Publications by authors named "Jason S Lee"

56 Publications

Correction to 'Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer'.

NAR Cancer 2021 Sep 22;3(3):zcab041. Epub 2021 Sep 22.

Queensland University of Technology (QUT), Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Woolloongabba QLD 4121, Australia.

[This corrects the article DOI: 10.1093/nar/zcab022.].
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http://dx.doi.org/10.1093/narcan/zcab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457359PMC
September 2021

Genome instability and pressure on non-homologous end joining drives chemotherapy resistance via a DNA repair crisis switch in triple negative breast cancer.

NAR Cancer 2021 Jun 15;3(2):zcab022. Epub 2021 Jun 15.

Queensland University of Technology (QUT), Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Woolloongabba QLD 4121, Australia.

Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of DNA repair driven chemotherapy resistance and tailor patient staging appropriately. There have been numerous studies into chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. In this study, we hypothesized that the emergence of chemotherapy resistance in triple negative breast cancer was driven by changes in functional signaling in the DNA repair pathways. We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurred to repair residual double strand DNA breaks. Further we demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination in clinical samples.
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http://dx.doi.org/10.1093/narcan/zcab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210242PMC
June 2021

Carbocation-Mediated Cyclization of Trienes in Acid Zeolites.

J Phys Chem A 2021 May 10;125(19):4062-4069. Epub 2021 May 10.

Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware 19716, United States.

The mechanism by which acid zeolites catalyze the formation of aromatic species is not fully understood and is important in an array of industrial processes such as the methanol to gasoline reaction. The so-called "carbon pool" mechanism is generally agreed to be the main channel for the formation of hydrocarbons from methanol. There is, however, no agreed sequence of elementary steps that explains how linear intermediates transform to cyclic intermediates, let alone aromatic rings. Recent work suggests the formation of conjugated trienes during zeolite-catalyzed aromatization, but mechanisms involving triene-derived carbocations have never been investigated using modern computational tools. In this work, we propose a new mechanism for cyclization of hexatriene over the Brønsted acid site of faujasite zeolite. Microkinetic models (MKM) using the results of Density Functional Theory (DFT) calculations predict selectivity for neutral 5-membered-ring intermediates over 6-membered-ring intermediates, as suggested by infrared and UV-vis spectroscopic results reported by others. Given that the products of aromatization are 6-membered rings, this result suggests that triene cyclization can only explain how linear hydrocarbons become cyclic intermediates but not the mechanisms that ultimately lead to the aromatic rings seen in industrial zeolite-catalyzed hydrocarbon processes.
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http://dx.doi.org/10.1021/acs.jpca.0c11574DOI Listing
May 2021

Histone Modifying Enzymes in Gynaecological Cancers.

Cancers (Basel) 2021 Feb 16;13(4). Epub 2021 Feb 16.

Medical Genomics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.
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http://dx.doi.org/10.3390/cancers13040816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919659PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma.

Clin Cancer Res 2021 May 15;27(9):2624-2635. Epub 2021 Feb 15.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Purpose: G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether , a G9a target gene, can predict treatment response.

Experimental Design: Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model.

Results: Patients with melanoma who responded to checkpoint inhibitor blockade were associated with not only a higher level of tumor LC3B but also a higher proportion of cells expressing LC3B. A higher expression of or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade, suggesting LC3B as a potential predictive biomarker. We demonstrate that G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death.

Conclusions: Checkpoint inhibitor blockade response is limited to a subset of the patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3463DOI Listing
May 2021

ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome.

Cancer Immunol Res 2020 08 22;8(8):1085-1098. Epub 2020 May 22.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8 T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8 T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0653DOI Listing
August 2020

G9a-mediated repression of CDH10 in hypoxia enhances breast tumour cell motility and associates with poor survival outcome.

Theranostics 2020 15;10(10):4515-4529. Epub 2020 Mar 15.

QIMR Berghofer Medical Research Institute, Herston Rd, Herston, QLD 4006, Australia.

