Publications by authors named "Brett D Hambly"

55 Publications

Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19.

Front Cardiovasc Med 2021 6;8:630767. Epub 2021 Aug 6.

School of Biomedical Engineering, The University of Sydney, Sydney, NSW, Australia.

Atherosclerosis, which is a primary cause of cardiovascular disease (CVD) deaths around the world, is a chronic inflammatory disease that is characterised by the accumulation of lipid plaques in the arterial wall, triggering inflammation that is regulated by cytokines/chemokines that mediate innate and adaptive immunity. This review focuses on IL-32, -34 and -37 in the stable vs. unstable plaques from atherosclerotic patients. Dysregulation of the novel cytokines IL-32, -34 and -37 has been discovered in atherosclerotic plaques. IL-32 and -34 are pro-atherogenic and associated with an unstable plaque phenotype; whereas IL-37 is anti-atherogenic and maintains plaque stability. It is speculated that these cytokines may contribute to the explanation for the increased occurrence of atherosclerotic plaque rupture seen in patients with COVID-19 infection. Understanding the roles of these cytokines in atherogenesis may provide future therapeutic perspectives, both in the management of unstable plaque and acute coronary syndrome, and may contribute to our understanding of the COVID-19 cytokine storm.
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http://dx.doi.org/10.3389/fcvm.2021.630767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377289PMC
August 2021

The Impact of COVID-19 on Primary Care General Practice Consultations in a Teaching Hospital in Shanghai, China.

Front Med (Lausanne) 2021 26;8:642496. Epub 2021 Mar 26.

Department of General Practice, Tongren Hospital, Shanghai, China.

The COVID-19 (2019 novel coronavirus disease) pandemic is deeply concerning because of its massive mortality and morbidity, creating adverse perceptions among patients likely to impact on their overall medical care. Thus, we evaluated the impact of the COVID-19 pandemic on the pattern of primary care consultations within a Shanghai health district. A retrospective observational cohort study was performed, with data analyzed concerning the pattern of patient visits to general practitioners within the Tongren Hospital network (the sole provider of general practice to the population of 700,000). Data from all general practice consultations for adults were collected for the first 6 months of 2020, which included a 60-day lockdown period (January 24-March 24, 2020) and compared to corresponding data from the first 6 months of 2019. We evaluated changes to the numbers and patterns of primary care consultations, including subgroup analysis based on age, sex, and primary diagnosis. A substantial reduction in patient visits, associated with increased median age, was observed during the first wave of the pandemic in the first 6 months of 2020, compared to the same interval during 2019. Additionally, reduced reappointments and waiting times, but increased costs per visit were observed. When analyzed by primary disease diagnosis, patient visits were reduced for all the major systems. The most striking visit reductions were in cardiovascular, respiratory, endocrine, and gastrointestinal diseases. However, psychological disorders were increased following lockdown, but there was also a dramatic fall in consultations for depression. Reduced monthly patient numbers correlated with both rate of reappointment and average waiting time during the first 6 months of both 2019 and 2020, but an inverse correlation was observed between cost per visit and monthly patient numbers. Specifically during the lockdown period, there was ~50% reduced patient visits. The lockdown has had a serious impact on patients' physical and psychological health. Our analysis provides objective health-related data that may inform the current controversy concerning the balance between the detrimental effects of the use of lockdown vs. the use of a more targeted approach to eliminate viral transmission. These data may improve decision-making in medical practice, policy, and education.
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http://dx.doi.org/10.3389/fmed.2021.642496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033033PMC
March 2021

Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities.

Redox Rep 2021 Dec;26(1):45-52

Discipline of Pathology and Charles Perkins Centre, The University of Sydney, Sydney, Australia.

The primary objective of this review was to explore the contribution of oxidative stress to the pathogenesis of genetically-triggered thoracic aortic aneurysm (TAA). Genetically-triggered TAAs manifest substantial variability in onset, progression, and risk of aortic dissection, posing a significant clinical management challenge. There is a need for non-invasive biomarkers that predict the natural course of TAA and therapeutics that prevent aneurysm progression. An online systematic search was conducted within PubMed, MEDLINE, Scopus and ScienceDirect databases using keywords including: oxidative stress, ROS, nitrosative stress, genetically triggered thoracic aortic aneurysm, aortic dilatation, aortic dissection, Marfan syndrome, Bicuspid Aortic Valve, familial TAAD, Loeys Dietz syndrome, and Ehlers Danlos syndrome. There is extensive evidence of oxidative stress and ROS imbalance in genetically triggered TAA. Sources of ROS imbalance are variable but include dysregulation of redox mediators leading to either insufficient ROS removal or increased ROS production. Therapeutic exploitation of redox mediators is being explored in other cardiovascular conditions, with potential application to TAA warranting further investigation. Oxidative stress occurs in genetically triggered TAA, but the precise contribution of ROS to pathogenesis remains incompletely understood. Further research is required to define causative pathological relationships in order to develop therapeutic options.
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http://dx.doi.org/10.1080/13510002.2021.1899473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971305PMC
December 2021

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms.

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Discipline of Pathology and Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia.

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets.
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http://dx.doi.org/10.3390/ijms21207678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590002PMC
October 2020

The Epidemiology of COVID-19 in the Gansu and Jinlin Provinces, China.

Front Public Health 2020 11;8:555550. Epub 2020 Sep 11.

School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China.

