ORCID Profile
0000-0002-6404-6839
Current Organisations
Northern Health
,
Monash University
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Medical Devices | Biomaterials | Biomechanical Engineering | Biomedical Engineering |
Education and Training Systems not elsewhere classified | Expanding Knowledge in Engineering | Expanding Knowledge in the Medical and Health Sciences
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2019
Publisher: Wiley
Date: 11-2018
DOI: 10.1111/BJU.14590
Publisher: Oxford University Press (OUP)
Date: 08-02-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2019
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2018
Publisher: Wiley
Date: 30-04-2008
DOI: 10.1002/IJC.23509
Abstract: Different subtypes of ovarian cancer appear to have different causes however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8 1.1-2.8) but not mucinous tumors (1.1 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer.
Publisher: Oxford University Press (OUP)
Date: 05-11-2008
DOI: 10.1093/JNCI/DJN345
Abstract: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction lification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood s les obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2 P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8 P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95 P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9 P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94 P = .03). Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer.
Publisher: Wiley
Date: 18-11-2020
DOI: 10.1111/CSP2.318
Publisher: Wiley
Date: 03-2009
DOI: 10.1002/IJC.23863
Abstract: Approximately 1-2% of colorectal cancers (CRC) arise because of germline mutations in DNA mismatch repair genes, referred to as Lynch syndrome. These tumours show microsatellite instability (MSI) and loss of expression of mismatch repair proteins. Pre-symptomatic identification of mutation carriers has been demonstrated to improve survival however, there is concern that many are not being identified using current practices. We evaluated population-based MSI screening of CRC in young patients as a means of ascertaining mutation carriers. CRC diagnosed in patients aged <60 years were identified from pathology records. No prior information was available on family history of cancer. PCR techniques were used to determine MSI in the BAT-26 mononucleotide repeat and mutation in the BRAF oncogene. Loss of MLH1, MSH2, MSH6 and PMS2 protein expression was evaluated in MSI+ tumours by immunohistochemistry. MSI+ tumours were found in 105/1,344 (7.8%) patients, of which 7 were excluded as possible Lynch syndrome because of BRAF mutation. Of the 98 "red flag" cases that were followed up, 25 were already known as mutation carriers or members of mutation carrier families. Germline test results were obtained for 35 patients and revealed that 22 showed no apparent mutation, 11 showed likely pathogenic mutations and 2 had unclassified variants. The proportion of MSI+ cases in different age groups that were estimated to be mutation carriers was 89% (<30 years), 83% (30-39), 68% (40-49) and 17% (50-59). We recommend MSI as the initial test for population-based screening of Lynch syndrome in younger CRC patients, regardless of family history.
Publisher: Wiley
Date: 04-2010
Publisher: Frontiers Media SA
Date: 12-11-2021
DOI: 10.3389/FCOSC.2021.781085
Abstract: The snow leopard ( Panthera uncia ) is one of the world's most elusive felids. In Bhutan, which is one of the 12 countries where the species still persists, reliable information on its distribution and habitat suitability is lacking, thus impeding effective conservation planning for the species. To fill this knowledge gap, we created a country-wide species distribution model using “presence-only” data from 420 snow leopard occurrences (345 from a sign survey and 77 from a camera-trapping survey) and 12 environmental covariates consisting of biophysical and anthropogenic factors. We analyzed the data in an ensemble model framework which combines the outputs from several species distribution models. To assess the adequacy of Bhutan's network of protected areas and their potential contribution toward the conservation of the species, we overlaid the output of the ensemble model on the spatial layers of protected areas and biological corridors. The ensemble model identified 7,206 km 2 of Bhutan as suitable for the snow leopard: 3,647 km 2 as highly suitable, 2,681 km 2 as moderately suitable, and 878 km 2 as marginally suitable. Forty percent of the total suitable habitat consisted of protected areas and a further 8% of biological corridors. These suitable habitats were characterized by a mean livestock density of 1.3 in iduals per hectare, and a mean slope of 25° they closely match the distribution of the snow leopard's main wild prey, the bharal ( Pseudois nayaur ). Our study shows that Bhutan's northern protected areas are a centre for snow leopard conservation both at the national and regional scale.
Publisher: Informa UK Limited
Date: 29-06-2016
Publisher: Oxford University Press (OUP)
Date: 15-05-2012
DOI: 10.1002/STEM.1092
Abstract: In mice, CD49fhi mammary stem cells (MaSCs) asymmetrically ide to generate CD49f+ committed progenitor cells that differentiate into CD49f− phenotypes of the milk-secreting tissue at the onset of pregnancy. We show CD49f+ primary mammary epithelial cells (PMECs) isolated from lactating tissue uniquely respond to pregnancy-associated hormones (PAH) compared with CD49f+ cells from nonlactating tissue. Differentiation of CD49f+ PMEC in extracellular matrix produces CD49f− luminal cells to form differentiated alveoli. The PAH prolactin and placental lactogen specifically stimulate ision of CD49f− luminal cells, while receptor activator of nuclear factor (NF)-κB ligand (RANKL) specifically stimulates ision of basal CD49f+ cells. In nondifferentiating conditions, we observed a greater proportion of multipotent self-renewing cells, and RANKL treatment activated the RANK pathway in these cultures. Furthermore, we observed the deposition of calcium nodules in a proportion of these cells. These data imply that a MaSC unique to the lactating breast exists in humans, which generates progeny with discrete lineages and distinct response to PAH. Disclosure of potential conflicts of interest is found at the end of this article.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2020
Publisher: Ubiquity Press, Ltd.
