy worldwide. These neoplasms, which arise from the mucous membranes of the various anatomical subsites of the upper aero-digestive tract, are heterogeneous in terms of aetiology and clinico-pathologic features. With current treatments, only about 50% of HNSCC patients survive beyond 5-years. Therefore, there is the pressing need to dissect NHSCC heterogeneity to inform treatment choices. In particular, reliable biomarkers of predictive and prognostic value are eagerly needed. This review describes the current state of the art and bio-pathological meaning of glycosylation signatures associated with HNSCC and explores the possible role of tumour specific glycoproteins as potential biomarkers and attractive therapeutic targets. We have also compiled data relating to altered glycosylation and the nature of glycoproteins as tools for the identification of circulating tumour cells (CTCs) in the new era of liquid biopsy.
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http://dx.doi.org/10.1016/j.bbcan.2020.188422DOI Listing
December 2020

Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell carcinoma.

Cancer Sci 2020 Oct 7;111(10):3854-3861. Epub 2020 Aug 7.

Saliva & Liquid Biopsy Translational Laboratory, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.

Given that oropharyngeal squamous cell carcinoma (OPSCC) have now surpassed cervical cancer as the most common human papillomavirus (HPV)-driven cancer, there is an interest in developing non-invasive predictive biomarkers to early detect HPV-driven OPSCC. In total, 665 cancer-free individuals were recruited from Queensland, Australia. Oral HPV16 DNA positivity in those individuals was determined by our in-house developed sensitive PCR method. Individuals with (n = 9) or without (n = 12) oral HPV16 infections at baseline were followed for a median duration of 24 mo. Individuals with persistent oral HPV16 infection (≥ 30 mo) were invited for clinical examination of their oral cavity and oropharynx by an otolaryngologist. Oral HPV16 DNA was detected in 12 out of 650 cancer-free individuals (1.8%; 95% confidence interval [CI]: 1.0-3.2). Of the 3 individuals with persistent oral HPV16 infection, the first individual showed no clinical evidence of pathology. The second individual was diagnosed with a 2 mm invasive squamous cell carcinoma (T1N0M0) positive for both p16INK4a expression and HPV16 DNA. The third individual was found to have a mildly dysplastic lesion in the tonsillar region that was negative for p16INK4a expression and HPV16 DNA and she continues to have HPV16 DNA in her saliva. Taken together, our data support the value of using an oral HPV16 DNA assay as a potential screening tool for the detection of microscopic HPV-driven OPSCC. Larger multicenter studies across various geographic regions recruiting populations at a higher risk of developing HPV-driven OPSCC are warranted to extend and confirm the results of the current investigation.
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http://dx.doi.org/10.1111/cas.14585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540991PMC
October 2020

The Use of Three-Dimensional DNA Fluorescent In Situ Hybridization (3D DNA FISH) for the Detection of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer (NSCLC) Circulating Tumor Cells.

Cells 2020 06 15;9(6). Epub 2020 Jun 15.

The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD 4035, Australia.

Tumor tissue biopsy is often limited for non-small cell lung cancer (NSCLC) patients and alternative sources of tumoral information are desirable to determine molecular alterations such as anaplastic lymphoma kinase (ALK) rearrangements. Circulating tumor cells (CTCs) are an appealing component of liquid biopsies, which can be sampled serially over the course of treatment. In this study, we enrolled a cohort of ALK-positive (n = 8) and ALK-negative (n = 12) NSCLC patients, enriched for CTCs using spiral microfluidic technology and performed DNA fluorescent in situ hybridization (FISH) for ALK. CTCs were identified in 12/20 NSCLC patients ranging from 1 to 26 CTCs/7.5 mL blood. Our study revealed that 3D imaging of CTCs for ALK translocations captured a well-defined separation of 3' and 5' signals indicative of ALK translocations and overlapping 3'/5' signal was easily resolved by imaging through the nuclear volume. This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC.
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http://dx.doi.org/10.3390/cells9061465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349512PMC
June 2020

DNA Methylation Changes in Human Papillomavirus-Driven Head and Neck Cancers.

Cells 2020 05 31;9(6). Epub 2020 May 31.

Queensland University of Technology (QUT), School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Saliva & Liquid Biopsy Translational Research Team, Queensland 4059, Australia.