The COVID-19 outbreak has become a pandemic. The outbreak was able to be controlled in China by mid-April through the implementation of critical measures; however, significant reverse transmission has resulted in hot spots perturbing prevention and control. To date, there have only been a total of 92 indigenous COVID-19 cases confirmed in the Gansu Province, which is considered to be a consequence of the strict screening approach applied during the outbreak. The emergency response level to COVID-19 were able to be decreased from high to low, despite some relatively minor reverse transmission cases from other countries in March 2020. The stringent preparative measures undertaken by the Gansu authorities, involving high-level, streamlined cooperation between the transportation, quarantine, and medical resource departments, have underpinned this success. There has been an emergence of clusters of freshly infected COVID-19 patients in the Jilin Province in northeast China. The single largest cluster has been in Shulan of the Jilin Province, involving 43 confirmed infections. A strict lockdown was implemented immediately. The source of the current outbreak of COVID-19 is suggested to be travelers returning from Russia. The current strategy from the Chinese authorities is aimed at preventing reverse transmission via international importation to avert a rebound of COVID-19 in China. These data highlight the need for an exceptionally high level of vigilance and for a pre-emptive response that is informative for the development of policy to prevent a second and further waves of infections in general.
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http://dx.doi.org/10.3389/fpubh.2020.555550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517784PMC
May 2021

Bibliometric Analysis on COVID-19: A Comparison of Research Between English and Chinese Studies.

Front Public Health 2020 14;8:477. Epub 2020 Aug 14.

School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China.

As an emerging infectious disease, COVID-19 has garnered great research interest. We aimed to explore the differences between English language and Chinese language Medical/Scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in English and Chinese in relation to the outcomes of management and characterization of COVID-19 during the early stage of COVID-19 pandemic. Publications on COVID-19 research were retrieved from both English and Chinese databases. Bibliometric analyses were performed using VOSviewer 1.6.14, and CiteSpace V software. Network maps were generated to evaluate the collaborations between different authors, countries/provinces, and institutions. A total of 143 English and 721 Chinese original research articles and reviews on COVID-19 were included in our study. Most of the authors and institutions of the papers were from China before March 1st, 2020, however, the distribution of authors and institutions were mainly in developed countries or more wealthy areas of China. The range of the keywords in English publications was more extensive than those in Chinese. Traditional Chinese Medicine was seen more frequently in Chinese papers than in English. Of the 143 articles published in English, 54 articles were published by Chinese authors only and 21 articles were published jointly by Chinese and other overseas authors. The publications in English have enabled medical practitioners and scientists to share/exchange information, while on the other hand, the publications in the Chinese language have provided complementary educational approaches for the local medical practitioners to understand the essential and key information to manage COVID-19 in the relatively remote regions of China, for the general population with a general level of education.
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http://dx.doi.org/10.3389/fpubh.2020.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456831PMC
May 2021

Inverse correlation between Interleukin-34 and gastric cancer, a potential biomarker for prognosis.

Cell Biosci 2020 4;10:94. Epub 2020 Aug 4.

Discipline of Pathology, Bosch Institute and School of Medical Sciences, Charles Perkins Center D17, Sydney Medical School, The University of Sydney, Sydney, NSW 2006 Australia.

Background: Gastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis. It is important to develop reliable biomarker(s) with specificity, sensitivity and convenience for early diagnosis. The role of tumour-associated macrophages (TAMs) and survival of GC patients are controversial. Macrophage colony stimulating factor (MCSF) regulates monocytes/macrophages. Elevated MCSF is correlated with invasion, metastasis and poor survival of tumour patients. IL-34, a ligand of the M-CSF receptor, acts as a "twin" to M-CSF, demonstrating overlapping and complimentary actions. IL-34 involvement in tumours is controversial, possibly due to the levels of M-CSF receptors. While the IL-34/M-CSF/M-CSFR axis is very important for regulating macrophage differentiation, the specific interplay between these cytokines, macrophages and tumour development is unclear.

Methods: A multi-factorial evaluation could provide more objective utility, particularly for either prediction and/or prognosis of gastric cancer. Precision medicine requires molecular diagnosis to determine the specifically mutant function of tumours, and is becoming popular in the treatment of malignancy. Therefore, elucidating specific molecular signalling pathways in specific cancers facilitates the success of a precision medicine approach. Gastric cancer tissue arrays were generated from stomach samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, M-CSF, IL-34 and macrophages were determined.

Results: We found that IL-34 may serve as a predictive biomarker, but not as an independent, prognostic factor in GC; M-CSF inversely correlated with survival of GC in TNM III-IV subtypes. Increased CD68 TAMs were a good prognostic factor in some cases and could be used as an independent prognostic factor in male T3 stage GC.

Conclusion: Our data support the potency of IL-34, M-CSF, TAMs and the combination of IL-34/TAMs as novel biological markers for GC, and may provide new insight for both diagnosis and cellular therapy of GC.
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http://dx.doi.org/10.1186/s13578-020-00454-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399616PMC
August 2020

The RNA-binding fragile-X mental retardation protein and its role beyond the brain.

Biophys Rev 2020 Aug 11;12(4):903-916. Epub 2020 Jul 11.

Discipline of Pathology and Bosch Institute, The University of Sydney, Level 4 West, Charles Perkins Centre D17, Sydney, NSW, 2006, Australia.