Date: 2023
DOI: 10.5334/DSJ-2023-036
Publisher: Public Library of Science (PLoS)
Date: 16-11-2015
Publisher: American Association for Cancer Research (AACR)
Date: 11-2007
DOI: 10.1158/1055-9965.EPI-07-0566
Abstract: It remains unclear whether physical activity is associated with epithelial ovarian cancer risk. We therefore examined the association between recreational physical activity and risk of ovarian cancer in a national population-based case-control study in Australia. We also systematically reviewed all the available evidence linking physical activity with ovarian cancer to provide the best summary estimate of the association. The case-control study included women ages 18 to 79 years with a new diagnosis of invasive (n = 1,269) or borderline (n = 311) epithelial ovarian cancer identified through a network of clinics, physicians, and state cancer registries throughout Australia. Controls (n = 1,509) were randomly selected from the national electoral roll and were frequency matched to cases by age and state. For the systematic review, we identified eligible studies using Medline, the ISI Science Citation Index, and manual review of retrieved references, and included all case-control or cohort studies that permitted assessment of an association between physical activity (recreational/occupational/sedentary behavior) and histologically confirmed ovarian cancer. Meta-analysis was restricted to the subset of these studies that reported on recreational physical activity. In our case-control study, we observed weakly inverse or null associations between recreational physical activity and risk of epithelial ovarian cancer overall. There was no evidence that the effects varied by tumor behavior or histologic subtype. Twelve studies were included in the meta-analysis, which gave summary estimates of 0.79 (95% confidence interval, 0.70-0.85) for case-control studies and 0.81 (95% confidence interval, 0.57-1.17) for cohort studies for the risk of ovarian cancer associated with highest versus lowest levels of recreational physical activity. Thus, pooled results from observational studies suggest that a modest inverse association exists between level of recreational physical activity and the risk of ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2007 (11):2321–30)
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2019
Publisher: Impact Journals, LLC
Date: 22-11-2015
Publisher: Wiley
Date: 03-03-2016
DOI: 10.1002/PON.4111
Abstract: The purpose of the study was to explore colorectal cancer survivors' health perceptions following cessation of active treatment for cancer and to explore the factors influencing participation in health-promoting behaviors that may help reduce cardiovascular disease risk. Face-to-face interviews were conducted with participants that had completed active treatment for cancer within the previous 2 years. Participants were colorectal cancer survivors (N = 24, men = 11, women = 13, M age = 69.38 years, SD = 4.19) recruited from a private hospital in Perth, Australia on the basis that they had existing morbidities that put them at increased risk of cardiovascular disease. Interview transcripts were analyzed using thematic analysis. Five main themes emerged: back to normal the pleasures in life: 'is it worth it?' beliefs about health behavior skepticism of eating guidelines and lack of motivation. The majority of participants felt they were in good health and had made a full recovery. Participants questioned whether it was worth changing their lifestyle given their life stage and referred to the desire to enjoy life. Lay health beliefs, skepticism of eating guidelines, and a lack of motivation were barriers to change. Interventions should target lay beliefs and skepticism in relation to health behaviors in order to reinforce the importance and value of participating in health-related behavior. Findings may inform the development of effective, patient-centered interventions that target lay health beliefs and build motivation for health behavior change. Copyright © 2016 John Wiley & Sons, Ltd.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/ONC.2017.31
Abstract: Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1038/BJC.2015.427
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2018
Publisher: Wiley
Date: 18-08-2016
DOI: 10.1002/PON.4234
Abstract: Lifestyle factors including inadequate physical activity may contribute to increased risk of developing cardiovascular disease in colorectal cancer survivors. Identification of the barriers to physical activity is important for forming an evidence base of factors to target in future physical activity programs aimed at improving cardiovascular health in this population. Colorectal cancer survivors (N = 24) from St. John of God Subiaco Hospital participated in semi-structured interviews about their current physical activity behaviors and perceived barriers to physical activity. Inductive thematic analysis of interviews revealed 5 overarching themes relating to barriers to physical activity: psychological barriers, environmental barriers, knowledge of guidelines, lack of practitioner support, and energy/age barriers. Novel findings revealed participants' dependence on practitioner support, including a reliance on practitioners to recommend lifestyle change. Survivors also revealed that regular checkups to monitor cardiovascular risk replaced the need for healthy lifestyle changes. With survivors holding the advice of clinicians in high regard, an opportunity exists for clinicians to facilitate lifestyle change. Health care professionals such as nurses can implement motivational strategies and provide additional health information during follow-up visits, to ensure long-term adherence. In iduals who reported psychological, motivational, and environmental barriers may benefit from interventions to improve self-regulation, planning, and problem-solving skills.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2011
Publisher: Mary Ann Liebert Inc
Date: 12-2011
Publisher: Springer Science and Business Media LLC
Date: 25-06-2011
DOI: 10.1007/S00439-011-1044-3
Abstract: Large-scale, public genomic databases have greatly improved the capacity of researchers to do genomic research. In order to ensure that the scientific community uses data from these public resources properly, data access agreements have been developed to complement already existing legal and ethical norms. Sanctions to address cases of data misuse constitute an essential part of this compliance framework meant to protect stakeholders in genomic research. Yet very little research and community debate has been done on this most important topic. This paper presents a review of different sanctions that could be invoked in cases of non-compliance from data users. They have been identified through comprehensive research and analysis of over 450 documents (journal articles, policy, guidelines, access policies, etc.) related to this topic. Given the considerable impact on users of even the milder sanctions considered in our paper, it is essential that stakeholders strive to achieve the highest degree of standardization and transparency when designing controlled-access agreements. It is only fair, after all, that users be able to expect that the border between acceptable and unacceptable conduct is clearly delineated and predictable in controlled-access policies. This suggests the importance for researchers to undertake additional empirical studies on the clarity and accessibility of existing database access agreements and related policies in the near future.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2019
Publisher: Elsevier BV
Date: 10-2018
Publisher: Impact Journals, LLC
Date: 17-02-2016
Publisher: IEEE
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/GM558
Publisher: Mary Ann Liebert Inc
Date: 02-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 17-01-2011
DOI: 10.1186/BCR2793
Publisher: Elsevier BV
Date: 09-2022
Publisher: Oxford University Press (OUP)
Date: 03-12-2014
Abstract: The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.
