Biology subjects

Falzon, M.

Publications and source records attributed to Falzon, M..

3 recordsLinked to original sources

bioRxiv2024

First report of astroviruses in Tanzanian bats

Emerging and re-emerging infectious diseases have posed significant global health threats, with many attributed to zoonotic RNA viruses. These pathogens can, under some conditions, cross species barriers, facilitating transmission from animal hosts to humans. Bats, characterised by unique physiological and ecological features, and remarkable species diversity, are recognized to host numerous viruses with cross-species transmission potential. This study aimed to investigate the presence of RNA viruses from a broad diversity of Tanzanian bats while valorising archived biological samples. RNA was extracted from 125 samples (28 faeces and 97 oral swabs) of 17 bat species, followed by PCR amplification targeting five distinct viral genera (Filovirus, Coronavirus, Hantavirus, Paramyxovirus and Astrovirus). Overall, 1.6 % (3/125) of the samples from two bat species (Scotophilus dinganii and Miniopterus fraterculus) tested positive for astrovirus, with the coinfection of one bat with two AstV strains. No samples tested positive for Filovirus, Coronavirus, Hantavirus and Paramyxovirus. Phylogenetic analysis based on RNA-dependent RNA polymerase sequences revealed these sequences are respectively clustering with astroviruses detected in other bat species from the genus Scotophilus from East Asia and with astroviruses detected in Miniopterus bats from Africa and Asia. Altogether, these results are the first report of astroviruses in Tanzanian bats.

molecular biology↗

bioRxiv2020

BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the lungs with few treatment options. We recently reported loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptors 4 (DR4) and 5 (DR5). Using tissue microarray (TMAs) of tumour samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptors. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wild-type BAP1, but not catalytically-inactive mutant BAP1, reduced promoter activities of DR4 and DR5, suggesting deubiquinase activity plays an important role in the regulation of gene expression. Co-IP studies demonstrated direct binding of BAP1 and the transcription factor Ying Yang 1 (YY1) and ChIP assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Notably, shRNA knockdown of YY1 also increased DR4 and DR5 expression, and sensitivity to TRAIL. These results demonstrate that BAP1 and YY1 together negatively regulate transcriptional activity of TRAIL receptors. BAP1 and YY1 may both therefore be strong therapeutic targets to enhance the efficacy of TRAIL-induced apoptosis. Statement of significanceWe describe how the most-frequently mutated tumour suppressor gene in mesothelioma regulates the response to TNF-related apoptosis-inducing ligand (TRAIL). These findings will accelerate a biomarker-driven cancer therapy.

cancer biology↗

bioRxiv2019

Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer

Before squamous cell lung cancer develops, pre-cancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. While recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of pre-cancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in-situ lesions harbour more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, TGF-beta signalling is overactive, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the CIS lesions as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. This study identifies mechanisms by which pre-cancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early stage lung cancer.

cancer biology↗