It is well-established that variations of a CGG repeat expansion in the gene FMR1, which encodes the fragile-X mental retardation protein (FMRP), cause the neurocognitive disorder, fragile-X syndrome (FXS). However, multiple observations suggest a general and complex regulatory role of FMRP in processes outside the brain: (1) FMRP is ubiquitously expressed in the body, suggesting it functions in multiple organ systems; (2) patients with FXS can exhibit a physical phenotype that is consistent with an underlying abnormality in connective tissue; (3) different CGG repeat expansion lengths in FMR1 result in different clinical outcomes due to different pathogenic mechanisms; (4) the function of FMRP as an RNA-binding protein suggests it has a general regulatory role. This review details the complex nature of FMRP and the different CGG repeat expansion lengths and the evidence supporting the essential role of the protein in a variety of biological and pathological processes.
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http://dx.doi.org/10.1007/s12551-020-00730-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429658PMC
August 2020

IL-34, IL-36 and IL-38 in colorectal cancer-key immunoregulators of carcinogenesis.

Biophys Rev 2020 Aug 7;12(4):925-930. Epub 2020 Jul 7.

Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.

Colorectal cancer (CRC) is still a big killer nowadays, but the precise underlying mechanism remains to be explored. It is believed that imbalance of host immunity in the local microenvironment plays a critical role in the tumorigenesis of CRC. IL-34 is inversely correlated with overall survival in CRC patients, perhaps via regulating terminal differentiation of a subset of macrophages (M2). It is believed that the recruitment/differentiation of M2 macrophages within the cancer simply represents an increase in number, but the function of these M2 macrophages may be compromised. IL-36s (IL-36α, β and γ) are constitutively expressed in non-cancer colon tissue, but colonic IL-36α, IL-36β and IL-36γ are substantially reduced in the CRC tissues (~ 80%). IL-36α is an independent factor affecting the survival of CRC patients. The level of IL-36α and/or IL-36γ in CRC tissue could potentially be used as biomarkers for predicting the prognosis of CRC at both the later or early stages of CRC. IL-38 is also an anti-inflammatory cytokine. Colonic IL-38 is ~ 95% lower in CRC compared to non-CRC colonic tissue, consistent with the positive correlation between differentiation of CRC, and colonic tumour expression of IL-38. IL-38 is a reliable/sensitive biomarker for distinguishing between CRC and non-cancer colonic tissue. There is a positive correlation between colonic IL-38 in CRC and prognosis and/or overall survival, particularly in advanced CRC, supporting IL-38 probably being a reliable and consistent independent factor in predicting the prognosis of CRC. The findings above may be useful in exploring therapeutic targeting for precision medicine.
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http://dx.doi.org/10.1007/s12551-020-00726-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429605PMC
August 2020

RUNX1T1 rs34269950 is associated with obesity and metabolic syndrome.

QJM 2020 Jun 26. Epub 2020 Jun 26.

Health Vertical, Torrens University Australia, Sydney, Australia.

Background: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated (FTO). However, the extent to which RUNX1T1 single nucleotide polymorphisms (SNPs), are associated with obesity risk or metabolic abnormalities in a community population basis is unknown.

Methods: Samples were obtained from the Australian Crossroads study bio-bank. SNPs located in the coding region and 3'untranslated regions of RUNX1T1 with minor allele frequency (MAF) ≥ 0.05 were analysed using Taqman genotyping assays.

Results: 8 candidate SNPs were genotyped successfully in 1440 participants. Of these SNPs only rs34269950 located in the "RRACH" motif, the most common N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was significantly associated with obesity risk and metabolic abnormalities. Specifically, compared to AA genotype, rs34269950 del/del genotype was associated with a 1.47 (95% CI: 1.01-2.14, P = 0.042) fold higher rate of obesity risk. Additionally, the del/del genotype was associated with a 60% increased risk of metabolic syndrome (MetS) (OR = 1.60, 95% CI: 1.10 - 2.32, P = 0.015), in comparison to the AA genotype. Finally, rs34269950 del/del increased the risk of a larger waist circumference (OR = 1.65, 95% CI: 1.15 - 2.36, P = 0.007), but not other components of MetS.

Conclusion: Our study demonstrates that RUNX1T1 rs34269950, located in a potential FTO recognition motif, is significantly associated with waist circumference. This provides novel evidence to suggest SNPs located in RRACH motif may be involved in RNA m6A modification and mechanistic pathways that influence abdominal obesity.
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http://dx.doi.org/10.1093/qjmed/hcaa208DOI Listing
June 2020

The epidemiology of reverse transmission of COVID-19 in Gansu Province, China.

Travel Med Infect Dis 2020 Sep-Oct;37:101741. Epub 2020 May 12.

School of Public Health, Gansu University of Chinese Medicine, No. 35 Dingxi East Road, Lanzhou, 730000, Gansu Province, China; Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkins Centre, The University of Sydney, NSW, 2006, Sydney, Australia. Electronic address:

Background: The transmission of COVID-19 is about to come under control within China, however, an emerging challenge to the Chinese authorities is reverse transmission due to COVID-19 patients/carriers evacuating from overseas to China.

Methods: We analysed the epidemiological characteristics of 311 Chinese citizens evacuated from Iran. All confirmed COVID-19 cases amongst the returnees were displayed by the spatial distribution pattern of the extent of COVID-19 infection.

Results: Characteristics that differed significantly amongst these returnees compared to the original infected cohorts in Gansu were mean age, occupation and sex. Differences observed between infected patients and non-patients amongst returnees were age, sex, race, occupation, the use of facemasks, and residential situation in Iran. The clinical features that were significantly related to infection were chill, shortness of breath, chest pain and nausea. Spatial distribution pattern analysis indicated that infected returnees had resided within Iranian provinces that had experienced high levels of COVID-19. The spatial distribution of the original homes of these returnees before departure for Iran demonstrated that returnees will largely return to northwest China, to regions that have only experienced low levels of infection within China.

