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Author Øverbye, A.; Skotland, T.; Koehler, C.J.; Thiede, B.; Seierstad, T.; Berge, V.; Sandvig, K.; Llorente, A. url  openurl
  Title Identification of prostate cancer biomarkers in urinary exosomes Type Journal Article
  Year 2015 Publication Abbreviated Journal Oncotarget  
  Volume 6 Issue 30 Pages 30357-30376  
  Keywords (up)  
  Abstract Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.  
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  Call Number UofT @ ankit.sinha @ Serial 45334  
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Author Rutten, M.J.; Sonke, G.S.; Westermann, A.M.; van Driel, W.J.; Trum, J.W.; Kenter, G.G.; Buist, M.R. url  openurl
  Title Prognostic Value of Residual Disease after Interval Debulking Surgery for FIGO Stage IIIC and IV Epithelial Ovarian Cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Obstet Gynecol Int  
  Volume 2015 Issue Pages 464123  
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  Abstract Although complete debulking surgery for epithelial ovarian cancer (EOC) is more often achieved with interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT), randomized evidence shows no long-term survival benefit compared to complete primary debulking surgery (PDS). We performed an observational cohort study of patients treated with debulking surgery for advanced EOC to evaluate the prognostic value of residual disease after debulking surgery. All patients treated between 1998 and 2010 in three Dutch referral gynaecological oncology centres were included. The prognostic value of residual disease after surgery for disease specific survival was assessed using Cox-regression analyses. In total, 462 patients underwent NACT-IDS and 227 PDS. Macroscopic residual disease after debulking surgery was an independent prognostic factor for survival in both treatment modalities. Yet, residual tumour less than one centimetre at IDS was associated with a survival benefit of five months compared to leaving residual tumour more than one centimetre, whereas this benefit was not seen after PDS. Leaving residual tumour at IDS is a poor prognostic sign as it is after PDS. The specific prognostic value of residual tumour seems to depend on the clinical setting, as minimal instead of gross residual tumour is associated with improved survival after IDS, but not after PDS.  
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  Call Number UofT @ ankit.sinha @ Serial 45336  
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Author Surinova, S.; Choi, M.; Tao, S.; Schüffler, P.J.; Chang, C.Y.; Clough, T.; Vysloužil, K.; Khoylou, M.; Srovnal, J.; Liu, Y.; Matondo, M.; Hüttenhain, R.; Weisser, H.; Buhmann, J.M.; Hajdúch, M.; Brenner, H.; Vitek, O.; Aebersold, R. url  openurl
  Title Prediction of colorectal cancer diagnosis based on circulating plasma proteins Type Journal Article
  Year 2015 Publication Abbreviated Journal EMBO Mol Med  
  Volume 7 Issue 9 Pages 1166-1178  
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  Abstract Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection.  
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  Call Number UofT @ ankit.sinha @ Serial 45345  
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Author Adamek, M.; Opelz, G.; Klein, K.; Morath, C.; Tran, T.H. url  openurl
  Title A fast and simple method for detecting and quantifying donor-derived cell-free DNA in sera of solid organ transplant recipients as a biomarker for graft function Type Journal Article
  Year 2015 Publication Abbreviated Journal Clin Chem Lab Med  
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  Abstract BACKGROUND: Timely detection of graft rejection is an important issue in the follow-up care after solid organ transplantation. Until now, biopsy has been considered the “gold standard” in the diagnosis of graft rejection. However, non-invasive tests such as monitoring the levels of cell-free DNA (cfDNA) as a sensitive biomarker for graft integrity have attracted increasing interest. The rationale of this approach is that a rejected organ will lead to a significant release of donor-derived cfDNA, which can be detected in the serum of the transplant recipient. METHODS: We have developed a novel quantitative real-time PCR (qPCR) approach for detecting an increase of donor-derived cfDNA in the recipient’s serum. Common insertion/deletion (InDel) genetic polymorphisms, which differ between donor and recipient, are targeted in our qPCR assay. In contrast to some other strategies, no specific donor/recipient constellations such as certain gender combinations or human leukocyte antigen (HLA) discrepancies are required for the application of our test. RESULTS: The method was first validated with serial dilutions of serum mixtures obtained from healthy blood donors and then used to determine donor-derived cfDNA levels in patients’ sera within the first 3 days after their kidney transplantation had been performed. CONCLUSIONS: Our method represents a universally applicable, simple and cost-effective tool which can potentially be used to detect graft dysfunction in transplant recipients.  