Disruption of DNA methylation patterns is one of the hallmarks of cancer. Similar to other cancer types, human papillomavirus (HPV)-driven head and neck cancer (HNC) also reveals alterations in its methylation profile. The intrinsic ability of HPV oncoproteins E6 and E7 to interfere with DNA methyltransferase activity contributes to these methylation changes. There are many genes that have been reported to be differentially methylated in HPV-driven HNC. Some of these genes are involved in major cellular pathways, indicating that DNA methylation, at least in certain instances, may contribute to the development and progression of HPV-driven HNC. Furthermore, the HPV genome itself becomes a target of the cellular DNA methylation machinery. Some of these methylation changes appearing in the viral long control region (LCR) may contribute to uncontrolled oncoprotein expression, leading to carcinogenesis. Consistent with these observations, demethylation therapy appears to have significant effects on HPV-driven HNC. This review article comprehensively summarizes DNA methylation changes and their diagnostic and therapeutic indications in HPV-driven HNC.
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http://dx.doi.org/10.3390/cells9061359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348958PMC
May 2020

An Occult HPV-Driven Oropharyngeal Squamous Cell Carcinoma Discovered Through a Saliva Test.

Front Oncol 2020 31;10:408. Epub 2020 Mar 31.

Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.
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http://dx.doi.org/10.3389/fonc.2020.00408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136454PMC
March 2020

Oral HPV16 Prevalence in Oral Potentially Malignant Disorders and Oral Cavity Cancers.

Biomolecules 2020 02 3;10(2). Epub 2020 Feb 3.

Saliva & Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology and the Translational Research Institute, Queensland, Brisbane QLD 4059, Australia.

The role of human papillomavirus type 16 (HPV16) in oral potentially malignant disorders (OPMD) and oral cavity carcinoma (OC) is still under debate. We investigated HPV16 prevalence in unstimulated saliva, oral rinse samples, oral swabs and tumour biopsies collected from OPMD ( = 83) and OC ( = 106) patients. HPV16 genotype, viral load, physical status (episomal vs. integrated) and tumour p16INK4a expression were determined. Oral HPV16 prevalence was higher in OC than in OPMD, but this difference was not statistically significant (7.5% (8/106) versus 3.6% (3/83), odds ratio (OR): 2.18, 95% confidence interval (CI): 0.56, 8.48, = 0.26). There was a significant association ( < 0.05) between oral HPV16 infection and heavy tobacco consumption. Real-time PCR results indicated that no integration events occurred in either OPMD or OC cases based on the HPV16 E2/E6 ratio. HPV16 positive OPMD and OC patients had similar HPV16 E2 and E6 viral loads. The inter-rater agreement between tumour p16INK4a expression and oral HPV16 infection was considered as fair (k = 0.361) for OC. Our data suggest that the involvement of HPV16 in oral carcinogenesis is limited.
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http://dx.doi.org/10.3390/biom10020223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072384PMC
February 2020

Salivary protein biomarkers for head and neck cancer.

Expert Rev Mol Diagn 2020 03 27;20(3):305-313. Epub 2020 Jan 27.

Saliva and Liquid Biopsy Translational Research Team, School of Biomedical Sciences, IHBI/TRI, QUT, Brisbane, Australia.

: Saliva has gained attention as an important diagnostic fluid because it contains biomolecules that have the potential to detect early-stage cancer or to monitor the response to treatment in patients. Several saliva-based proteins have been proposed as potential biomarkers for head and neck cancers (HNC).: This review aims to provide an update on saliva-based protein biomarkers for HNC, often studied in observational research and clinical trials.: Despite the increasing number of studies relating to salivary proteins as biomarkers for HNC, there is no consensus regarding which proteins have the best clinical utility. Most studies have analyzed individual proteins and not a protein panel approach. It must be considered that combining different proteins as a panel can increase the accuracy and will have the potential to change the current clinical practice for HNC patients.
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http://dx.doi.org/10.1080/14737159.2020.1722102DOI Listing
March 2020

Correction to: The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

Clin Res Cardiol 2020 06;109(6):693

Saliva and Liquid Biopsy Translational Research Team, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, GPO Box 2434, Brisbane, QLD, 4001, Australia.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00392-019-01583-yDOI Listing
June 2020

Salivary Protein Panel to Diagnose Systolic Heart Failure.

Biomolecules 2019 11 22;9(12). Epub 2019 Nov 22.

Saliva and Liquid Biopsy Translational Research Team, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.