Conclusion: Blocking the reverse transmission of COVID-19 is critical in preventing a secondary outbreak of COVID-19.
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http://dx.doi.org/10.1016/j.tmaid.2020.101741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215163PMC
October 2020

IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

BMC Cancer 2020 Feb 3;20(1):92. Epub 2020 Feb 3.

Department of Pathology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background And Aims: Colorectal cancer (CRC) is a major killer. Host immunity is important in tumorigenesis. Direct comparison among IL-36α, IL-36β and IL-36γ in the prognosis of CRC is unclear.

Methods: CRC tissue arrays were generated from colorectostomy samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, IL-36α, IL-36β and IL-36γ were determined, in comparison to non-cancer tissues.

Results: A significant association was observed between colonic IL-36α, IL-36β or IL-36γ and the presence of cancer (with all P < 0.0001). Using ROC curve analysis, specificity and sensitivity of IL-36α, IL-36β or IL-36γ were confirmed, with area under the curve (AUC) values of 0.68, 0.73 and 0.65, respectively. Significant differences in survival were observed between IL-36α and IL-36α (P = 0.003) or IL-36γ and IL-36γ (P = 0.03). Survival curves varied significantly when further stratification into sub-groups, on the basis of combined levels of expression of two isotypes of IL-36 was undertaken. A significant difference was observed when levels of IL-36α and IL-36β were combined (P = 0.01), or a combination of IL-36α plus IL-36γ (P = 0.002). The sub-groups with a combination of IL-36α plus IL-36β, or IL-36α plus IL-36γ exhibited the longest survival time among CRC patients. In contrast, the sub-groups of IL-36α plus IL-36β or IL-36α plus IL-36γ had the shortest overall survival. Using the log-rank test, IL-36α expression significantly improved survival in patients with an invasion depth of T4 (P < 0.0001), lymph node metastasis (P = 0.04), TNM III-IV (P = 0.03) or with a right-sided colon tumour (P = 0.02). Similarly, IL-36γ expression was significantly associated with improved survival in patients with no lymph node metastasis (P = 0.008), TNM I-II (P = 0.03) or with a left-sided colon tumour (P = 0.05). Multivariate analysis demonstrated that among IL-36α, IL-36β and IL-36γ, only IL-36α (HR, 0.37; 95% CI, 0.16-0.87; P = 0.02) was an independent factor in survival, using Cox proportional hazards regression analysis.

Conclusion: IL-36α or IL-36γ are reliable biomarkers in predicting the prognosis of CRC during the later or early stages of the disease, respectively. Combining IL-36α plus IL-36γ appears to more accurately predict the postoperative prognosis of CRC patients. Our data may be useful in the management of CRC.
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http://dx.doi.org/10.1186/s12885-020-6587-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998229PMC
February 2020

Interleukin-38 in colorectal cancer: a potential role in precision medicine.

Cancer Immunol Immunother 2020 Jan 30;69(1):69-79. Epub 2019 Nov 30.

Department of Pathology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Level 6, Building 6, Shanghai, 200050, China.

Colorectal cancer (CRC) is a leading cause of cancer-related death, partly due to a lack of reliable biomarkers for early diagnosis. To improve the outcome of CRC, it is critical to provide diagnosis at an early stage using promising sensitive/specific marker(s). Using immunohistochemistry and histopathology, IL-38 expression was determined in tissue arrays of CRC with different TNM status and depth of tumour invasion. Data were compared to IL-38 in adjacent non-cancer tissue and correlated with demographic information, including survival. A substantial reduction of IL-38 was detected in the CRC tissue compared to adjacent non-cancer colonic tissue. IL-38 correlated with the extent of tumour differentiation (P < 0.0001); CRC location in the left side of the colon (P < 0.05), and smaller tumour size (≤ 5 cm; P < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated both high specificity and high sensitivity of IL-38 for the diagnosis of CRC [area under the curve (AUC) = 0.89)]. By sub-group analysis, AUC of IL-38 for the diagnosis of CRC was higher in poorly differentiated, right-sided CRC or tumour size > 5 cm (all AUC > 0.9). Significantly, longer survival was observed for the IL-38 versus the IL-38 groups in CRC patients (P = 0.04). Survival was also longer for IL-38 patients with lymph node metastasis (P = 0.01) and TNM stage III-IV (P = 0.02). Multivariate analysis demonstrated that IL-38 (P = 0.05) and tumour invasion depth (P = 0.04) were independent factors for survival. High IL38 in CRC is an independent prognostic factor for the longer survival of CRC patients. IL-38 signalling may constitute a therapeutic target in CRC.
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http://dx.doi.org/10.1007/s00262-019-02440-7DOI Listing
January 2020

Epigenetic influences on genetically triggered thoracic aortic aneurysm.

Biophys Rev 2018 Oct 28;10(5):1241-1256. Epub 2018 Sep 28.

Discipline of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.

Genetically triggered thoracic aortic aneurysms (TAAs) account for 30% of all TAAs and can result in early morbidity and mortality in affected individuals. Epigenetic factors are now recognised to influence the phenotype of many genetically triggered conditions and have become an area of interest because of the potential for therapeutic manipulation. Major epigenetic modulators include DNA methylation, histone modification and non-coding RNA. This review examines epigenetic modulators that have been significantly associated with genetically triggered TAAs and their potential utility for translation to clinical practice.
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http://dx.doi.org/10.1007/s12551-018-0460-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233334PMC
October 2018

Calcium-axonemal microtubuli interactions underlie mechanism(s) of primary cilia morphological changes.

