Ruby C Y Lin

Westmead Institute for Medical Research · Centre for Infectious Diseases and Microbiology

We previously showed that paternal high-fat diet (HFD) consumption programs β-cell dysfunction in female rat offspring, together with transcriptome alterations in islets. Here we investigated the retroperitoneal white adipose tissue (RpWAT) transcriptome using gene and pathway enrichment and pathway analysis to determine whether commonly affected n...

Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110α) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110α) directly...

The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offsp...

Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110 alpha)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110 alpha) provides protection in a setting of MI is unknown, a...

A possible link between the glucocorticoid receptor gene ( GRL , 5q31-q32) and overweight has been suggested in a study of 42 families with morbid obesity.1 Data from another small study—of pairs of siblings—although not significant, showed a trend towards similar body mass index (weight(kg)/(height(m)2); difference=2.4) for 20 pairs sharing simila...

Cystic fibrosis (CF) is the most prevalent serious inherited disease in Australia, imposing significant health risks. CF is characterised by chronic lung inflammation and recurrent pulmonary infections that increase morbidity and premature mortality rates. The emergence of antimicrobial resistance (AMR) places further challenges on the treatment an...

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and...

Background: Concerns about the rise in antimicrobial resistance have led to renewed interest in phage therapy worldwide, but perceptions among relevant medical professionals in Korea remain largely unknown. Methods: We conducted a semi-quantitative online survey to evaluate the Korean Infectious Disease specialists' perception of phage therapy. Res...

Background: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-...

Infection is expected to be the leading cause of death within decades in a backdrop of rising antimicrobial resistance (AMR)1. Phage is a bacteria-killing virus used to treat AMR bacterial infections and is an effective therapeutic option when antibiotics fail1. To establish phages’ clinical value, we report here a pipeline consisting of genomic ch...

Due to the rise in antimicrobial resistance (AMR), there has been an increased interest in phage therapy to treat multi-drug resistant infections. In Australia, phage therapy is predominantly used in small clinical studies or for compassionate use, however, despite its potential expansion in modern medicine, the perception of phage therapy among me...

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here we applied highly purified phage T4, free from bacterial by-products and...

Introduction There has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy. Methods and analysis We propose an open-label, single-arm trial investigating a standardised treatment and monitoring pro...

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 2...

This is a white paper written for the purpose of explaining what Phage Australia is building and reflects on the past experience of phage therapy that led to the creation of STAMP protocol version 1.0 at Westmead Institute, Australia

Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in...

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 2...

Impact of Phage Therapy in AMR Sepsis Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The alarming increase of antimicrobial resistance (AMR) has resulted in the threat of sepsis being dramatically heightened. Almost any type of infection can lead to sepsis if not treated appropriately. B...

Prosthetic joint infections (PJI) are a catastrophic complication after a joint replacement which place a substantial economic burden on the health-care system. PJIs lead to substantial reduced quality of life, functional deficits, and increased mortality (1). The lack of success treating PJIs with conventional antibiotics alone is primarily relate...

The escalating issue of multidrug-resistant (MDR) bacteria indicates the urgent need for new and effective strategies to combat this global health challenge. Here, we describe a new combinatorial approach that can be put forward for experimental therapy application against MDR bacteria. Specifically, we have developed a tri-system that includes the...

Phage Directory has recently partnered with Phage Australia to help optimize Australia's data-centric standardized approach to personalized phage therapy. Here is a behind-the-scenes look at the genesis of Phage Australia, how the Phage Directory-Phage Australia partnership started, and what it is working toward.

Report: Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child. https://www.embopress.org/toc/17574684/2021/13/9

Adjunctive phage therapy was used in an attempt to avoid catastrophic outcomes from extensive chronic Pseudomonas aeruginosa osteoarticular infection in a 7-year-old child. Monitoring of phage and bacterial kinetics allowed real-time phage dose adjustment, and along with markers of the human host response, indicated a significant therapeutic effect...

The mechanisms underpinning beta‐cell compensation for obesity‐associated insulin resistance and beta‐cell failure in type 2 diabetes remain poorly understood. We used a large‐scale strategy to determine the time‐dependent transcriptomic changes in islets of diabetes‐prone db/db and diabetes‐resistant ob/ob mice at 6 and 16 weeks of age. Differenti...

Approximately 10% of global health research is devoted to 90% of global disease burden (the so-called “10/90 Gap”) and it often neglects those diseases most prevalent in low-income countries. Antibiotic resistant bacterial infections are known to impact on healthcare, food security, and socio-economic fabric in the developing countries. With a glob...

After a century of use in human infection, the preparation and administration of therapeutic bacteriophages (phages) still relies on ad hoc partnerships of researchers, biotech companies, clinicians and regulators. There is a clear need to improve the reproducibility, safety and speed of the provision of suitable phages. Here we discuss the specifi...

Successful phage therapy for extensive chronic osteoarticular infection in a child resulted in an initial flush of bacterial contents into the bloodstream with an inflammatory response marked by fever, local pain and upregulation of genes associated with autophagy and innate immunity. Monitoring of phage and bacterial kinetics and the human host re...