: Epigenetic mechanisms are fundamental processes that can modulate gene expression, allowing cellular adaptation to environmental conditions. Hypoxia is an important factor known to initiate the metastatic cascade in cancer, activating cell motility and invasion by silencing cell adhesion genes. G9a is a histone methyltransferase previously shown to accumulate in hypoxic conditions. While its oncogenic activity has been previously reported, not much is known about the role G9a plays in the hypoxia-mediated metastatic cascade. : The role of G9a in cell motility in hypoxic condition was determined by inhibiting G9a either by short-hairpin mediated knock down or pharmacologically using a small molecule inhibitor. Through gene expression profiling, we identified CDH10 to be an important G9a target that regulates breast cancer cell motility. Lung metastasis assay in mice was used to determine the physiological significance of G9a. : We demonstrate that, while hypoxia enhances breast cancer migratory capacity, blocking G9a severely reduces cellular motility under both normoxic and hypoxic conditions and prevents the hypoxia-mediated induction of cellular movement. Moreover, inhibition of G9a histone methyltransferase activity in mice using a specific small molecule inhibitor significantly reduced growth and colonisation of breast cancer cells in the lung. We identify the type-II cadherin as being a novel hypoxia-dependent gene, directly repressed by G9a through histone methylation. CDH10 overexpression significantly reduces cellular movements in breast cancer cell lines and prevents the hypoxia-mediated increase in cell motility. In addition, we show that expression is prognostic in breast cancer and that it is inversely correlated to (G9a) transcript levels in many tumor-types, including breast cancer. : We propose that G9a promotes cellular motility during hypoxic stress through the silencing of the cell adhesion molecule CDH10 and we describe as a novel prognostic biomarker for breast cancer.
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http://dx.doi.org/10.7150/thno.41453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150496PMC
April 2021

Chromatin interactome mapping at 139 independent breast cancer risk signals.

Genome Biol 2020 01 7;21(1). Epub 2020 Jan 7.

Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression.

Results: We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region.

Conclusions: Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.
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http://dx.doi.org/10.1186/s13059-019-1877-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947858PMC
January 2020

Marine biofilm bacterial community response and carbon steel loss following Deepwater Horizon spill contaminant exposure.

Biofouling 2019 09 11;35(8):870-882. Epub 2019 Oct 11.

Division of Coastal Sciences, School of Ocean Science and Engineering, University of Southern Mississippi, Ocean Springs, MS, USA.

Steel marine structures provide foci of biodiversity when they develop into artificial reefs. Development begins with deposition of a biofilm. The effects of contaminants from oil spills on biofilm microbiomes, microbially-induced corrosion (MIC) and metal loss may impact preservation of marine metal structures. A microcosm experiment exposed biofilms on carbon steel disks (CSDs) to crude oil, dispersant, and dispersed oil to address their impacts on bacterial composition and metal loss and pitting. Biofilm diversity increased over time in all exposures. Community composition in dispersant and dispersed oil treatments deviated from the controls for the duration of a 12-week experiment. As biofilms matured, Pseudomonadaceae increased while Rhodobacteraceae decreased in abundance in dispersed oil treatments compared to the controls and dispersant treatments. Greatest mass loss and deepest pitting on CSDs were observed in dispersed oil treatments, suggesting impacts manifest as a consequence of increased MIC potential on carbon steel.
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http://dx.doi.org/10.1080/08927014.2019.1673377DOI Listing
September 2019

Molecular basis of distinct oestrogen responses in endometrial and breast cancer.

Endocr Relat Cancer 2019 01;26(1):31-46

UCD School of Medicine, Catherine McAuley Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland.

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.
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http://dx.doi.org/10.1530/ERC-17-0563DOI Listing
January 2019

Millennial Resident Study Habits and Factors that Influence American Board of Anesthesiology In-Training Examination Performance: A Multi-Institutional Study.

J Educ Perioper Med 2018 Apr-Jun;20(2):E623. Epub 2018 Apr 1.

Background: In this study, we described Millennial anesthesiology residents' learning preferences and study habits and how they correlate with performance on the In-Training Exam (ITE).

Methods: A confidential questionnaire including personal characteristics, previous examination performance, study habits, study material preferences, and perceived residency program support was emailed to 1047 anesthesiology residents from 30 ACGME-accredited residency programs across the United States.

