An exploratory study for the discovery of non-invasive hepatocellular carcinoma biomarkers among high-risk hepatitis C virus infected patients

Hepatocellular Carcinoma (HCC) is a major healthcare problem, representing the third most common cause of cancer-related mortality worldwide. Chronic infections with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) are the major risk factors for the development of HCC. The incidence of HBV -associated HCC is in decline as a result of an effective HBV vaccine; however, since an equally effective HCV vaccine has not yet been developed, there are 130 million HCV infected patients worldwide who are at a high-risk for developing HCC. Because reliable parameters and/or tools for the early detection of HCC among high-risk individuals are severely lacking, HCC patients are always diagnosed at a late stage where surgical solutions or effective treatment are not possible. Using urine as a non-invasive sample source, two different approaches (proteomic-based and genomic-based approaches) were pursued with the common goal of discovering potential biomarker candidates for the early detection of HCC among high-risk chronic HCV infected patients. Urine was collected from 106 HCV infected Egyptian patients, 32 of whom had already developed HCC and 74 patients who were diagnosed as HCC-free at the time of initial sample collection. In addition to these patients, urine samples were also collected from 12 healthy control individuals. Total urinary proteins, Trans-renal nucleic acid (Tr-NA) and microRNA (miRNA) were isolated from urine using novel methodologies and silicon carbide-loaded spin columns. In the first, "proteomic-based", approach, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to identify potential candidates from pooled urine samples. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR (qRT-PCR). This approach revealed that significant over-expression of three proteins: DJ-1, Chromatin Assembly Factor-1 (CAF-1) and 11 Moemen Abdalla HCC Biomarkers Heat Shock Protein 60 (HSP60), were characteristic events among HCC-post HCV infected patients. As a single-based HCC biomarker, CAF-1 over-expression identified HCC among HCV infected patients with a specificity of 90%, sensitivity of 66% and with an overall diagnostic accuracy of 78%. Moreover, the CAF-lIHSP60 tandem identified HCC among HCV infected patients with a specificity of 92%, sensitivity of 61 % and with an overall diagnostic accuracy of 77%. In the second genomic-based approach, two different approaches were processed. The first approach was the miRNA-based approach. The expression levels of miRNAs isolated from urine were studied using the Illumina MicroRNA Expression Profiling Assay. This was followed by qRT-PCR-based validation of deregulated expression of identified miRNA candidates among all the patients. This approach shed the light on the deregulated expression of a number of miRNAs, which may have a role in either the development of HCC among HCV infected patients (i.e. miR-640, miR-765, miR-200a, miR-521 and miR-520) or may allow for a better understanding of the viral-host interaction (miR-152, miR-486, miR-219, miR452, miR-425, miR-154 and miR-31). Moreover, the deregulated expression of both miR-618 and miR-650 appeared to be a common event among HCC-post HCV infected patients. The results of the search for putative targets of these two miRNA suggested that miR-618 may be a potent oncogene, as it targets the tumor-suppressor gene Low density lipoprotein-related protein 12 (LPR12), while miR-650 may be a potent tumor-suppressor gene, as it is supposed to downregulate the TNF receptor-associated factor-4 (TRAF4) oncogene. The specificity of miR-618 and miR-650 deregulated expression patterns for the early detection of HCC among HCV infected patients was 68% and 58%, respectively, whereas the sensitivity was 64% and 72%, respectively. When the deregulated expression of both miRNAs was combined as a tandem biomarker, the specificity and the sensitivity were 75% and 58% respectively. 111 Moemen Abdalla HCC Biomarkers In the second, "Trans-renal nucleic acid-based", approach, the urinary apoptotic nucleic acid (uaNA) levels of 70ng/mL or more were found to be a good predictor of HCC among chronic HCV infected patients. The specificity and the sensitivity of this diagnostic approach were 76% and 86%, respectively, with an overall diagnostic value of 81 %. The uaNA levels positively correlated to HCC disease progression as monitored by epigenetic changes of a panel of eight tumor-suppressor genes (TSGs) using methylation-sensitive PCR. Moreover, the pairing of high uaNA levels (:::: 70 ng/mL) and CAF-1 over-expreSSIOn produced a highly specific (l 00%) multiple-based HCC biomarker with an acceptable sensitivity of 64%, and with a diagnostic accuracy of 82%. In comparison to the previous pairing, the uaNA levels (:::: 70 ng/mL) in tandem with HSP60 over-expression was less specific (89%) but highly sensitive (72%), resulting in a diagnostic accuracy of 64%. The specificities of miR-650 deregulated expression in combination with either high uaNA content or HSP 60 over-expression were 82% and 79%, respectively, whereas, the sensitivities of these combinations were 64% and 58%, respectively. The potential biomarkers identified in this study compare favorably with the diagnostic accuracy of the a-fetoprotein levels test, which has a specificity of 75%, sensitivity of 68% and an overall diagnostic accuracy of 70%. Here we present an intriguing study which shows the significance of using urine as a noninvasive sample source for the identification of promising HCC biomarkers. We have also introduced new techniques for the isolation of different urinary macromolecules, especially miRNA, from urine. Furthermore, we strongly recommend the potential biomarkers indentified in this study as focal points of any future research on HCC diagnosis. A larger testing pool will determine if their use is practical for mass population screening. This explorative study identified potential targets that merit further investigation for the development of diagnostically accurate biomarkers isolated from 1-2 mL urine samples that were acquired in a non-invasive manner.