Objective: Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging, and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic gl...

Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome‐wide transcriptome of aortic tissue from Trail−/− versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses sho...

In this single-arm non-comparative trial, 13 patients in an Australian hospital with severe Staphylococcus aureus infections were intravenously administered a good manufacturing practice-quality preparation of three Myoviridae bacteriophages (AB-SA01) as adjunctive therapy. AB-SA01 was intravenously administered twice daily for 14 d and the clinica...

The effect of intravenous administration of bacteriophages manufactured under Good Manufacturing Practice (GMP) conditions in severe Staphylococcus aureus bacteraemia is unknown. A GMP-quality preparation of three Myoviridae bacteriophages (AB-SA01), was administered intravenously to thirteen patients with severe S. aureus infections receiving anti...

Objectives: Evaluate the role of porins in the susceptibility of Klebsiella pneumoniae to ceftaroline and ceftaroline-avibactam. Methods: Susceptibility to ceftaroline and ceftaroline-avibactam was tested by broth microdilution method in Klebsiella pneumoniae isolates (n = 65), including isogenic mutants (n = 30) and clinical isolates (n = 35), wit...

Introduction: Bacteriophage therapy is emerging as an approach to highly resistant and severe infection. Randomised studies are lacking but there have been some high-profile examples of successful salvage therapy using phages for highly antibiotic-resistant infection in critically ill patients. Here we describe the likely place of these agents in t...

Background: Polyclonal, coagulase-negative staphylococci are common contaminants of blood cultures (1), but polyclonal, coagulase-positive staphylococci (Staphylococcus aureus) have yet to be unambiguously identified as a cause of bacteremia. Objective: To describe a patient with simultaneous and persistent bacteremia from 2 strains of S aureus. Ca...

• Bacteriophage (phage) therapy is re-emerging a century after it began. • Activity against antibiotic-resistant pathogens and a lack of serious side effects make phage therapy an attractive treatment option in refractory bacterial infection. • Phages are highly specific for their bacterial targets but the relationship between in vitro activity and...

Pseudomonas aeruginosa is a frequent causative agent of ventilation-associated pneumonia (VAP) with high attributable mortality (~13%), which may double in patients with multi-drug resistant (MDR) infection. Bacteriophage therapy was first utilised as antibacterial therapy in the early 1900s. Losing favour in the West with the advent of antibiotics...

Phage researchers and clinicians from the Westmead Institute and Westmead Hospital brief us on how phage therapy is regulated in Australia, through the lens of their experience treating 14 patients with IV phage therapy.

Importance: The effect of IV administration of a bacteriophage cocktail produced under GMP conditions on patients with severe S. aureus infection, including complicated bacteraemia, endocarditis and septic shock, is unknown. Objective: To assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections...

Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic...

The rise of multiple antibiotic resistance in clinically relevant bacteria has created a global crisis with increasing burden on healthcare systems. The need to optimise alternative therapies to antibiotics, particularly in high risk nosocomial settings, is therefore immediate. Bacteriophages are specialised lethal viruses of bacteria, and an under...

Circulating TNF-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis, and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protecti...

Aims: Definitive diagnosis of malignant pleural mesothelioma (MPM) is difficult and requires invasive tumour biopsy.MicroRNAs are proven to be dysregulated in MPM and have therapeutic potential. Circular RNAs (circRNAs) are noncoding competitive endogenous RNAs (ceRNAs) that interact with microRNAs as ‘sponges’ via direct binding, subsequently lead...

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial–me...

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterised by frequent chromosomal deletions of tumour suppressors, including microRNAs. MiR-137 plays a tumour suppressor role in other cancers, so the aim of this study was to characterise it and its target Y-bo...

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of vitamin D are mediated through binding to the vitamin D receptor (VDR). Here, we report on the unexpected finding that stable knockdown of VDR expres¬sion in the human breast and...

Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders, however choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield of neural precursors from small samples of adult canine skin. Here we probe their gene and protein expression pr...

Document S1. Supplemental Experimental Procedures, Figures S1–S7, and Tables S1–S3

Malignant pleural mesothelioma (MPM) is a tumor originating in the mesothelium, the membrane lining the thoracic cavities, and is induced by exposure to asbestos. Australia suffers one of the world's highest rates of MPMand the incidence is yet to peak. The prognosis for patients withMPMis poor and median survival following diagnosis is 4–18 months...

Background Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional r...

Key points: MicroRNA (miRNA)-based therapies are in development for numerous diseases, including heart disease. Currently, very limited basic information is available on the regulation of specific miRNAs in male and female hearts in settings of disease. The identification of sex-specific miRNA signatures has implications for translation into the c...

Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription fac...

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult mal...

miRNAs are small non-coding RNAs (ncRNAs), which regulate gene expression. Here, the authors describe the contribution of miRNAs to cardiac biology and disease. They discuss various strategies for manipulating miRNA activity including antisense oligonucleotides (antimiRs, blockmiRs), mimics, miRNA sponges, Tough Decoys and miRNA mowers. They review...