J Biol Phys 2018 03 31;44(1):53-80. Epub 2017 Oct 31.

Brain Tumor Research Laboratories, Brain and Mind Center, Sydney Medical School and Faculty of Health Sciences, University of Sydney, Sydney, NSW, 2050, Australia.

We have used cell culture of astrocytes aligned within microchannels to investigate calcium effects on primary cilia morphology. In the absence of calcium and in the presence of flow of media (10 μL.s) the majority (90%) of primary cilia showed reversible bending with an average curvature of 2.1 ± 0.9 × 10 nm. When 1.0 mM calcium was present, 90% of cilia underwent bending. Forty percent of these cilia demonstrated strong irreversible bending, resulting in a final average curvature of 3.9 ± 1 × 10 nm, while 50% of cilia underwent bending similar to that observed during calcium-free flow. The average length of cilia was shifted toward shorter values (3.67 ± 0.34 μm) when exposed to excess calcium (1.0 mM), compared to media devoid of calcium (3.96 ± 0.26 μm). The number of primary cilia that became curved after calcium application was reduced when the cell culture was pre-incubated with 15 μM of the microtubule stabilizer, taxol, for 60 min prior to calcium application. Calcium caused single microtubules to curve at a concentration ≈1.0 mM in vitro, but at higher concentration (≈1.5 mM) multiple microtubule curving occurred. Additionally, calcium causes microtubule-associated protein-2 conformational changes and its dislocation from the microtubule wall at the location of microtubule curvature. A very small amount of calcium, that is 1.45 × 10 times lower than the maximal capacity of TRPPs calcium channels, may cause gross morphological changes (curving) of primary cilia, while global cytosol calcium levels are expected to remain unchanged. These findings reflect the non-linear manner in which primary cilia may respond to calcium signaling, which in turn may influence the course of development of ciliopathies and cancer.
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http://dx.doi.org/10.1007/s10867-017-9475-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834999PMC
March 2018

IL-37 and 38 signalling in gestational diabetes.

J Reprod Immunol 2017 11 28;124:8-14. Epub 2017 Sep 28.

Discipline of Pathology, Bosch Institute and School of Medical Sciences, University of Sydney, 2006, Australia. Electronic address:

Gestational diabetes mellitus (GDM) is still a clinical challenge around world. Inflammation contributes to the pathogenesis of GDM, the precise underlying mechanism remains to be explored. IL-37 and 38 play important role in autoimmunity, but their role in the development of GDM is unclear. Using histopathology and immunohistochemistry, the thickness of the umbilical artery, the area of capillaries within the placental chorionic villi, and the production of IL-37/38 were determined. Placental mRNA of IL-37/IL-38 from GDM and Non-GMD was measured using qRT-PCR. serum IL-37/IL38 levels were evaluated, using ELISA. IL-37 was reduced 49%, 48% or 57% in chorionic villi of placentas (P<0.05), umbilical artery (P<0.05), or umbilical vein (P<0.05) from GDM women, respectively, compared to that from non-GDM women. In contrast, IL-38 was increased 3.3, 2.6, or 2.6 fold in chorionic villi (P<0.01), umbilical artery (P<0.05), umbilical vein (P<0.05) from GDM women, respectively, compared to that from non-GDM women. IL-37 in GDM placentas or serum was reduced ∼52% or 33%, compared to that from Non-GDM subjects, respectively; whereas IL-38 in the GDM placentas or serum was increased by 1.6 fold or 1.3 fold, compare to that from Non-GDM, respectively. Our data suggest that IL-37 protect pregnant women from the development of GDM. IL-38 produced in the chorionic villi and umbilical cords may be a response to local inflammation during the development of GDM. Such a dysregulated micro-environment may contribute to the development of GDM via an immune-mediated mechanism. These data may provide useful information for the intervention for GDM.
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http://dx.doi.org/10.1016/j.jri.2017.09.011DOI Listing
November 2017

FTO associations with obesity and telomere length.

J Biomed Sci 2017 Sep 1;24(1):65. Epub 2017 Sep 1.

Rural Clinical School, University of New South Wales, Sydney, 2052, Australia.

This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity.
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http://dx.doi.org/10.1186/s12929-017-0372-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580219PMC
September 2017

ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

Circ Res 2017 Aug 12;121(5):512-524. Epub 2017 Jul 12.

From the Agnes Ginges Laboratory for Diseases of the Aorta, Vascular Biology Program (R.L., L.L., H.L.) and Centre for the Endothelium, Vascular Biology Program (A.J.L., Y.Z., K.K.T., S.J., Z.Z., M.A.V., J.R.G.), Centenary Institute, Camperdown, New South Wales, Australia; Discipline of Pathology and Bosch Institute, Charles Perkins Center (E.N.R., B.D.H.) and Sydney Medical School (R.L., E.N.R., R.W.J., P.G.B., M.A.V., J.R.G.), University of Sydney, New South Wales, Australia; The Baird Institute (A.G.S., R.W.J., P.G.B.) and Department of Cardiology (D.R.R.), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; and Department of Vascular Surgery, Renji Hospital, Shanghai Jiaotong University, China (Z.Z.).

Rationale: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype.

Objective: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA.

Methods And Results: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. global knockout () mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the and promoters in -deficient SMC. We further show that TAA formation in the mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of -deficient SMC.