David Skene-Melvin papers, 1918, 1995, n.d.

David Skene-Melvin, literary historian and bibliographer, donated his extensive collection of books on Crime, Mystery and Detective fiction to the Popular Culture Program at Brock University in July 2001. The donation forms a significant part of the Skene-Melvin Collection of Crime, Mystery and Detective Fiction, James A. Gibson Library, Brock University.

Clopton Charter

Translation of Clopton Charter Let those who are present and those in future know that I Robert de Clopton gave and granted to my son, William, one yardland which is part of the Clopton estate / manorial demesne with all its appurtenances in exchange for his homage and service , and that I have confirmed it with this charter . The yardland in question is that which he once held as heriot / heritable property . [I have given and granted it to him] to be held and kept by him and his heirs freely and undisputedly as a holding granted in return for services and as hereditable property from me and my heirs. For this he has to pay an annual rent of twelve silver pennies, in two installments per year: six on the Feast Day of St. Michael and six on the Feast Day of St. Mary in March , on the income that belongs to me and to my heirs, without neglecting income from elsewhere; together with all goods and privileges attached to the aformentioned land in the form of fields and pastures and everything which belongs to said yardland. And I, Robert, and all my heirs shall warrant all this aforementioned yardland together with all its appurtenances to said William and his heirs against all other claims in perpetuity . However, in order that this gift and grant of mine may remain firm and immovable, I have validated this charter with my seal in the presence of [the following] witnesses: the knights Sir William of Ludinton [and] Sir Robert of Valle. William of Edricheston, William of Waleford, Robert of Sidesam, Richard of Ludinton, Nicholas the scribe , and others.

Roberta "Bobbie" Styran fonds, 1707-2013, n.d.

Roberta “Bobbie” Styran was born and rasied in Fredericton, N.B. She graduated from McMaster University with a B.A. (1962) and M.A. (1964), before furthering her studies at the University of Toronto, where she received a Ph. D in History. From 1967 to 1978, she taught Medieval History at Brock University, where she developed an interest in the Welland Canal. She began a collaboration with Prof. Robert R. Taylor of the History Department at this time, researching the history of the Welland Canals. She later moved to Toronto and worked for the Ministry of Education, but returned to St. Catharines in 1988 to facilitate her work with Prof. Taylor. The two have co-authored several books, including The Welland Canals: the Growth of Mr. Merritt’s Ditch; Mr. Merritt’s Ditch: A Welland Canals Album; The Great “Swivel Link”: Canada’s Welland Canal and This Great National Object: Building the Nineteenth-Century Welland Canals. Bobbie travelled extensively, visiting many canal and industrial revolution sites in Great Britain and the United States. She was active in many canal associations, including the Canadian Canal Society (where she served as president and editor of the Society’s newsletter), the American Canal Society, and the Council of Inland Waterways International. She also helped to found the Welland Canals Preservation Association and organized and chaired the 2004 World Canals Conference at Brock University. In 2009, she received the W. Gordon Plewes Award from the Canadian Society for Civil Engineering, an award that recognized her services to Canadian engineering history.

Notebook with H.K. Woodruff written on the front cover

Notebook with H.K. Woodruff written on the front cover (soft cover). Inside, there is a list of 48 diverse items which include: sword found at Lundy’s Lane, stuffed frog from Long Point, Indian pipe, 5 curious old revolutionary pistols and Mrs. S. Bull’s slippers. At the back of the book there is a list of 22 items including: proclamation issued by Sir Isaac Brock on Feb. 24, 1812 and Egyptian mummy, 1884-1885.