The role of microRNA alterations in post-ischemic neovascularization

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, and thus, novel therapies are required. CVDs generally result in local shortages in the blood supply, known as ischemia. Neovascularization is the body's innate response mechanism that stimulates the restoration of blood flow to ischemic tissues. During the last decade, microRNAs have emerged as critical regulators of both CVD and neovascularization. Recent studies demonstrated that microRNAs are altered in many ways; however, whether these microRNA modifications could be physiologically relevant remained unclear. We examined whether specific microRNAs with a known cardiovascular function are subject to particular microRNA-alterations and if they could be relevant in cardiovascular disease. Our experiments demonstrated that the level of specific microRNA alterations, including isomiR formation, adenosine-to-inosine editing, and N6-adenosine methylation, changed in response to cardiovascular pathology. Many of these alterations changed the microRNAs function, which had a direct effect on processes like neovascularization. For example, microRNA adenosine-to-inosine editing increased after ischemia in both mice and humans and promoted neovascularization. These findings suggest that microRNA modifications can potentially be harnessed as a biomarker for cardiovascular disease, or even a novel therapeutic target. The Dutch Heart FoundationLUMC / Geneeskund

Interval carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam

BACKGROUND: The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. METHODS: We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. RESULTS: During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. CONCLUSION: The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable

Cellular and genetic requirements for delayed type hypersensitivity

All living organisms are continuously exposed to pathogenic agents from the surrounding milieu, e.g. viruses, bacteria, fungi and parasites. Skin and mucous membranes form efficient barriers to these agents, but sometimes this defense is overcome. If an infectious agent succeeds in penetrating into the "milieu int€rieur", at first granulocytes and mononuclear phagocytes become involved in the elimination of the intruding microorganisms. This part of the defense system is largely aspecific. Apart from this, vertebrates have a well developed immune system which can mount specific immune responses to invading organisms and foreign substances. The specificity of the immune reaction is based on the presence of receptors on the individual lymphocytes which recognize specifically any one of many foreign substances. Only after the recognition of the immunogenic material is a lymphocyte activated to perform its function. Immunogenic substances or antigens are operationally defined by their capacity to induce an immune response. The recognition of a particular antigen by the receptors of an individual lymphocyte is predetermined, i.e. the diversity of lymphocytes, each specific for one of the numerous imaginable foreign substances is generated before encounter with immunogenic material. In addition to the specificity of lymphocytes for a particular antigen, lymphocytes must also discriminate between self and non-self. If they should fail to do so, an immune response to tissues of the individual's own body would arise, leading to autoimmune disease (Burnet, 1972)