Conclusion: We have identified as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.310692DOI Listing
August 2017

Electrocardiogram QRS duration and associations with telomere length: A cross-sectional analysis in Australian rural diabetic and non-diabetic population.

J Electrocardiol 2017 Jul - Aug;50(4):450-456. Epub 2017 Feb 20.

Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address:

Prolonged electrocardiogram QRS durations are often present in aging populations. Shorter telomere length is considered a biomarker of cellular aging. Decreased telomere length has been associated with coronary artery risk, and ventricular remodeling. However, the association between telomeres and cardiac conduction abnormalities, such as increased QRS duration are not well understood. A retrospective cross-sectional population was obtained from the CSU Diabetes Screening Research Initiative database where 273 participants had both ECG-derived QRS duration and DNA to permit leukocyte telomere length (LTL) determination. Telomere length was determined using the monochrome multiplex quantitative PCR method to measure mean relative LTL. Resting 12-lead electrocardiograms were obtained from each subject using a Welch Allyn PC-Based ECG system. Relative LTL was moderately negatively associated with QRS duration in type 2 diabetes mellitus (T2DM) patients (R=0.055), compared to controls (R=0.010). In general linear models with no adjustments a significant interaction between QRS duration and LTL is observed for a combined population of T2DM and non-diabetics. When we compared T2DM to non-diabetics, we found that T2DM increased the effect size for relative LTL on QRS duration in comparison to controls. Hence, for each 0.1 unit of relative LTL attrition, QRS duration in T2DM patients increased by 3.24ms (95% CI, -63.00 to -1.84), compared to 1.65ms in controls (95% CI, -40.44 to 7.40). In summary we have observed an association between LTL in a rural aging mixed population of T2DM and non-diabetes. We have observed an unadjusted association between QRS duration and LTL in T2DM. We noted that the control group demonstrated no such association. This highlights the complexity of T2DM when exploring disease phenotype-telomere interactions.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.02.010DOI Listing
May 2018

The association of uncoupling protein 2 (UCP2) exon 8 insertion/deletion polymorphism and ECG derived QRS duration: A cross-sectional study in an Australian rural population.

Int J Cardiol 2017 Feb 9;228:507-510. Epub 2016 Nov 9.

Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address:

Background: Associations between inherited mitochondrial disease and cardiac conduction have been previously described. However, there are no available studies exploring the mitochondrial uncoupling protein 2 gene (UCP2) insertion/deletion (I/D) polymorphisms interaction on cardiac electrical conduction. Our aim was to determine if ECG-derived QRS duration is associated with UCP2 DD genotype in a cross-sectional Australian aging rural population.

Methods: A retrospective study design utilizing a rural health diabetic screening clinic data-base containing observational data from September 2011 to September 2014. Inclusion criteria included were having ECG parameters such as QRS duration measures and a DNA sample within the same subject. Genomic DNA was extracted and subjects were genotyped for the 45-bp I/D polymorphism in the 3'-untranslated region of UCP2.

Results: 281 individuals were available for analysis. On the basis of QRS duration >140ms we found an increased percentage of our population with DD homozygotes, compared to ID heterozygotes and II homozygotes (p=0.047). For other ECG parameters; mean PQ duration, QTc across UCP2 genotypes was not significant (p=NS). QTc using a cut-off >440ms in contingency table analysis revealed no significant differences across UCP2 I/D genotypes. Mean QT dispersion (QTd) was paradoxically less in the UCP2 DD genotype compared to UCP2 II subgroup (p=0.034).

Discussion: We have demonstrated an association between increasing ECG-derived QRS duration >140ms and the UCP2 DD polymorphism. The lack of association with ECG derived QTd and UCP2 DD may suggest that gene-related QRS duration prolongation is independent of cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.ijcard.2016.11.100DOI Listing
February 2017

Interactions between UCP2 SNPs and telomere length exist in the absence of diabetes or pre-diabetes.

Sci Rep 2016 09 12;6:33147. Epub 2016 Sep 12.

University of New South Wales, Rural Clinical School, Sydney, Australia.

Mitochondrial uncoupling protein 2 (UCP2) can affect oxidative stress levels. UCP2 polymorphisms are associated with leukocyte telomere length (LTL) in Type 2 Diabetes, which also induces considerable background oxidative stress. The effects of UCP2 polymorphisms on LTL in populations without diabetes have not been well described. Our aims are to evaluate the interaction between LTL and UCP2 polymorphisms in 950 subjects without diabetes. The monochrome multiplex quantitative PCR method was used to measure relative LTL. Taqman SNP genotyping assay was applied to genotypes for UCP2 rs659366 and rs660339. We found shorter LTL associated with increased age (P < 0.001) and triglyceride levels (P = 0.041). After adjustment for cardiovascular risk factors, rs659336 GG genotype carriers demonstrated a shorter LTL (1.257 ± 0.186), compared to GA carriers (1.288 ± 0.230, P = 0.022) and AA carriers (1.314 ± 0.253, P = 0.002). LTL was shorter in the CC rs660339 genotype (1.254 ± 0.187) compared to TT (1.297 ± 0.242, P = 0.007) and CT carriers (1.292 ± 0.229, P = 0.016). The T allele of rs660339 is associated with a longer LTL of approximately 0.04 compared to CC homozygotes. Thus, UCP2 rs659366 A allele and rs660339 T allele are both related to longer LTL in subjects without diabetes, independent of cardiovascular risk factors.
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http://dx.doi.org/10.1038/srep33147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018875PMC
September 2016

Thoracic aortic dissection and heritability: forensic implications.

Forensic Sci Med Pathol 2016 Sep 8;12(3):366-8. Epub 2016 Jul 8.