Publisher: SAGE Publications
Date: 16-03-2009
Abstract: Cell death is of broad physiological and pathological importance, making quantification of biochemical events associated with cell demise a high priority for experimental pathology. Fibrosis is a common consequence of tissue injury involving necrotic cell death. Using tissue specimens from experimental mouse models of traumatic brain injury, cardiac fibrosis, and cancer, as well as human tumor specimens assembled in tissue microarray (TMA) format, we undertook computer-assisted quantification of specific immunohistochemical and histological parameters that characterize processes associated with cell death. In this study, we demonstrated the utility of image analysis algorithms for color deconvolution, colocalization, and nuclear morphometry to characterize cell death events in tissue specimens: (a) subjected to immunostaining for detecting cleaved caspase-3, cleaved poly(ADP-ribose)-polymerase, cleaved lamin-A, phosphorylated histone H2AX, and Bcl-2 (b) analyzed by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling assay to detect DNA fragmentation and (c) evaluated with Masson's trichrome staining. We developed novel algorithm-based scoring methods and validated them using TMAs as a high-throughput format. The proposed computer-assisted scoring methods for digital images by brightfield microscopy permit linear quantification of immunohistochemical and histochemical stainings. Ex les are provided of digital image analysis performed in automated or semiautomated fashion for successful quantification of molecular events associated with cell death in tissue sections. (J Histochem Cytochem 57:649–663, 2009)
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 10-2020
Publisher: Wiley
Date: 22-04-2008
DOI: 10.1002/IJC.23448
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/NATURE14169
Publisher: Wiley
Date: 03-12-2017
DOI: 10.1111/ANS.13394
Abstract: Pathological complete response following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer is associated with reduced local recurrence and improved long-term outcome. However, the prognostic value of a partial response, or of tumour regression in patients with metastatic disease, is less clear. We present a single-centre cohort study of 205 patients with stage II-IV rectal cancer treated with surgery and neoadjuvant CRT between 2006 and 2013. Tumour regression was assessed using the Dworak system. The probability of 3-year recurrence-free survival (RFS) was 95% for Dworak grade 4, 82% for grade 3, 64% for grade 2 and 53% for grade 1 (P = 0.0005). In univariate regression analysis, Dworak grade was associated with RFS (hazard ratio (HR) 0.51, P < 0.0001 trend analysis) and cancer-specific survival (HR 0.52, P = 0.002). In multivariate analysis, Dworak grade remained an independent predictor of RFS (HR 0.62, P = 0.012), along with clinical metastases stage, resection margin status, the presence or absence of extramural venous invasion and type of surgical procedure. Tumour regression grade after neoadjuvant CRT was an independent prognostic factor for RFS, highlighting the importance of the degree of local response to CRT.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2021
Publisher: Elsevier BV
Date: 05-2000
Publisher: Springer Science and Business Media LLC
Date: 06-2014
DOI: 10.1038/NBT.2926
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2021
Publisher: Springer Science and Business Media LLC
Date: 28-11-1996
Abstract: The fate of iding mouse mammary epithelial cells was followed by use of tritiated thymidine (3H-Tdr) autoradiography. Loss of label consistent with halving kinetics was observed at various times after injection however, heavily labelled cells were frequently observed at two weeks and later, when none was expected. The grain count over these heavily labelled cells was often comparable with that 1 h after 3H-Tdr injection. Extensive serial sectioning revealed that the heavily labelled cells were often single cells surrounded by many unlabelled cells or that their label was in stark contrast (in excess of 20 reduced silver grains) to the surrounding group of cells whose label was just above background (a maximum of 3 grains). In addition, by injecting mice at different stages of oestrus, we demonstrated that these long-lived cells, although influenced by oestrus, replicated independently of the oestrogen peak. Our data support a model for mouse mammary epithelium that has a single 'stem' cell positioned within a group of its progeny to form a discrete proliferative unit. This model requires many such stem cells within the mammary epithelium and is consistent with similar models proposed for other tissues.
Publisher: Neoplasia Research
Date: 26-12-2014
DOI: 10.6000/1927-7229.2014.03.04.4
Abstract: Wnt proteins are often up-regulated in cancer. The secreted frizzled-related proteins (sFRPs) can abrogate Wnt signalling and are involved in apoptosis. We investigated the expression of Wnt1, β-Catenin, and an antagonist, sFRP4, as well as apoptosis in breast cancer using tissue micro-arrays (TMAs) comprising 191 tissue cores. Results demonstrated stronger staining intensity for Wnt1 in tumour versus non-tumour s les (p .05). Epithelial sFRP4 did not differ between invasive and non-invasive tissue however, there was increased sFRP4 expression in the blood vessels and lymphocyte cells of tumour compared to non-tumour tissue. These data suggest Wnt involvement in determining the breast cancer phenotype and highlight a potential new role for sFRP4 as a diagnostic rognostic marker.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2019
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1038/GIM.2012.105
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Wiley
Date: 12-06-2019
DOI: 10.1002/AJP.22995
Abstract: Despite the golden langur's (Trachypithecus geei) endangered and totally protected status, local awareness and attitude toward this species is poorly understood. We investigated local awareness and attitude in Bhutan by interviewing 1,143 households in the districts of Dagana, Sarpang, Trongsa, Tsirang, and Zhemgang, and analyzing data through a conditional inference tree analysis. Most respondents were not aware of the golden langur's nationally protected (53% n = 604) and globally endangered status (64% n = 730), but their location of residence (inside/outside a protected area p < .001) and education level (p < .001) significantly influenced awareness. The majority of respondents (87% n = 999) liked the golden langur but the attitude was significantly influenced primarily by whether or not they experienced crop damage by golden langurs (p < .001), and subsequently by location of residence (p < .001), local belief (p < .01), gender (p < .05), and personal encounter with a golden langur (p < .001). Socioeconomic variables like age, education level, and annual income did not influence attitude. We recommend environmental education and awareness c aigns outside protected areas, and intensifying existing programs inside protected areas to forge harmonious human-golden langur coexistence.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2020
DOI: 10.1097/ALN.0000000000003020
