1,720,959 research outputs found
SIP1/ZEB2 induced epthelial to mesenchymal transition promotes metastasis and chemoresistance in colorectal cancer
No full textColorectal cancer (CRC) is the second commonest cause of cancer-associated mortality in Europe, and a key public health issue. Cancer metastasis is the principle cause of death and occurs in up to 30% at presentation, and subsequently develops in 50% after curative surgery. The majority of patients with metastases are incurable, and can expect a median survival of only up to 2 years, even with the latest chemotherapeutic and biological agents. Additionally, not all patients respond and side effects are frequent and at times life threatening. These findings highlight the pressing need for identification of new markers of metastatic capability and chemotherapy response, to improve precision with which therapy can be tailor to patients. Although development of primary CRC has served as a paradigm for understanding multistage carcinogenesis, the mechanisms influencing metastasis and chemoresistance are still poorly understood.Epithelial-Mesenchymal Transition (EMT) is an embryologically conserved genetic program by which cancer cells down regulate epithelial junctions, express mesenchymal markers, and manifest a migratory phenotype. While the significance of EMT during development and embryogenesis is well established, an emerging role is its involvement in metastasis and chemo/radio resistance in cancer. EMT is activated by TGFβ, FGF, EGF, WNT and Notch signalling pathways, which converge to activate transcription factors that subsequently repress the expression of critical epithelial genes. Key transcription factors in this process include members of the SNAIL, Twist, and ZEB families, which promote cellular phenotypic switch. In addition to enhanced migration, metastatic cells also acquire apoptosis resistance to chemo/radio therapy through currently poorly understood mechanism. Despite growing evidence that EMT promotes apoptosis resistance to DNA damaging agents, ZEB family of transcription factors have been sparsely studied in gastrointestinal malignancies and the molecular mechanism mediating apoptosis resistance poorly understood.Based on these observations the following hypothesis was formulated:• SMAD interacting protein (SIP1/ZEB2) induced EMT promotes metastasis and apoptosis resistance in colorectal cancer (CRC).The primary objectives of the study are: -1. Assess if SIP1/ZEB2 induces EMT in CRC.2. Investigate whether expression of SIP1/ZEB2 could serve as a biomarker to detect patients at high risk or recurrence after surgical resection in CRC.3. Study the molecular mechanisms that promote SIP1/ZEB2 induced apoptosis resistance to chemotherapeutic and radiotherapeutic treatment regimens.4. Validate in-vitro findings in a murine model SIP1/ZEB2 expression resulted in the acquisition of all the cardinal features of EMT, namely E-cadherin down regulation, increased metastatic capacity and apoptosis resistance to chemotherapeutic agents commonly using in clinical practice.SIP/ZEB2 expression in primary CRC, exhibited a statistically significant association with increased risk of distant recurrence in two independent patient cohorts. Addition of SIP1/ZEB2 expression status to the TNM staging system improved precision in the ability to identify patients at high risk of disease recurrence after curative surgery. Further studied also highlighted an important association between SIP1/ZEB2 expression and chemoresistance to cytotoxic drugs used to in the FOLFOX regimen. A qPCR array, with a focus on DNA damage response highlighted SIP1/ZEB2 induced EMT associated with increased expression of multiple components of the nucleotide excision repair (NER) pathway, in particular excision repair cross complementation group 1 (ERCC1).ERCC1 hetero-dimerises with excision repair cross complementation group 4, which functions as an exonuclease during repair of DNA crosslinks generated by platinum based chemotherapeutic agents such as oxaliplatin. Stable over expression of ERCC1; lead to attenuate DNA damage, apoptosis resistance and enhanced viability. Whilst siRNA mediated knockdown (KD) sensitise cells to oxaliplatin treatment. Assessment of DNA repair kinetics, as a mechanism of repair kinetics revealed higher expression levels of ERCC1 associated with faster kinetics of DNA cross-link clearance. The influence of ERCC1 over expression in vivo was demonstrated by impaired tumour regression in ERCC1 over-expressing cells in an orthotopic murine model of primary CRC.ZEB proteins have also been implicated with the enhanced ability to repair DNA DSB’s and consequently promote resistance to ionising radiation. For many decades, models of DNA DSB repair have highlighted the critical influence of the histone architecture in accessing damaged DNA and subsequently undertaking DNA repair. Heterochromatin rich DNA domains are known to be prone to accruing mutations, due to attenuated DNA repair. Recent studies have suggested EMT leads to epigenetic reprograming, which results in genome wide loss of