Sydney Medical School, University of Sydney, Sydney, NSW, 2008, Australia.

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http://dx.doi.org/10.1007/s12024-016-9788-7DOI Listing
September 2016

Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways.

Clin Transl Med 2016 Mar 7;5(1). Epub 2016 Mar 7.

Faculty of Medicine, Rural Clinical School, University of New South Wales, Samuels Building, Level 3, Room 327, Sydney, 2052, Australia.

Current debate in type 2 diabetes (T2DM) has focused on shortened leukocyte telomere length (LTL) as the result of a number of possible causes, including polymorphisms in mitochondrial uncoupling proteins (UCPs) leading to oxidative stress, telomere regulatory pathway gene polymorphisms, or as a direct result of associated cardiovascular complications inducing tissue organ inflammation and oxidative stress. There is evidence that a heritable shorter telomere trait is a risk factor for development of T2DM. This review discusses the contribution and balance of genetic regulation of UCPs and telomere pathways in the context of T2DM. We discuss genotypes that are well known to influence the shortening of LTL, in particular OBFC1 and telomerase genotypes such as TERC. Interestingly, the interaction between short telomeres and T2DM risk appears to involve mitochondrial dysfunction as an intermediate process. A hypothesis is presented that genetic heterogeneity within UCPs may directly affect oxidative stress that feeds back to influence the fine balance of telomere regulation, cell cycle regulation and diabetes risk and/or metabolic disease progression.
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http://dx.doi.org/10.1186/s40169-016-0089-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781821PMC
March 2016

Electrocardiogram derived QRS duration associations with elevated central aortic systolic pressure (CASP) in a rural Australian population.

Clin Hypertens 2015 16;22. Epub 2016 Feb 16.

Rural Clinical School, Faculty of Medicine, University of New South Wales, Room 327, Samuels Building, Sydney, NSW 2052 Australia.

Background: Prolonged electrocardiogram QRS durations are often present in hypertensive patients. Small increases in QRS duration serve as independent risk factors for both increased cardiovascular and all-cause mortality. Aortic stiffness is associated with increases in central aortic systolic blood pressure (CASP). However CASP and ECG QRS duration interactions have not been established in rural community populations. Our aims are to determine if QRS duration > 100 msec is associated with an elevated CASP measure in an Australian rural population.

Methods: A retrospective cross sectional population was obtained from the CSU Diabetes Screening Research Initiative data base where 68 participants had both central aortic pressure recorded and ECG derived QRS duration. Central aortic pressure was determined by directly recording radial arterial tonometry and brachial cuff pressure (HealthStats, Singapore). Resting 12-lead electrocardiograms were obtained from each subject using a Welch Allyn PC-Based ECG system.

Results: The population had a mean CASP of 137.8 mmHg, higher than previously reported in other population studies. In 8/68 subjects with a prolonged cardiac QRS duration >120 msec, CASP ranged from 129 mmHg - 182 mmHg. When subgroup analysis was stratified on the basis QRS duration <100 msec and ≥100 msec significant differences (p = 0.036) were observed for mean CASP, 130.6 mmHg ± 15.6 (SD) versus 140.6 mmHg ± 16.8 (SD), respectively.

Conclusions: Our results suggest that an arbitrary CASP reading greater than a value 140 mmHg raises suspicion of a prolonged QRS duration. QRS durations ≥100 msec in an aging rural population are associated with higher CASP measures. Our results also suggest in aging Australian rural populations CASP is likely to be elevated, possibly due to age related aortic stiffening.
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http://dx.doi.org/10.1186/s40885-016-0039-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754924PMC
February 2016

Methodological Comparisons of Heart Rate Variability Analysis in Patients With Type 2 Diabetes and Angiotensin Converting Enzyme Polymorphism.

IEEE J Biomed Health Inform 2016 Jan 26;20(1):55-63. Epub 2015 Oct 26.

Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate.
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http://dx.doi.org/10.1109/JBHI.2015.2480778DOI Listing
January 2016

Structural basis for phosphorylation and lysine acetylation cross-talk in a kinase motif associated with myocardial ischemia and cardioprotection.

J Biol Chem 2014 Sep 9;289(37):25890-906. Epub 2014 Jul 9.

From the Discipline of Pathology, School of Medical Sciences, University of Sydney, Sydney 2006, Australia, the School of Molecular Bioscience and the Charles Perkins Centre, University of Sydney, Sydney 2006, Australia, and

Myocardial ischemia and cardioprotection by ischemic pre-conditioning induce signal networks aimed at survival or cell death if the ischemic period is prolonged. These pathways are mediated by protein post-translational modifications that are hypothesized to cross-talk with and regulate each other. Phosphopeptides and lysine-acetylated peptides were quantified in isolated rat hearts subjected to ischemia or ischemic pre-conditioning, with and without splitomicin inhibition of lysine deacetylation. We show lysine acetylation (acetyl-Lys)-dependent activation of AMP-activated protein kinase, AKT, and PKA kinases during ischemia. Phosphorylation and acetyl-Lys sites mapped onto tertiary structures were proximal in >50% of proteins investigated, yet they were mutually exclusive in 50 ischemic pre-conditioning- and/or ischemia-associated peptides containing the KXXS basophilic protein kinase consensus motif. Modifications in this motif were modeled in the C terminus of muscle-type creatine kinase. Acetyl-Lys increased proximal dephosphorylation by 10-fold. Structural analysis of modified muscle-type creatine kinase peptide variants by two-dimensional NMR revealed stabilization via a lysine-phosphate salt bridge, which was disrupted by acetyl-Lys resulting in backbone flexibility and increased phosphatase accessibility.
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http://dx.doi.org/10.1074/jbc.M114.556035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162189PMC
September 2014

Perturbations of mechanotransduction and aneurysm formation in heritable aortopathies.

