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Kanaroglou S.,Hamilton Center for Kidney Research | Nair V.,Hamilton Health Sciences | Nair V.,McMaster University | Fernandes J.R.,Hamilton Health Sciences | Fernandes J.R.,McMaster University
Cardiovascular Pathology | Year: 2015

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS), cardiac tamponade and sudden cardiac death that typically affects young women in the postpartum period. Rarely, it can be caused by systemic inflammatory conditions such as sarcoidosis. Sarcoidosis is an inflammatory disease most often affecting the lung and lymph nodes that can sometimes affect the heart. The authors report a case of sudden cardiac death caused by SCAD in the context of undiagnosed and subclinical cardiac sarcoidosis. The decedent was a 47-year-old male with a relatively innocuous past medical history. He was found dead in bed. At autopsy, there was a lethal hemopericardium resulting in cardiac tamponade. Gross examination of the heart revealed dissection of the posterior descending coronary branch of the right coronary artery. Histologically, the coronary artery showed acute and organizing dissection with evidence of vasculitis. A chronic inflammatory infiltrate consisting of lymphocytes, histiocytes, eosinophils and giant cells was seen. Sections of the myocardium showed myocarditis with a nonnecrotizing granuloma. The death was attributed to cardiac tamponade secondary to SCAD in the context of systemic sarcoidosis. The presented case demonstrates two concurrent rare pathologies and highlights the importance of considering SCAD in cases of sudden cardiac death at autopsy. © 2015 Elsevier Inc.

Lin X.,McMaster University | Lin X.,Father Sean OSullivan Research Institute | Lin X.,Hamilton Center for Kidney Research | Lin X.,Central South University | And 4 more authors.
Current Medicinal Chemistry | Year: 2013

Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD). Approximately, one third of diabetic patients develop diabetic nephropathy. As diabetes and its associated metabolic diseases are becoming epidemic, DN is emerging as a major health threat to humans. Currently, there are no effective therapeutic treatments for the disease. As a result, most DN cases progress to ESRD; patients with ESRD will need to undergo renal replacement through either dialysis or kidney transplantation. Therefore, developing new and effective means to control DN has been a major focus in the diabetes research. DN is a complex disease with pathological changes occurred in the glomerulus and renal tubules. It is, nonetheless, widely believed that the primary defects lie in the glomeruli, which lead to disrupting the integrity of the glomerular filtration barrier. While a variety of factors contribute to the impairment of glomerular filtration function, a large body of evidence demonstrates that damage in podocytes is the leading cause. Renal fibrosis plays critical roles in promoting DN progression. The primary mechanism responsible for renal fibrosis is abnormal activation of the transforming growth factor (TGF)-β pathway. Based on this understanding of DN pathogenesis, one strategy to control DN is to specifically protect podocytes from diabetes-induced injuries and to inhibit TGF-β signaling using gene therapy methodology. In this review, we will discuss the current research effort in developing gene therapy for DN. © 2013 Bentham Science Publishers.

Lin X.,McMaster University | Lin X.,Father Sean OSullivan Research Institute | Lin X.,Hamilton Center for Kidney Research | Yan J.,McMaster University | And 5 more authors.
Histology and Histopathology | Year: 2013

DNA damage response (DDR) is the critical surveillance mechanism in maintaining genome integrity. The mechanism activates checkpoints to prevent cell cycle progression in the presence of DNA lesions, and mediates lesion repair. DDR is coordinated by three apical PI3 kinase related kinases (PIKKs), including ataxia-telangiectasia mutated (ATM), ATMand Rad3-related (ATR), and DNA-PKcs (the catalytic subunit of the DNA dependent protein kinase). These kinases are activated in response to specific DNA damage or lesions, resulting in checkpoint activation and DNA lesion repair. While it is clear that the pathways of ATM, ATR, and DNA-PK are the core components of DDR, there is accumulating evidence revealing the involvement of other cellular pathways in regulating DDR; this is in line with the concept that in addition to being a nuclear event DDR is also a cellular process. One of these pathways is the extracellular signalregulated kinase (ERK) MAPK (mitogen-activated protein kinase) pathway. ERK is a converging point of multiple signal transduction pathways involved in cell proliferation, differentiation, and apoptosis. Adding to this list of pathways is the recent development of ERK in DDR. The ERK kinases (ERK1 and ERK2) contribute to the proper execution of DDR in terms of checkpoint activation and the repair of DNA lesions. This review summarizes the contributions of ERK to DDR with emphasis on the relationship of ERK kinases with the activation of ATM, ATR, and DNA-PKcs.

Yan J.,McMaster University | Yan J.,Father Sean ullivan Research Center | Yan J.,Hamilton Center for Kidney Research | De Melo J.,McMaster University | And 7 more authors.
British Journal of Cancer | Year: 2014

Background:Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear.Methods:ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression.Results:In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated.Conclusions:We report here the association of ALDH3A1 with PC progression. © 2014 Cancer Research UK.

Wong N.,McMaster University | Wong N.,Father Sean oSullivan Research Center | Wong N.,Hamilton Center for Kidney Research | De Melo J.,McMaster University | And 5 more authors.
International Journal of Cell Biology | Year: 2013

Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis. © 2013 Nicholas Wong et al.

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