heterochromatin rich domains. SIP1/ZEB2 expression in DLD-SIP1 cells enhanced apoptosis resistance secondary to faster repair of DNA DSB’s. ChIP-Seq analysis of SIP1/ZEB2 expressing mesenchymal cells highlighted genome wide loss of heterochromatin mark H3K27me3. The mechanism responsible for this epigenetic change was found to be direct transcriptional repression of the methyltransferase EZH2, by SIP1/ZEB2. Inhibition of EZH2 by small molecule inhibitor GSK126 in uninduced DLDSIP1 cells enhanced apoptosis resistance and viability in response to IR. The above results suggest the epigenetic architecture of mesenchymal cancer can influence DNA repair kinetics and consequently resistance to IR. The above body of work clearly demonstrates SIP1/ZEB2 plays a central role in promoting metastasis and treatment resistance in CRC. Further in vitro studies and clinical trials to dissect the impact of SIP1/ZEB2 expression in CRC will facilitate clinical translation in future years
ERCC1 abundance is an indicator of DNA repair-apoptosis decision upon DNA damage
No full textDNA repair is essential for successful propagation of genetic material and fidelity of transcription. Nucleotide excision repair (NER) is one of the earliest DNA repair mechanisms, functionally conserved from bacteria to human. The fact that number of NER genes vary significantly between prokaryotes and metazoans gives the insight that NER proteins have evolved to acquire additional functions to combat challenges associated with a diploid genome, including being involved in the decision between DNA repair and apoptosis. However, no direct association between apoptosis and NER proteins has been shown to date. In this study, we induced apoptosis with a variety of agents, including oxaliplatin, doxorubicin and TRAIL, and observed changes in the abundance and molecular weight of NER complex proteins. Our results showed that XPA, XPC and ERCC1 protein levels change during DNA damage-induced apoptosis. Among these, ERCC1 decrease was observed as a pre-mitochondria depolarisation event which marks the “point of no return” in apoptosis signalling. ERCC1 decrease was due to proteasomal degradation upon lethal doses of oxaliplatin exposure. When ERCC1 protein was stabilised using proteasome inhibitors, the pro-apoptotic activity of oxaliplatin was attenuated. These results explain why clinical trials using proteasome inhibitors and platinum derivatives showed limited efficacy in carcinoma treatment and also the importance of how deep understanding of DNA repair mechanisms can improve cancer therapy
Risk assessment using a novel scoring system (NUn score) to predict major complications after oesophageal resection
No full textBackground: the aim of this study was to establish a numerical scoring system that categorises a patients’ risk of developing major post-operative complications after oesophageal resection based on routine blood tests.Methods: a prospective database of all upperGI resectionswith an oesophageal anastomosis between 2005 and 2010 was reviewed. C-reactive protein (CRP), white cell count (WCC) and albumin were recorded once pre-operatively and post-operatively daily until discharge or day 14. All post-operative complications were recorded using the Clavien-Dindo (CD) classification. The diagnostic accuracy of CRP,WCCand albumin levels were analysed by receiver operating characteristic (ROC) curve analysis with anastomotic leak and major complication or death (CD 3–5) as outcome measures.Results: a total of 258 patients were identified (Median age 67 (37–85) years, Male 78%, Female 22%). A minimally invasive procedure was performed in 101 (40%) cases. A total of 63 (25%) patients developed a major complication and there were 7 (2•7%) deaths. 27 (10•5%) patients were diagnosed with an anastomotic leak at median post-operative day (POD) 7 (Range: 5–15). On univariable analysis there were no pre-operative patient or tumour characteristics that could predict post-operative complications. CRP (p=0•08), WCC (p=0•08) and albumin (p=0•003) were independent predictors of a major complication or death at POD 5. After multivariable analysis these factors were combined to create a novel scoring system (NUn score). On POD 4 the NUn score was highly predictive of an anastomotic leak (NUn score >0•97: sensitivity 100%, specificity 66%, diagnostic accuracy 0•78 (95%CI 0•655–0•905, p<0•0001)) and a major complication or death (NUn >0•9: sensitivity 73%, specificity 79%, diagnostic accuracy 0•71 (95%CI 0•609–0•81, p<0•0001)).Conclusion: we describe the development of a novel (NUn) scoring system that accurately categorises patients at risk of anastomotic leak and major complications following oesophageal resection. In this cohort the NUn score accurately identified patients at risk of anastomotic leak 3 days prior to diagnosis. The sensitivity of the POD4NUnscore for anastomotic leak is such that patients with a score <0•97 can be confidently fast-tracked to enteral feeding and early discharge<br/
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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