Abstract: There is intense debate around the use of altered and waived consent for pragmatic trials. Those in favor argue that traditional consent compromises the internal and external validity of these trials. Those against, warn that the resultant loss of autonomy compromises respect for persons and could undermine trust in the research enterprise. This article examines whether international ethical guidelines and the policy frameworks in three countries—the United States, England, and Australia—permit altered and waived consent for minimal-risk pragmatic trials conducted outside the emergency setting. Provisions for both are clearly articulated in U.S. regulations, but many countries do not have equivalent frameworks. Investigators should not assume that all consent models permitted in the United States are legal in their jurisdictions, even if they are deemed ethically defensible. The authors summarize ethical and regulatory considerations and present a framework for investigators contemplating trials with altered or waived consent.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2021
Publisher: Elsevier BV
Date: 05-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2020
Publisher: IEEE
Date: 05-2018
Publisher: Springer Science and Business Media LLC
Date: 05-12-2019
DOI: 10.1007/S10329-019-00777-2
Abstract: Threat assessment is critical to species conservation and management planning, because prior identification and assessment of key threats to conservation planning can assist in developing appropriate interventions or strategies. Comprehensive threat assessments are currently lacking for many threatened primates. In this paper, we classify and rank all direct threats to the endangered golden langur (Trachypithecus geei) in Bhutan in order to provide a practical guide to future conservation of the species. Information on threats was based on interviews with local people, discussion with field forestry staff, and social media interaction. We classified threats to golden langur habitats and populations, and ranked them using Miradi™, an analytical software for the adaptive management of conservation projects. We identified five habitat threats: (1) hydropower development, (2) road development, (3) housing development, (4) resource extraction, and (5) agricultural expansion. We also identified seven population threats: (1) electrocution, (2) road kill, (3) road injury, (4) dog kill, (5) retaliatory killing, (6) illegal pet keeping, and (7) hybridization with capped langurs. We rated the overall threat to golden langurs in Bhutan as 'medium'. Hydropower, road, and housing development constituted 'high' impact, while agricultural expansion, resource extraction, electrocution, and road kill had 'medium' impact the remaining threats had 'low' impact. To immediately mitigate threats to golden langurs, we recommend: (a) installing speed limit signage and speed breakers with strict enforcement of speed limits (b) installing insulated electric cables and fencing around power transformers and (c) reducing and restraining domestic dog populations.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 17-02-2009
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/S1542-3565(04)00451-3
Abstract: Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome usually present in younger patients, show loss of mismatch repair (MMR) gene expression, and exhibit microsatellite instability (MSI). About 12% of sporadic colorectal cancers also show MMR loss and MSI. The aims of this study were to evaluate MMR loss and MSI in relation to patient age, sex, tumor stage, and site in the large bowel. Tissue microarrays were created from 1020 stage II and III colorectal cancer cases and immunohistochemical staining performed to detect expression of the 2 major MMR proteins, hMLH1 and hMSH2. MSI was determined using the BAT-26 mononucleotide repeat. Ten percent of tumors showed loss of hMLH1 expression and 1.2% showed loss of hMSH2 expression. hMLH1 loss was more frequent in women (P < .001), older patients (P = .004), earlier stage tumors (P = .0001), and proximal colon tumors ( P < .0001). In contrast, tumors showing hMSH2 loss were more frequent in younger (P < .001), male (P = .05) patients and were distributed evenly between the proximal colon and distal colon/rectum. Eleven percent of tumors were MSI+ and these showed similar age, sex, stage, and site characteristics as tumors with hMLH1 loss. Discordance between MMR loss and MSI+ was found in 24 of 983 (2.4%) tumors. Of the 231 patients aged <60 years at diagnosis, 12 (5.2%) showed loss of hMLH1 and 8 (3.5%) showed loss of hMSH2. Routine immunohistochemical screening for MMR loss in younger colorectal cancer patients may provide a useful, first-step screening tool for the population-based detection of HNPCC.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Elsevier BV
Date: 05-2008
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2019
Publisher: Informa UK Limited
Date: 15-01-2011
Abstract: The mammary gland is a dynamic organ that only undergoes complete differentiation during pregnancy. Differentiation is fuelled by asymmetric ision of stem cells that reside in normally quiescent niches in the resting gland in response to pregnancy-associated hormones. Loss of regulation of stem cells is believed to underlie some breast cancers. This process is poorly understood in humans since it is difficult to extract stem cells from the lactating gland. We have identified a p63-positive population in breastmilk that proliferates and differentiates into at least two separate mammary lineages in culture. Nuclear translocation of p63 coincides with expression of the cell-cycle arrest protein 14-3-3σ (Sigma) and precedes differentiation. Transient down-regulation of Sigma promotes maintenance of the p63-positive population without affecting normal differentiation. We propose that p63-postive cells from breastmilk represent a novel source of cells to model regulation of mammary gland development and tumorigenesis.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NATURE16965
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous (2) pancreatic progenitor (3) immunogenic and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2020
Publisher: Impact Journals, LLC
Date: 03-02-2017
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2018
Publisher: Wildlife Information Liaison Development Society
Date: 26-09-2017
DOI: 10.11609/JOTT.3091.9.9.10649-10655
Abstract: The Dhole is a little-studied wild canid with decreasing populations throughout its global range. We conducted this study in Bhutan’s Jigme Dorji National Park (JDNP) to establish baseline records of Dhole distribution and habitat use. We used trail transects and recorded animal presence via tracks, scats, direct sightings and camera traps. Ancillary habitat characteristics such as elevation, slope and vegetation cover were recorded to characterise habitat use. We used MaxEnt model to estimate distribution within JDNP. We recorded 609 indicators of Dhole presence over a 60-day survey period. The model estimated almost one-fourth of JDNP as having a high probability of Dhole occurrence, which closely corresponds to the distribution of cool broadleaved forests (CBLF) and areas close to human settlements. The highest number of indicators was obtained from CBLF, between slope ranges of 2 – 38 degree and elevation ranges of 1,468 m – 4,620 m above sea level, indicating a new record upper altitude limit for Dhole distribution across its global range. We highlight JDNP as an important Dhole conservation area in the Eastern Himalayas, and recommend drafting a pragmatic conservation plan that will strive to minimize conflicts with livestock owners and include key components such as farmer education and livestock insurance to cover Dhole kills.
