Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies

Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment

Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies

<div><p>Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.</p></div

Global 5hmC levels in normal testis and testicular neoplasms.

<p>(A) Sertoli cells (arrowheads) show strong immunoreactivity in normal testicular tubules. (B) Low 5hmC staining in intratubular germ cell neoplasia (ITGCN) of the testis (arrows). (C) Representative seminoma case with low nuclear 5hmC staining. (D) Representative mature teratoma exhibiting robust nuclear staining. Representative embryonal carcinoma (E) and yolk sack tumor (F) exhibiting variable degrees of 5hmC staining levels in neoplastic cell nuclei. (G) Boxplots summarizing staining distribution in testicular germ cell tumors (seminoma n = 48; embryonal carcinoma; n = 24, yolk sac tumor n = 16; teratoma n = 16) (TGCT) lesions. Note that in tumors with mixed morphologies, components were scored separately. All images were taken at original magnification of 200x. Scale bars indicate 50 μm.</p

Urothelial carcinoma of the bladder shows low 5hmC levels.

<p>(A) Normal transitional cell epithelium of the bladder shows strong nuclear 5hmC staining in apical cell layers; basal cell layers exhibit reduced staining intensities (arrowhead). (B) Urothelial carcinoma shows reduced nuclear 5hmC (arrow). Note that tumor-associated stromal cells show robust strong staining and function as an internal staining control. (C) Boxplots depicting H-score distribution in normal urothelium and urothelial carcinoma. All images were taken at original magnification of 200x. Scale bars indicate 50 μm.</p

Global loss of 5hmC in primary renal cell carcinoma and metastases.

<p>(A) Normal kidney tissue shows uniformly strong staining for 5hmC in tubules and glomerular cells. (B) Clear cell renal cell carcinoma exhibit greatly reduced 5hmC levels (arrows). Note that stromal and endothelial cells show labeling with 5hmC antibodies. (C) Boxplots illustrating H-score distribution in normal kidney tissue, primary renal cell carcinoma and metastases. All images were taken at original magnification of 200x. Scale bars indicate 50 μm.</p

The commentariat and discourse failure: language and atrocity in Cool Britannia

Recent terrorist events in the UK, such as the security alerts at British airports in August 2006 and the London bombings of July 2005 gained extensive media and academic analysis. This study contends, however, that much of the commentary demonstrated a wide degree of failure among government agencies, academic and analytic experts and the wider media, about the nature of the threat and continues to distort comprehension of the extant danger. The principal failure, this argument maintains, was, and continues to be, one of an asymmetry of comprehension that mistakes the still relatively limited means of violent jihadist radicals with limited political ends. The misapprehension often stems from the language that surrounds the idea of 'terrorism', which increasingly restricts debate to an intellectually redundant search for the 'root causes' that give rise to the politics of complacency. In recent times this outlook has consistently underestimated the level of the threat to the security of the UK. This article argues that a more realistic appreciation of the current security condition requires abandoning the prevailing view that the domestic threat is best prosecuted as a criminal conspiracy. It demands instead a total strategy to deal with a totalizing threat. The empirical evidence demonstrates the existence of a physical threat, not merely the political fear of threat. The implementation of a coherent set of social policies for confronting the threat at home recognizes that securing state borders and maintaining internal stability are the first tasks of government. Fundamentally, this requires a return to an understanding of the Hobbesian conditions for sovereignty, which, despite the delusions of post-Cold War cosmopolitan multiculturalism, never went away