Results: Four hundred and twelve residents (39.4%) responded to the survey, and 240 of those respondents (58.3%) self-reported their 2017 ITE scores. The majority (95.9%) were Millennials. Respondents preferentially used online multiple-choice questions (92.3%) to prepare for the ITE, but many also used traditional anesthesiology textbooks (35.5%) and review books (46.7%). Respondents preferred independent study (94.6%) to group study (5.4%), and handwritten notes (69.4%) to taking notes on a laptop (26.8%) or tablet (3.8%). Less than half (47.5%) of respondents felt supported by their residency program in exam preparation, and 30.7% felt lack of support. Factors correlated with ITE scores on univariate analysis included prior USMLE 1 scores (p < .0000) and USMLE 2 scores (p < .0000), clinical anesthesia year (p < .0000), test anxiety score (p = .0004), prior failure of the basic exam (p = .0026), and prior failure of any board exam (p = .0124).

Conclusions: Millennial learners have consistent performance on ITE exams regardless of personal characteristics, preferred study methods, or materials used. Prior exam performance is the most important predictor of future performance. Currently available study materials are meeting residents' needs and preferences, and while residency program offerings do not affect ITE performance, residents would like to feel more supported.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055534PMC
April 2018

Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130.

J Immunol 2018 05 6;200(10):3547-3555. Epub 2018 Apr 6.

Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia;

IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Rα or soluble IL-6Rα. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p-STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex. Furthermore, we demonstrate that this is due to a lack of gp130 expression on mouse and human granulocytes, despite their expression of membrane-bound IL-6R. Importantly, the absence of gp130 is not only a feature of mature granulocytes in healthy individuals, it is also observed after allogeneic stem cell transplantation. Moreover, granulocyte gp130 expression is lost during maturation, because granulocyte-monocyte progenitor cells express gp130 and respond to IL-6. Given that granulocytes constitute 50-70% of circulating leukocytes, this indicates a significantly smaller scope of IL-6 signaling than previously anticipated and has important implications for therapeutic IL-6 inhibition and the mechanisms of action thereof.
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http://dx.doi.org/10.4049/jimmunol.1701191DOI Listing
May 2018

G9a in hypoxia: Linking tumor hypoxia and epigenetic regulation.

Cell Cycle 2017 3;16(21):2001-2002. Epub 2017 Oct 3.

a Control of Gene Expression Laboratory, QIMR Berghofer Medical Research Institute , Herston Rd, Herston , QLD , Australia.

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http://dx.doi.org/10.1080/15384101.2017.1377505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731417PMC
May 2019

Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells.

Nat Immunol 2017 Sep 31;18(9):1004-1015. Epub 2017 Jul 31.

Immunology in Cancer and Infection, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49aCD49bEomes) into intermediate type 1 innate lymphoid cell (intILC1) (CD49aCD49bEomes) populations and ILC1 (CD49aCD49bEomes) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.
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http://dx.doi.org/10.1038/ni.3800DOI Listing
September 2017

Eomesodermin promotes the development of type 1 regulatory T (T1) cells.

Sci Immunol 2017 Apr;2(10)

QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Type 1 regulatory T (T1) cells are Foxp3 interleukin-10 (IL-10)-producing CD4 T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that T1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for T1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages. We further show that Eomes induction in T1 cells requires T-bet and donor macrophage-derived IL-27. Thus, we define the cellular and transcriptional control of T1 cell differentiation during BMT, opening new avenues to therapeutic manipulation.
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http://dx.doi.org/10.1126/sciimmunol.aah7152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714294PMC
April 2017

Improving Efficiency While Improving Patient Care in a Student-Run Free Clinic.

J Am Board Fam Med 2017 Jul-Aug;30(4):513-519

From the Department of Medical Education, University of Central Florida College of Medicine, Orlando.

Introduction: Student-run free clinics (SRFCs) have the capacity to decrease health care inequity in underserved populations. These facilities can benefit from improved patient experience and outcomes. We implemented a series of quality improvement interventions with the objectives to decrease patient wait times and to increase the variety of services provided.

Methods: A needs assessment was performed. Problems related to time management, communication between staff and providers, clinic resources, and methods for assessing clinic performance were identified as targets to reduce wait times and improve the variety of services provided. Seventeen interventions were designed and implemented over a 2-month period.