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2021
Publisher: SAGE Publications
Date: 10-1999
DOI: 10.1177/002215549904701012
Abstract: The ovarian steroids estrogen and progesterone are important in directing the normal growth and development of the mouse mammary gland. Previously, we have demonstrated that the majority of proliferating mammary epithelial cells do not express estrogen receptor-α (ERα). In this study we examined the relationship between progesterone receptor (PR) expression and proliferation in mammary epithelial cells using simultaneous immunohistochemistry for progesterone receptor (PR) and tritiated thymidine [ 3 H]-Tdr) autoradiography. Results showed that the majority ( %) of mammary epithelial cells labeled with [ 3 H]-Tdr were PR-positive in the terminal end buds (TEBs) of pubertal mice and the ducts of pubertal and adult mice. Whereas the majority of mammary epithelial cells were also PR-positive, the basal cell population, which comprises the minority of mammary epithelial cells in the mammary ducts, was predominantly PR-negative. Nevertheless, the PR-positive phenotype remained the major proliferating cell type in the basal population. These findings suggest that the progesterone signaling pathway is involved in the proliferation of basal cell populations, potentially directing formation of tertiary side branching during pubertal development and alveolar bud formation in adult glands. A proportion of the basal cells exhibited weak expression of ERβ suggesting that the role of ERβ in mediating normal estrogen-induced responses should be further studied.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2009
Publisher: AMPCo
Date: 04-2016
DOI: 10.5694/MJA15.01007
Abstract: Reporting adverse events (AEs) and serious AEs (SAEs) are practical steps to ensure safety for volunteers and patients in medical research involving medications, treatments and devices. However, the burden and cost of reporting should be proportionate with the public health benefit of this information. Unfortunately, in Australia there is clear evidence of ever-increasing requirements from sponsors and ethics committees to report AEs and SAEs unnecessarily, leading to a decrease in the uptake of research, particularly less well funded investigator-initiated trials. We believe that in idual AE reports to ethics committees serve no useful purpose, because in most cases the study group identity (drug exposure) is not known in studies with blinded treatment arms and their value is limited. Pragmatic, investigator-initiated Phase IV clinical trials of post-marketed drugs or devices are needed to understand their role in everyday clinical practice. In this setting, the workload and costs of systematic, complete reporting of all AEs and SAEs (independent of whether these are treatment-related) is wasteful, and mostly unnecessary. A trial data safety and monitoring committee is in the unique position of being able to review safety information according to the blinded treatment arms of the study. This enables safety data to be analysed appropriately and a summary report provided to the trial steering committee, principal investigators and the relevant ethics committees in a meaningful way. Defined trial endpoints do not need to be reported as safety events (because they are being properly monitored and analysed).
Publisher: Frontiers Media SA
Date: 16-04-2021
DOI: 10.3389/FCOSC.2021.654976
Abstract: Most canids face population declines and range contractions worldwide. Although the dhole ( Cuon alpinus ) is widely distributed across 10 countries in South and Southeast Asia, limited studies exist on this species. Despite its globally “Endangered” status and ecological role as an apex predator, assessments on its distribution are limited to a few landscapes and countries. This explains the lack of a dhole-specific species conservation plan in most range countries, including Bhutan where no current population estimate exists. The species has also recovered from a country-wide poisoning c aign in the 1970s and 80s. In this study, we determine the dhole's distribution pattern and assess the protection and connectivity of dhole habitat in Bhutan. We anticipated dholes to be extant within their habitat well-represented in protected areas (PAs) and biological corridors (BCs). We used 721 georeferenced dhole occurrence records and eight environmental variables in MaxEnt software to model potential dhole distribution and habitat suitability. The model output was overlaid on the spatial layers of PAs and BCs to assess habitat protection and connectivity. As anticipated, we found the dhole widely distributed in all districts, PAs, and BCs in Bhutan. Dholes were recorded at the highest elevation range limit of 4,980 m above sea level, which overlapped with the “Vulnerable” snow leopard ( Panthera uncia ). Our model identified 72% (27,634 km 2 ) of the country as suitable areas for dholes, of which, 31% (11,899 km 2 ) was highly suitable and 41% (15,735 km 2 ) was moderately suitable. Contrary to our expectation, PAs and BCs encompassed only 29% (8,046 km 2 ) and 12% (3,185 km 2 ) of suitable areas for dholes, respectively. A vast majority of the areas we deemed suitable for dholes currently remain unprotected, thus making dholes more vulnerable to human persecution and local extermination. We recommend adjusting PA boundaries to fully encompass suitable dhole habitat, and also advocate improved livestock husbandry to reduce dhole related livestock predation and minimize conflict, thereby ensuring its long-term survival in Bhutan.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1038/GIM.2012.163
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2021
Publisher: Mary Ann Liebert Inc
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 02-08-2019
DOI: 10.1007/S10329-019-00737-W
Abstract: Reliable population estimates are lacking for many South Asian primate species, including the golden langur (Trachypithecus geei), which is endangered and restricted to Bhutan and northeast India. Although well studied in India, few studies exist on this species in Bhutan. In November 2017, we undertook a nationwide survey of golden langurs in Bhutan using double observers along trail-based transects in 17 blocks within its habitat, and modeled its distribution using MaxEnt. A total of 2439 golden langurs in 222 groups were collectively encountered by 17 teams of double observers, from which, an overall population of 2516 ± SE 363 in iduals and 236 ± SE 9 groups were estimated. Group sizes varied from 2 to 35 in iduals with a mean of 11 ± SD 0.38 in iduals. A total of 468 adult males (19%), 924 adult females (38%), 649 juveniles (27%), and 398 infants (16%) were counted. Adult male-to-female sex ratio was 1:1.97 and adult female-to-infant ratio was 1:0.43. We determined 2848 km
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1038/GIM.2011.67
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2009
Abstract: To determine the prognostic significance of FOXP3 + lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8 + and CD45RO + lymphocyte densities. Tissue microarrays and immunohistochemistry were used to assess the densities of CD8 + , CD45RO + , and FOXP3 + lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. FOXP3 + Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8 + and CD45RO + cell densities were lower. FOXP3 + Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3 + Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8 + and CD45RO + . High FOXP3 + Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51 95% CI, 1.07 to 2.13 P = .019). In contrast, a high density of FOXP3 + Tregs in tumor tissue was associated with improved survival (HR = 0.54 95% CI, 0.38 to 0.77 P = .001). FOXP3 + Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8 + and CD45RO + lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3 + Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3 + Treg density may help to improve the prognostication of early-stage colorectal cancer.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2020