Screening for systolic heart failure (SHF) has been problematic. Heart failure management guidelines suggest screening for structural heart disease and SHF prevention strategies should be a top priority. We developed a multi-protein biomarker panel using saliva as a diagnostic medium to discriminate SHF patients and healthy controls. We collected saliva samples from healthy controls (n = 88) and from SHF patients (n = 100). We developed enzyme linked immunosorbent assays to quantify three specific proteins/peptide (Kallikrein-1, Protein S100-A7, and Cathelicidin antimicrobial peptide) in saliva samples. The analytical and clinical performances and predictive value of the proteins were evaluated. The analytical performances of the immunoassays were all within acceptable analytical ranges. The multi-protein panel was able to significantly ( < 0.001) discriminate saliva samples collected from patients with SHF from controls. The multi-protein panel demonstrated good performance with an overall diagnostic accuracy of 81.6% (sensitivity of 79.2% and specificity of 85.7%) when distinguishing SHF patients from healthy individuals. In conclusion, we have developed immunoassays to measure the salivary concentrations of three proteins combined as a panel to accurately distinguish SHF patients from healthy controls. While this requires confirmation in larger cohorts, our findings suggest that this three-protein panel has the potential to be used as a biomarker for early detection of SHF.
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http://dx.doi.org/10.3390/biom9120766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995570PMC
November 2019

An update: circulating tumor cells in head and neck cancer.

Expert Rev Mol Diagn 2019 12 7;19(12):1109-1115. Epub 2019 Nov 7.

Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical, Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.

: Local and distant metastatic disease occurs in approximately half of head and neck squamous cell carcinoma (HNSCC) patients, representing an ongoing cause for treatment failure. Circulating tumor cells (CTCs) are transient cancer cells which have the capacity to metastasize to distant sites such as the lungs and liver in HNSCC. When metastatic disease is radiographically evident, the patient prognosis is often poor. Therefore, methodologies to assess micrometastatic disease are needed to (1) identify patients likely to develop metastatic disease and (2) treat and monitor these patients more aggressively. Whilst CTCs are well documented in other tumor streams such as breast, colorectal cancer and prostate cancers, the data and clinical utility in HNSCC remains limited.: Here we summarize the recent advances of CTCs and applications in HNSCC.: CTC enumeration can be prognostic in HNSCC; further studies are warranted to investigate the role of CTC clusters in HNSCC; CTC culture (/) may present a possibility to expand these rare cells to a critical mass for functional testing; PD-L1 expression of HNSCC CTCs may present a means by which to determine patients likely to respond to therapy; a HNSCC CTC-specific marker is warranted.
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http://dx.doi.org/10.1080/14737159.2020.1688145DOI Listing
December 2019

Circulating biomarkers in patients with glioblastoma.

Br J Cancer 2020 02 31;122(3):295-305. Epub 2019 Oct 31.

Saliva and Liquid Biopsy Translational Research Team, The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, 4059, Australia.

Gliomas are the most common tumours of the central nervous system and the most aggressive form is glioblastoma (GBM). Despite advances in treatment, patient survival remains low. GBM diagnosis typically relies on imaging techniques and postoperative pathological diagnosis; however, both procedures have their inherent limitations. Imaging modalities cannot differentiate tumour progression from treatment-related changes that mimic progression, known as pseudoprogression, which might lead to misinterpretation of therapy response and delay clinical interventions. In addition to imaging limitations, tissue biopsies are invasive and most of the time cannot be performed over the course of treatment to evaluate 'real-time' tumour dynamics. In an attempt to address these limitations, liquid biopsies have been proposed in the field. Blood sampling is a minimally invasive procedure for a patient to endure and could provide tumoural information to guide therapy. Tumours shed tumoural content, such as circulating tumour cells, cell-free nucleic acids, proteins and extracellular vesicles, into the circulation, and these biomarkers are reported to cross the blood-brain barrier. The use of liquid biopsies is emerging in the field of GBM. In this review, we aim to summarise the current literature on circulating biomarkers, namely circulating tumour cells, circulating tumour DNA and extracellular vesicles as potential non-invasively sampled biomarkers to manage the treatment of patients with GBM.
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http://dx.doi.org/10.1038/s41416-019-0603-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000822PMC
February 2020

Evaluation of sample preparation methods for label-free quantitative profiling of salivary proteome.

J Proteomics 2020 01 16;210:103532. Epub 2019 Oct 16.

Saliva and Liquid Biopsy Translational Research Team, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Australia. Electronic address:

Saliva has become one of the more attractive body fluids for protein biomarker discovery studies because of its ease of collection, non-invasiveness and multiple samples can be collected from an individual at a single time point. With the development of modern data acquisition strategies, such as Sequential Window Acquisition of all Theoretical Mass Spectrometry (SWATH-MS), the quality of saliva sample preparation has become a crucial factor for a successful protein identification and quantification. Several sample preparation methods have been proposed, but there has been no systematic evaluation conducted to date that compared each of these methods. We have therefore, performed an extensive assessment using technical and biological repeats to evaluate the number of protein IDs and repeatability of three most commonly used techniques, in-solution digestion, filter-aided sample preparation (FASP) and in stage-tip (iST) digestion. We discovered that in the case of human saliva sample, FASP provided the highest number of proteins (human and microbial) identifiable from a pool saliva sample, and there were no significant differences in terms of repeatability among the three methods investigated.
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http://dx.doi.org/10.1016/j.jprot.2019.103532DOI Listing
January 2020

The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

Clin Res Cardiol 2020 Jun 9;109(6):685-692. Epub 2019 Oct 9.