Int J Cardiol 2013 Oct 27;169(1):7-16. Epub 2013 Aug 27.

Sydney Medical School, University of Sydney, NSW, Australia. Electronic address:

Thoracic aortic aneurysm and dissection in young and middle aged patients is increasingly recognised as due to genetic aortopathy. Mutations in multiple genes affecting proteins in the extracellular matrix, microfibrillar structure, the endothelium and cell signalling pathways have been associated with thoracic aortic disease. The TGFß signalling pathway appears to play a key role in mediating abnormal aortic growth and aneurysm formation. A challenge remains in understanding how the many different gene mutations can result in deranged TGFß signalling. This review examines the functional relationships between key structural and signalling proteins, with reference to the need for maintenance of homeostasis in mechanotransduction within the aortic wall. A mechanism, through which perturbations in mechanotransduction, arising from different gene mutations, results in altered TGFß signalling is described.
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http://dx.doi.org/10.1016/j.ijcard.2013.08.056DOI Listing
October 2013

Intrinsic microtubule GTP-cap dynamics in semi-confined systems: kinetochore-microtubule interface.

J Biol Phys 2013 Jan 18;39(1):81-98. Epub 2012 Oct 18.

Brain and Mind Research Institute, Sydney Medical School, The University of Sydney, Sydney, NSW, 2050, Australia.

In order to quantify the intrinsic dynamics associated with the tip of a GTP-cap under semi-confined conditions, such as those within a neuronal cone and at a kinetochore-microtubule interface, we propose a novel quantitative concept of critical nano local GTP-tubulin concentration (CNLC). A simulation of a rate constant of GTP-tubulin hydrolysis, under varying conditions based on this concept, generates results in the range of 0-420 s(-1). These results are in agreement with published experimental data, validating our model. The major outcome of this model is the prediction of 11 random and distinct outbursts of GTP hydrolysis per single layer of a GTP-cap. GTP hydrolysis is accompanied by an energy release and the formation of discrete expanding zones, built by less-stable, skewed GDP-tubulin subunits. We suggest that the front of these expanding zones within the walls of the microtubule represent soliton-like movements of local deformation triggered by energy released from an outburst of hydrolysis. We propose that these solitons might be helpful in addressing a long-standing question relating to the mechanism underlying how GTP-tubulin hydrolysis controls dynamic instability. This result strongly supports the prediction that large conformational movements in tubulin subunits, termed dynamic transitions, occur as a result of the conversion of chemical energy that is triggered by GTP hydrolysis (Satarić et al., Electromagn Biol Med 24:255-264, 2005). Although simple, the concept of CNLC enables the formulation of a rationale to explain the intrinsic nature of the "push-and-pull" mechanism associated with a kinetochore-microtubule complex. In addition, the capacity of the microtubule wall to produce and mediate localized spatio-temporal excitations, i.e., soliton-like bursts of energy coupled with an abundance of microtubules in dendritic spines supports the hypothesis that microtubule dynamics may underlie neural information processing including neurocomputation (Hameroff, J Biol Phys 36:71-93, 2010; Hameroff, Cognit Sci 31:1035-1045, 2007; Hameroff and Watt, J Theor Biol 98:549-561, 1982).
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http://dx.doi.org/10.1007/s10867-012-9287-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532662PMC
January 2013

Sirolimus reduces vasculopathy but exacerbates proteinuria in association with inhibition of VEGF and VEGFR in a rat kidney model of chronic allograft dysfunction.

Nephrol Dial Transplant 2013 Feb 9;28(2):327-36. Epub 2012 Dec 9.

Collaborative transplantation laboratory, Sydney Medical School and Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.

Background: Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology.

Methods: Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed.

Results: Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells.

Conclusions: Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.
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http://dx.doi.org/10.1093/ndt/gfs453DOI Listing
February 2013

Metformin inhibits the development and metastasis of ovarian cancer.

Oncol Rep 2012 Sep 29;28(3):903-8. Epub 2012 Jun 29.

Department of Obstetrics and Gynecology, Ren-Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.

The aim of this study was to investigate the role of metformin in the regulation of development and metastasis of ovarian carcinoma cell lines in vitro and ovarian cancer in a nude mouse model in vivo. The effects of metformin on the ability of two high-metastatic potential human ovarian cancer cell lines (SKOV3 and HO8910-PM) to adhere, invade and migrate in vitro were observed by means of a cell adhesion test, cell invasion test and cell migration test. The size and number of the inoculated and metastatic tumours in vivo in a nude mouse were determined following intraperitoneal injection of metformin. Furthermore, the extent of angiogenesis (vWF) and macrophage infiltration in the tumour were determined. Proliferation, migration, invasion and adhesion of ovarian cancer cells were significantly inhibited (P<0.05) in a dose-dependent manner in vitro. In addition, metformin inhibited hepatic, intestinal and lung metastasis (P<0.05), with no weight loss in vivo, consistent with decreased expression of vWF and macrophage infiltration. Our data suggest that metformin inhibits the development and metastasis of ovarian cancer by reducing cellular-ECM interactions, neovascularisation and macrophage infiltration.
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http://dx.doi.org/10.3892/or.2012.1890DOI Listing
September 2012
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