Publisher: Elsevier BV
Date: 03-2018
Publisher: Public Library of Science (PLoS)
Date: 26-07-2011
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.CANLET.2005.01.026
Abstract: Alterations to the Wnt signalling pathway occur in the majority of colorectal cancers and result in abnormal accumulation of beta-catenin. The secreted frizzled related proteins (sFRPs) are antagonists that bind Wnt and inhibit signalling along this pathway. We investigated expression of the sFRP family member, sFRP-4, and beta-catenin in 1,044 human colorectal carcinomas using tissue microarrays and immunohistochemistry. Both proteins showed markedly increased expression levels in tumors compared to normal mucosa, but no significant associations with pathological features or with patient outcome. sFRP-4 was co-expressed with beta-catenin, p53, and COX-2, while the absence of beta-catenin expression was strongly associated with loss of expression of the MLH1 mismatch repair gene. In contrast to other sFRP family members, sFRP-4 expression appears to be upregulated in colorectal carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
DOI: 10.1038/NATURE24462
Publisher: Neoplasia Research
Date: 15-01-2014
DOI: 10.6000/1927-7229.2014.03.01.1
Abstract: The Wnt signalling pathway is involved in regulating cellular proliferation and differentiation, and aberrant activation has been described in several cancers including breast. Oestradiol up regulates Wnt pathway gene expression, and thereby activates the Wnt signalling pathway. We used the oestrogen-responsive breast cancer cell line MCF-7 to examine the effects of secreted frizzled related protein 4 (sFRP-4) on oestradiol-induced growth, including gene expression of the Wnt signalling pathway genes Frizzled Receptor, Wnt-10b, and catenin. We demonstrate here that sFRP-4 inhibits oestradiol-induced cell growth in the MCF-7 cell line and also down regulates oestradiol-induced expression of selected Wnt signalling genes includingcatenin. We propose that sFRP-4 is a potent inhibitor of the Wnt signalling pathway and may negatively regulate oestradiol-mediated proliferation in human breast cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2012
Abstract: Ovarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death. In vitro experimental models determined that sFRP4 was differentially expressed in chemosensitive (A2780) and chemoresistant (A2780 ADR and A2780 Cis) ovarian cell lines, with chemosensitive cells expressing significantly higher levels of sFRP4. Transfection of the chemoresistant cell lines with sFRP4 significantly increased their sensitivity to chemotherapy. Conversely, silencing of sFRP4 expression in the chemosensitive cell line resulted in a corresponding increase in chemoresistance. Comparison of sFRP4 expression in tumour biopsies revealed a positive trend between sFRP4 expression and tumour grade, with mucinous cyst adenocarcinomas exhibiting significantly decreased sFRP4 levels compared to mucinous borderline tumours. This study indicates a role for sFRP4 as a predictive marker of chemosensitivity in ovarian cancer and suggests that this pathway may be worth exploiting for novel therapies.
Publisher: Wiley
Date: 26-10-2008
DOI: 10.1002/IJC.23017
Abstract: Chronic inflammation has been proposed as the possible causal mechanism that explains the observed association between certain risk factors, such as the use of talcum powder (talc) in the pelvic region and epithelial ovarian cancer. To address this issue we evaluated the potential role of chronic local ovarian inflammation in the development of the major subtypes of epithelial ovarian cancer. Factors potentially linked to ovarian inflammation were examined in an Australia-wide case-control study comprising 1,576 women with invasive and low malignant potential (LMP) ovarian tumours and 1,509 population-based controls. We confirmed a statistically significant increase in ovarian cancer risk associated with use of talc in the pelvic region (adjusted odds ratio 1.17, 95% CI: 1.01-1.36) that was strongest for the serous and endometrioid subtypes although the latter was not statistically significant (adjusted odds ratios 1.21, 95% CI 1.03-1.44 and 1.18, 95% CI 0.81-1.70, respectively). Other factors potentially associated with ovarian inflammation (pelvic inflammatory disease, human papilloma virus infection and mumps) were not associated with risk but, like others, we found an increased risk of endometrioid and clear cell ovarian cancer only among women with a history of endometriosis. Regular use of aspirin and other nonsteroidal anti-inflammatory drugs was inversely associated with risk of LMP mucinous ovarian tumours only. We conclude that on balance chronic inflammation does not play a major role in the development of ovarian cancer.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-2019
Publisher: Oxford University Press (OUP)
Date: 04-05-2016
DOI: 10.1093/JLB/LSW018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2020
Publisher: BMJ
Date: 10-11-2022
Abstract: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine) GCs biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3–6 months, treatment should be based on stratification according to risk factors With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.
Publisher: IEEE
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 20-01-2016
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.17.00221
Abstract: Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.
Publisher: Massachusetts Medical Society
Date: 30-10-2003
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NATURE21063
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Publisher: Springer Science and Business Media LLC
Date: 24-09-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-0009
Publisher: Public Library of Science (PLoS)
Date: 05-05-2016
Publisher: Elsevier BV
Date: 02-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 12-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2019
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2020
Publisher: Elsevier BV
Date: 04-2012
Publisher: Mark Allen Group
Date: 02-2017
DOI: 10.12968/JOWC.2017.26.SUP2.S23
Abstract: The effectiveness of negative pressure wound therapy (NPWT) in the prevention of postoperative surgical wound dehiscence (SWD) is the subject of much debate and remains to be determined. This study will identify in iduals at risk of postoperative SWD and trial the use of NPWT as a prophylactic measure against the occurrence of SWD, compared with a non-NPWT standard surgical dressing (SSD). A prospective multicentre randomised controlled trial comparing NPWT dressing against standard surgical dressings (SSD) will be conducted. An intention-to-treat (ITT) approach will be used for the trial. The primary outcome is the prevention of postoperative SWD up to and including day 30 postoperative. Secondary outcomes are: prevention of surgical site infection (SSI) and economic analysis of treatment groups. This study will determine the effectiveness of NPWT in the prevention of postoperative abdominal SWD in a predefined level of risk population. This level 1 study will provide further data for abdominal SWD risk classification, which is anticipated to inform preventive postoperative management. The study design uses a prospective real-world scenario in order to identify clinically significant differences between the intervention and control groups. This trial was prospectively registered on 10 December 2012 with Australian and New Zealand Clinical Trials Network (ANZCTR): 12612001275853.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2019