Results: The interventions resulted in improved efficiency for clinic operations and reduced patient wait times. The number of specialty providers, patient visits for specialty care, lifestyle education visits for disease prevention and treatment, free medications, and free laboratory investigations increased to achieve the goal of improving the availability and the variety of services provided.

Conclusions: We demonstrated that it is feasible to implement successful quality improvement interventions in SRFCs to decrease patient wait times and to increase the variety of services provided. We believe that the changes we implemented can serve as a model for other SRFCs to improve their performance.
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http://dx.doi.org/10.3122/jabfm.2017.04.170044DOI Listing
February 2018

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis.

Proc Natl Acad Sci U S A 2017 07 19;114(27):7077-7082. Epub 2017 Jun 19.

QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia;

G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including , , , , , and This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a-suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers.
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http://dx.doi.org/10.1073/pnas.1618706114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502591PMC
July 2017

Sumoylation and Its Contribution to Cancer.

Adv Exp Med Biol 2017 ;963:283-298

Department of Biological Sciences, Seoul National University, Seoul, 151-742, South Korea.

Post-translational modifications play an important role in regulating protein activity by altering their functions. Sumoylation is a highly dynamic process which is tightly regulated by a fine balance between conjugating and deconjugating enzyme activities. It affects intracellular localization and their interaction with their binding partners, thereby changing gene expression. Consequently, these changes in turn affect signaling mechanisms that regulate many cellular functions, such as cell growth, proliferation, apoptosis , DNA repair , and cell survival. It is becoming apparent that deregulation in the SUMO pathway contributes to oncogenic transformation by affecting sumoylation/desumoylation of many oncoproteins and tumor suppressors. Loss of balance between sumoylation and desumoylation has been reported in a number of studies in a variety of disease types including cancer. This chapter summarizes the mechanisms and functions of the deregulated SUMO pathway affecting oncogenes and tumor suppressor genes.
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http://dx.doi.org/10.1007/978-3-319-50044-7_17DOI Listing
September 2017

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.

Am J Hum Genet 2016 Oct 15;99(4):903-911. Epub 2016 Sep 15.

Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany.

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER) breast cancer (per-g allele OR ER = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER) breast cancer (lead SNP rs6864776: per-a allele OR ER = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10), and a single signal 3 SNP (rs200229088: per-t allele OR ER = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2016.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065698PMC
October 2016

Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity.

Immunity 2016 08;45(2):333-45

QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4029, Australia. Electronic address:

Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.
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http://dx.doi.org/10.1016/j.immuni.2016.07.017DOI Listing
August 2016

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Am J Hum Genet 2016 05 14;98(5):830-842. Epub 2016 Apr 14.

Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863475PMC
May 2016

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Nat Genet 2016 Apr 29;48(4):374-86. Epub 2016 Feb 29.

Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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http://dx.doi.org/10.1038/ng.3521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938803PMC
April 2016

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.

Oncotarget 2016 Feb;7(6):6353-68

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
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http://dx.doi.org/10.18632/oncotarget.7047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872719PMC
February 2016

Functional Role of G9a Histone Methyltransferase in Cancer.

Front Immunol 2015 25;6:487. Epub 2015 Sep 25.

Control of Gene Expression Laboratory, QIMR Berghofer Medical Research Institute , Herston, QLD , Australia ; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology , Kelvin Grove, QLD , Australia ; School of Chemistry and Molecular Biosciences, University of Queensland , Brisbane, QLD , Australia.

Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes. A number of different epigenetic enzymes are actively involved in the addition or the removal of various covalent modifications, which include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Deregulation of these processes is a hallmark of cancer. For instance, G9a, a histone methyltransferase responsible for histone H3 lysine 9 (H3K9) mono- and dimethylation, has been observed to be upregulated in different types of cancer and its overexpression has been associated with poor prognosis. Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies. Several small molecule inhibitors have been developed to specifically block the epigenetic activity of these enzymes, representing promising therapeutic tools in the treatment of human malignancies, such as cancer. In this review, the role of one of these epigenetic enzymes, G9a, is discussed, focusing on its functional role in regulating gene expression as well as its implications in cancer initiation and progression. We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.
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http://dx.doi.org/10.3389/fimmu.2015.00487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585248PMC
October 2015

Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants.