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  ISSN 1434-6621 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial 45414  
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Author Abbasi, F.; Azizi, F.; Javaheri, M.; Mosallanejad, A.; Ebrahim-Habibi, A.; Ghafouri-Fard, S. url  openurl
  Title Segregation of a novel homozygous 6 nucleotide deletion in GLUT2 gene in a Fanconi-Bickel syndrome family Type Journal Article
  Year 2015 Publication Abbreviated Journal Gene  
  Volume 557 Issue 1 Pages 103-105  
  Keywords (up)  
  Abstract Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, impaired utilization of glucose and galactose, rickets, and severe short stature. It has been shown to be caused by mutations in GLUT2 gene, a member of the facilitative glucose transporter family. Here, we report an Iranian family with 2 affected siblings. The clinical findings in the patients include developmental delay, failure to thrive, hepatomegaly, enlarged kidneys and rickets. A novel 6 nucleotide deletion (c.10611066del6, p.V355S356del2) is shown to be segregated with the disease in this family.  
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  ISSN 0378-1119 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45434  
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Author ACMG, B. of D. url  openurl
  Title ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing Type Journal Article
  Year 2015 Publication Abbreviated Journal Genet Med  
  Volume 17 Issue 1 Pages 68-69  
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  Abstract DISCLAIMER: These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these recommendations.  
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  ISSN 1098-3600 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45436  
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Author Abraham, G.; Inouye, M. url  openurl
  Title Genomic risk prediction of complex human disease and its clinical application Type Journal Article
  Year 2015 Publication Abbreviated Journal Curr Opin Genet Dev  
  Volume 33 Issue Pages 10-16  
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  Abstract Recent advances in genome-wide association studies have stimulated interest in the genomic prediction of disease risk, potentially enabling individual-level risk estimates for early intervention and improved diagnostic procedures. Here, we review recent findings and approaches to genomic prediction model construction and performance, then contrast the potential benefits of such models in two complex human diseases, aiding diagnosis in celiac disease and prospective risk prediction for cardiovascular disease. Early indications are that optimal application of genomic risk scores will differ substantially for each disease depending on underlying genetic architecture as well as current clinical and public health practice. As costs decline, genomic profiles become common, and popular understanding of risk and its communication improves, genomic risk will become increasingly useful for the individual and the clinician.  
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  ISSN 0959-437x ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial 45437  
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Author Alkuraya, F.S. url  openurl
  Title Human knockout research: new horizons and opportunities Type Journal Article
  Year 2015 Publication Abbreviated Journal Trends Genet  
  Volume 31 Issue 2 Pages 108-115  
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  Abstract Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to ‘disease’ states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in ‘healthy’ individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits.  
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  ISSN 0168-9525 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45506  
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Author Adebayo, D.; Morabito, V.; Davenport, A.; Jalan, R. url  openurl
  Title Renal dysfunction in cirrhosis is not just a vasomotor nephropathy Type Journal Article
  Year 2015 Publication Abbreviated Journal Kidney Int  
  Volume 87 Issue 3 Pages 509-515  
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  Abstract The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high, and as such the treatment of this condition is an unmet need. Although features of kidney injury are well recognized in these patients, the pathophysiology is complex and not completely understood. Improved understanding of the pathophysiological mechanisms involved in renal dysfunction occurring on a background of cirrhosis is key to developing effective treatment strategies to improve survival. Renal dysfunction due to hepatorenal syndrome (HRS) is characteristic of cirrhosis. Our current understanding is that HRS is functional in nature and occurs as a consequence of hemodynamic changes associated with portal hypertension. However, there is evidence in the literature suggesting that, histologically, the kidneys are not always normal in the vast majority of patients who present with renal dysfunction on the background of cirrhosis. Furthermore, there is emerging data implicating nonvasomotor mechanisms in the pathophysiology of renal dysfunction in cirrhosis. This mini-review aims to present the evidence suggesting that factors other than hemodynamic dysregulation have an important role in the development of this major complication for patients with progressive cirrhosis.  
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  ISSN 0085-2538 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial 45609  
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Author Andersson, R.; Sandelin, A.; Danko, C.G. url  openurl
  Title A unified architecture of transcriptional regulatory elements Type Journal Article
  Year 2015 Publication Abbreviated Journal Trends Genet  
  Volume 31 Issue 8 Pages 426-433  
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  Abstract Gene expression is precisely controlled in time and space through the integration of signals that act at gene promoters and gene-distal enhancers. Classically, promoters and enhancers are considered separate classes of regulatory elements, often distinguished by histone modifications. However, recent studies have revealed broad similarities between enhancers and promoters, blurring the distinction: active enhancers often initiate transcription, and some gene promoters have the potential to enhance transcriptional output of other promoters. Here, we propose a model in which promoters and enhancers are considered a single class of functional element, with a unified architecture for transcription initiation. The context of interacting regulatory elements and the surrounding sequences determine local transcriptional output as well as the enhancer and promoter activities of individual elements.  
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  ISSN 0168-9525 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45626  
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