Publisher: Wiley
Date: 28-03-2020
DOI: 10.1111/ACV.12580
Publisher: American Association for Cancer Research (AACR)
Date: 12-2014
DOI: 10.1158/0008-5472.SABCS-09-4055
Abstract: Background: We previously developed a marker profile with a risk of recurrence algorithm for patients with operable, hormone receptor-positive breast cancer to help guide the appropriate level of adjuvant treatment. Development was done using robust cross-validation methods in two patient sets: University Hospital Basel (UHB) and Institut Paoli-Calmettes (IPC). Unlike most similar tests, which assess RNA transcript levels in homogenized mixtures of tumor and surrounding normal cells, our profile is based predominantly on functional protein markers assessed specifically in tumor cells by certified pathologists. In addition, standard clinicopathologic risk factors (tumor size, tumor grade, and nodal status) are incorporated into the algorithm to the extent that they are not replaced by the molecular markers, enabling a global assessment of risk. The goal of this study was to translate the profile into a validated laboratory test available for clinical use and to assess its performance in all available patients.Methods: ER, PR, HER2, EGFR, BCL2, and p53 (IHC) and MYC/8q24 (FISH) assays were validated in a CLIA-certified central reference laboratory. The assays were conducted on TMAs of patients from Royal Perth Hospital (RPH). An algorithm was used to assign a risk score to all stage I-IIIA patients in all three patient sets (UHB, IPC, and RPH) on a scale of 0 to 10+. A pre-determined risk score threshold of 3.8 was used to separate patients into low and high risk groups.Results: In an independent validation of the algorithm in the hormone therapy (HT) only-treated RPH patients (n=144), the low-risk group had a 10-year recurrence rate & %, and the high-risk group had a recurrence rate more than ten times higher (p& .0001). When all HT only-treated patients from the UHB, IPC, and RPH patient sets were combined (n=444), the profile separated patients into low and high risk groups with 10-year recurrence rates of 4% and 40%, respectively (HR=10, 95%CI=5 to 20, p& .0001). In multivariate analyses, the profile was independent and fully replaced the significance of all in idual prognostic factors and clinical treatment guideline combinations. A continuous risk curve demonstrated that risk of recurrence increased steadily with higher risk scores (p& .0001). Within the group of patients with Adjuvant! Online scores & % (n=228), the profile reclassified as low risk 85% (n=77/92) of pN0 patients and 35% (n=33/90) of pN1 patients, and both of these low-risk subgroups had only a 6% 10-year recurrence rate.Conclusion: The marker profile was validated both analytically and clinically in a CLIA-certified reference laboratory. It replaced and exceeded the prognostic value of all available in idual factors and current multivariate treatment guidelines. This justified release to clinicians for diagnostic use and indicates that it is a strong candidate for future comparative studies with other treatment decision-making tools. Citation Information: Cancer Res 2009 (24 Suppl):Abstract nr 4055.
Publisher: Bioscientifica
Date: 09-1999
Abstract: Maintenance of the size and differentiated function of the adult prostate is dependent on testicular androgens. In this study, simultaneous androgen receptor (AR) immunohistochemistry and [(3)H]thymidine labelling was used to characterise the proliferating epithelial cells of the murine ventral prostate. Proliferation in the adult prostate was more prevalent in the basal cell population with 1.8 AR-negative cells labelled with [(3)H]thymidine as compared with 0.7% AR-expressing luminal cells. Three weeks following castration of mice, the atrophied prostate contained rudimentary glands composed of both luminal and basal cells with the proportion of AR-expressing basal cells reduced from 50 to 25%. Administration of testosterone enanthate to castrated mice induced a recapitulation of the prostate gland that was preceded by up-regulation of AR expression in basal cells to normal adult levels (50% AR-positive cells) by 12 h following testosterone injection. Proliferation of AR-positive luminal cells peaked at 48 h (22.8%) while proliferation of AR-negative basal cells peaked at 96 h (6.1%) following testosterone administration. These results suggest that distinct populations of luminal and basal cells are resistant to castration-induced involution of the prostate but remain responsive to direct or indirect testosterone effects and recapitulate the gland following administration of testosterone.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 09-05-2014
DOI: 10.1038/SREP04669
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 12-2018
Publisher: Frontiers Media SA
Date: 19-07-2021
DOI: 10.3389/FCOSC.2021.691507
Abstract: Understanding human–canid conflict and coexistence must focus on documenting human–canid interactions and identifying the underlying drivers of reciprocal human attitude which enables appropriate strategies to minimize conflict and forge coexistence. The dhole ( Cuon alpinus ), Asia's most widely distributed wild canid, is highly threatened by human persecution and anthropogenic activities. Despite its “endangered” status, its ecological role as an apex predator, negative interactions with humans, and dhole-specific attitude studies are limited, thus hindering the development of a comprehensive dhole-conservation strategy. Here, we investigate the influence of socioeconomic factors of age, gender, income, residency inside/outside a protected area (PA), and other variables (cultural beliefs, livestock loss, and quantity of livestock loss) on the attitudes of local people and support for dhole conservation in the Himalayan Kingdom of Bhutan. We conducted a semi-structured questionnaire survey of 1,444 households located within the PA and non-PA from four representative regions in the country. Using R programming, we ran Pearson's chi-square test of independence to test the overall difference in the attitude and support for dhole conservation, followed by recursive partitioning through a conditional inference regression tree to identify its significant covariates with the highest explanatory power. Majority (79.1%) of respondents (χ 2 = 488.6 df = 1 p & 0.001) disliked the dhole over those who liked it. More than half (57.7%) (χ 2 = 412.7 df = 2 p & 0.001) opposed dhole conservation over those who either supported or remained neutral. Experience of livestock loss to dholes was the primary ( p & 0.001) factor influencing the negative attitude and opposition to dhole conservation, despite an acknowledgment of the ecological role of the dhole in controlling agricultural crop predators. Our study, which is the first-ever survey in Bhutan, solely focused on investigating human attitudes and perceptions toward the dhole, indicating that livestock loss to dholes transcends all positive attitudes to the species and drives a predominant dislike and opposition to its conservation. To improve the attitude and support toward the dhole and to foster dhole–human coexistence, livestock predation by dholes needs alleviation by improving the existing animal husbandry, in conjunction with promoting conservation awareness on this species.