Am J Hum Genet 2015 Aug 23;97(2):329-36. Epub 2015 Jul 23.

QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia. Electronic address:

The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases.
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http://dx.doi.org/10.1016/j.ajhg.2015.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573275PMC
August 2015

Understanding Small-Molecule Interactions in Metal-Organic Frameworks: Coupling Experiment with Theory.

Adv Mater 2015 Oct 28;27(38):5785-96. Epub 2015 May 28.

The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.

Metal-organic frameworks (MOFs) have gained much attention as next-generation porous media for various applications, especially gas separation/storage, and catalysis. New MOFs are regularly reported; however, to develop better materials in a timely manner for specific applications, the interactions between guest molecules and the internal surface of the framework must first be understood. A combined experimental and theoretical approach is presented, which proves essential for the elucidation of small-molecule interactions in a model MOF system known as M2 (dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M = Mg, Mn, Fe, Co, Ni, Cu, or Zn), a material whose adsorption properties can be readily tuned via chemical substitution. It is additionally shown that the study of extensive families like this one can provide a platform to test the efficacy and accuracy of developing computational methodologies in slightly varying chemical environments, a task that is necessary for their evolution into viable, robust tools for screening large numbers of materials.
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http://dx.doi.org/10.1002/adma.201500966DOI Listing
October 2015

DNAM-1 expression marks an alternative program of NK cell maturation.

Cell Rep 2015 Apr 26;11(1):85-97. Epub 2015 Mar 26.

Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, Herston, QLD 4006, Australia. Electronic address:

Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1(+) and DNAM-1(-) NK cells. DNAM-1(+) NK cells produce high levels of inflammatory cytokines, have enhanced interleukin 15 signaling, and proliferate vigorously. By contrast, DNAM-1(-) NK cells that differentiate from DNAM-1(+) NK cells have greater expression of NK-cell-receptor-related genes and are higher producers of MIP1 chemokines. Collectively, our data reveal the existence of a functional program of NK cell maturation marked by DNAM-1 expression.
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http://dx.doi.org/10.1016/j.celrep.2015.03.006DOI Listing
April 2015

Mini-review: the morphology, mineralogy and microbiology of accumulated iron corrosion products.

Biofouling 2014 Sep;30(8):941-8

a Naval Research Laboratory , Stennis Space Center , MS , USA.

Despite obvious differences in morphology, substratum chemistry and the electrolyte in which they form, accumulations of iron corrosion products have the following characteristics in common: stratification of iron oxides/hydroxides with a preponderance of α-FeOOH (goethite) and accumulation of metals. Bacteria, particularly iron-oxidizing and sulfate-reducing bacteria have been identified in some accumulations. Both biotic and abiotic mechanisms have been used to rationalize observations for particular sets of environmental data. This review is the first to compare observations and interpretations.
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http://dx.doi.org/10.1080/08927014.2014.951039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226311PMC
September 2014

Issues for storing plant-based alternative fuels in marine environments.

Bioelectrochemistry 2014 Jun 24;97:145-53. Epub 2013 Dec 24.

Department of Microbiology and Plant Biology, 770 Van Vleet Oval, University of Oklahoma, Norman, OK 73019, USA.

Two coastal seawaters (Key West, FL, USA and the Persian Gulf, Bahrain, representing oligotrophic and eutrophic environments, respectively) were used to evaluate potential biodegradation and corrosion problems during exposure to alternative and conventional fuels. Uncoated carbon steel was exposed at the fuel/seawater interface and polarization resistance was monitored. Under typical marine storage conditions, dioxygen in natural seawater exposed to fuel and carbon steel was reduced to <0.1parts-per-million within 2d due to consumption by corrosion reactions and aerobic microbial respiration. Sulfides, produced by anaerobic sulfate-reducing bacteria, and chlorides were co-located in corrosion products. Transient dioxygen influenced both metabolic degradation pathways and resulting metabolites. Catechols, indicative of aerobic biodegradation, persisted after 90d exposures. Detection of catechols suggested that initial exposure to dioxygen resulted in the formation of aerobic metabolites that exacerbated subsequent corrosion processes.
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http://dx.doi.org/10.1016/j.bioelechem.2013.12.003DOI Listing
June 2014
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