Saliva and Liquid Biopsy Translational Research Team, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, GPO Box 2434, Brisbane, QLD, 4001, Australia.

Background: Patients with HF are at a higher risk of rehospitalisation and, as such, significant costs to our healthcare system. A non-invasive method to collect body fluids and measure Gal-3 could improve the current management of HF. In this study, we investigated the potential prognostic utility of salivary Galectin-3 (Gal-3) in patients with heart failure (HF).

Methods: We collected saliva samples from patients with HF (n = 105) either at hospital discharge or during routine clinical visits. Gal-3 concentrations in saliva samples were measured by ELISA. The Kaplan-Meier survival curve analysis and Cox proportional regression model were used to determine the potential prognostic utility of salivary Gal-3 concentrations.

Results: The primary end point was either cardiovascular death or hospitalisation. Salivary Gal-3 concentrations were significantly higher (p < 0.05) in patients with HF who subsequently experienced the primary endpoint compared to those who did not. HF patients with salivary Gal-3 concentrations > 172.58 ng/mL had a significantly (p < 0.05) higher cumulative risk of the primary endpoint compared to those with lower salivary Gal-3 concentrations. In patients with HF, salivary Gal-3 concentration was a predictor of the primary endpoint even after adjusting for other covariates.

Conclusions: In our pilot study, HF patients with salivary Gal-3 concentrations of > 172.58 ng/mL demonstrated a higher cumulative risk of the primary outcome compared to those with lower Gal-3 levels, even after adjusting for other variables. Confirming our findings in a larger multi-centre clinical trial in the future would enable salivary Gal-3 measurements to form part of routine management for patients with HF.
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http://dx.doi.org/10.1007/s00392-019-01557-0DOI Listing
June 2020

Relationship between p16 expression and prognosis in different anatomic subsites of OSCC.

Cancer Biomark 2019 ;26(3):375-383

Central Laboratory, Nanjing Stomatological Hospital, Medical School, Nanjing University, Nanjing, Jiangsu, China.

Background: p16 has often been found to be overexpressed in patients oral squamous cell carcinoma (OSCC), but its prognostic value between anatomic subsites is still unclear.

Objective: The aim of this study was to investigate the diagnostic and prognostic values of p16 in OSCC originating from tongue, gingiva or buccal mucosa.

Methods: A total of 147 OSCC patients with tumors arising from the tongue, gingiva or buccal mucosa were enrolled in this study. p16 expression was detected using immunohistochemistry (IHC), and the presence of HPV16 was determined by real-time PCR in p16 positive patients. The correlation of p16 expression with the clinical parameters was evaluated.

Results: Only one p16 positive patient with a cut off value of 25% and 75% was HPV16 positive. Although overall survival (OS), recurrence free survival (RFS) and metastasis free survival (MFS) had no significant differences between the p16 positive and negative patients, p16 negative patients (cut off value 25%) had more RFS in the buccal mucosa cancer (p= 0.03) than the p16-positive patients.

Conclusions: The prevalence of HPV16 in Chinese OSCC patients was low. p16 overexpression decoupled from HPV infection was not a prognostic marker for OSCC patients except for patients with the buccal mucosa cancer.
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http://dx.doi.org/10.3233/CBM-192402DOI Listing
April 2020

The Isolation and Characterization of Circulating Tumor Cells from Head and Neck Cancer Patient Blood Samples Using Spiral Microfluidic Technology.

Methods Mol Biol 2019 ;2054:129-136

The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Kelvin Grove, QLD, Australia.

Metastasis is responsible for 90% of cancer-related deaths. The study of circulating tumor cells (CTCs) enables the study of the units of disease responsible for the process of metastasis. While the biology of the primary tissue is relatively known, little is understood about the cells en route to distant sites. Here we describe the isolation of CTCs using the spiral microfluidic technology for the efficient sorting of CTCs from head and neck cancer (HNC) patient blood samples. Furthermore, the molecular characterization of CTCs can aid in stratifying patients for targeted therapy such as immunotherapy, which is having a profound impact in the treatment of metastatic HNC.
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http://dx.doi.org/10.1007/978-1-4939-9769-5_8DOI Listing
June 2020
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