Publisher: MDPI AG
Date: 30-03-2020
Abstract: Forest fire is an environmental disaster that poses immense threat to public safety, infrastructure, and bio ersity. Therefore, it is essential to have a rapid and robust method to produce reliable forest fire maps, especially in a data-poor country or region. In this study, the knowledge-based qualitative Analytic Hierarchy Process (AHP) and the statistical-based quantitative Frequency Ratio (FR) techniques were utilized to model forest fire-prone areas in the Himalayan Kingdom of Bhutan. Seven forest fire conditioning factors were used: land-use land cover, distance from human settlement, distance from road, distance from international border, aspect, elevation, and slope. The fire-prone maps generated by both models were validated using the Area Under Curve assessment method. The FR-based model yielded a fire-prone map with higher accuracy (87% success rate 82% prediction rate) than the AHP-based model (71% success rate 63% prediction rate). However, both the models showed almost similar extent of ‘very high’ prone areas in Bhutan, which corresponded to coniferous-dominated areas, lower elevations, steeper slopes, and areas close to human settlements, roads, and the southern international border. Moderate Resolution Imaging Spectroradiometer (MODIS) fire points were overlaid on the model generated maps to assess their reliability in predicting forest fires. They were found to be not reliable in Bhutan, as most of them overlapped with fire-prone classes, such as ‘moderate’, ‘low’, and ‘very low’. The fire-prone map derived from the FR model will assist Bhutan’s Department of Forests and Park Services to update its current National Forest Fire Management Strategy.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2013
DOI: 10.1038/TPJ.2012.26
Abstract: Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2007
DOI: 10.1158/1055-9965.EPI-07-0542
Abstract: Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148 r2 = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation s les, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition. (Cancer Epidemiol Biomarkers Prev 2007 (12):2557–9)
Publisher: Springer Science and Business Media LLC
Date: 28-09-2018
DOI: 10.1038/S41467-018-05564-Z
Abstract: Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2 -mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1 -methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1- methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
DOI: 10.1038/NATURE11547
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2020
Publisher: Mary Ann Liebert Inc
Date: 09-2011
Abstract: The biobanking literature frequently addresses donor and societal issues surrounding biobanking, but the biobanker's perspective is rarely highlighted. While not comprehensive, this article offers an overview of the human aspects of biobanking from the viewpoint of biobank personnel-from biobank formation, through the process, and in addressing post-biobanking issues. As every biobank and biobank network may differ, such factors may vary. Before biobanking can commence, the purpose of the biobank network must be defined, and buy-in achieved from many stakeholders. An attitude of trust and sharing is essential, as is good communication. Developing a biobank is time consuming and laborious. Forming a network requires significantly more time due to the need for cross-institutional harmonization of policies, procedures, information technology considerations, and ethics. Circumstances may dictate whether development occurs top-down and/or bottom-up, as well as whether network management may be independent or by personnel from participating biobanks. Funding tends to be a prominent issue for biobanks and networks alike. In particular, networks function optimally with some level of government support, particularly for personnel. Quality biospecimen collection involves meticulously documented coordination with a network of medical and nursing staff. Examining and s ling operative specimens requires timely collaboration between the surgical and pathology teams. "Catch rates" for s les may be difficult to predict and may occur at a frequency less than anticipated due to factors related to the institution, staff, or specimen. These factors may affect specimen quality, and have a downstream effect on competition for specimens for research. Thus, release of s les requires a fair, carefully constructed s le access policy, usually incorporating an incentive for researchers, and an encouragement to form collaborations. Finally, the public and patient groups should aim to understand the benefits of a biobank network, so that patient care is improved through coordinated biobanking activity.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1053/J.GASTRO.2013.10.054
Abstract: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T(17) intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T(17) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17). HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor s les with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16 95% confidence interval, 0.012–0.8 P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA.
Publisher: Radiation Research Society
Date: 04-2016
DOI: 10.1667/RR14235.1
Publisher: Wiley
Date: 09-2008
DOI: 10.1002/PATH.2385
Abstract: WWP1 is a ubiquitin ligase, associated with the post-translational regulation of several tumour-promoting and tumour suppressor proteins. Here we show that WWP1 expression is up-regulated in a subset of breast tumour cell lines and primary breast tumours. We overexpressed WWP1 in MCF10A breast epithelial cells and demonstrated increased cell growth and anchorage-independent colony formation. RNAi knockdown of WWP1 expression in T47D and MCF7 breast tumour cell lines reduced anchorage-independent colony formation. We used WWP1 protein expression levels, in combination with its sub-cellular localization, to classify breast tumours into four categories. Surprisingly, a category with low/absent WWP1 expression displayed a consistently worse prognosis compared with WWP1-expressing tumours. Importantly, the association with disease-free survival was independent of the status of other commonly used prognostic indicators. Thus, WWP1 is a prognostic marker and may be a potential therapeutic target for a subset of breast tumours.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41598-019-48804-Y
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC , has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1 , BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Publisher: Springer Netherlands
Date: 12-07-2015
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41467-019-10968-6
Abstract: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.
Publisher: Wiley
Date: 30-03-2018
DOI: 10.1111/BJU.14226
Abstract: To determine patient satisfaction and experience after robot-assisted radical prostatectomy (RARP) for prostate cancer, using a convergent mixed-method qualitative analysis approach. 412 patients who underwent RARP between January 2014 and June 2016 were mailed questionnaires and invited to participate in focus groups. Qualitative data was thematically analysed using NVivo. Descriptive statistics were obtained from the questionnaire using SPSS. 214 patients responded (52% of s le size) of whom 97.6% were satisfied and 91.1% would likely recommend RARP. Key themes from the qualitative data highlighted the psychosocial impacts of the diagnosis and RARP process. The importance of early recovery, the benefits of pelvic floor exercises and educational resources were emphasised. Patients were overwhelmingly satisfied with RARP, largely due to relevance and timeliness of the information and support provided both before and after surgery. With an increased understanding of the factors and outcomes that are most important to patients regarding all aspects of hospital care, we can create more targeted care pathways. Key themes will help inform the implementation of an enhanced recovery after surgery (ERAS) protocol to further improve recovery and early return to function.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2018
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 26-06-2014
DOI: 10.1007/S11673-014-9552-1
Abstract: International transfers of human biological material (biospecimens) and data are increasing, and commentators are starting to raise concerns about how donor wishes are protected in such circumstances. These exchanges are generally made under contractual material transfer agreements (MTAs). This paper asks what role, if any, should research ethics committees (RECs) play in ensuring legal and ethical conduct in such exchanges. It is recommended that RECs should play a more active role in the future development of best practice MTAs involving exchange of biospecimens and data and in monitoring compliance.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 09-2019
End Date: 07-2025
Amount: $4,000,000.00
Funder: Australian Research Council
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