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    • br It has been recognised

    2018-10-23


    It has been recognised that up to 25% of breast cancer overexpresses the transmembrane human epidermal growth factor receptor 2 (HER2), which, in the absence of treatment, is associated with an adverse prognosis for patients . The monoclonal antibody trastuzumab, which targets the HER2 receptor, has significantly improved both overall and disease-free survival for patients with advanced and early stage disease . However, an unexpected finding during the clinical trials of trastuzumab was the development of cardiotoxicity, mostly manifested as a decline in left ventricular ejection fraction (LVEF) and, more rarely, congestive XMU-MP-1 failure. Despite extensive research, the mechanisms underlying trastuzumab-related cardiotoxicity remain poorly understood. Against this background, the article in this issue of by Reijers et al. , investigated the effects of trastuzumab administration on a group of healthy male volunteers and its impact on cardiac function. This report focuses, in part, on a clinical trial, in which a developmental trastuzumab drug product was shown to have bio-equivalence to the currently approved formulation of trastuzumab (Herceptin®) . As part of this study, volunteers (n=118) underwent serial measurements of body weight and biomarkers, including haemoglobin, haematocrit, albumin, total protein, cardiac Troponin (cTn)-T and N-terminal pro-peptide of B-type natriuretic peptide (NT-proBNP), along with assessments of cardiac function by echocardiography. The current report focuses more narrowly on cardiac function in 54/118 men who received either trastuzumab (n=46) or placebo (n=8). Mean haemoglobin (−0.3mM), haematocrit (−0.013L/L), total protein (−2g/dL) and albumin (−2g/dL) all significantly decreased post exposure to trastuzumab compared with placebo. There was also a corresponding increase in body weight (+0.4kg), although this result was not statistically significant (p=0.226) and the time for change to return to baseline was not reported. There was no detectable increase in the cardiac specific blood parameters, NT-proBNP and cTn-T in either trastuzumab-treated volunteers (n=46) or those who received placebo (n=6). In a further subset analysis, there was no significant difference in LVEF in volunteers who received trastuzumab (n=9) compared to placebo (n=8) at either 4 or 63days. No cardiac events were reported in the study, which is not unexpected, given the small number of subjects and exposure to trastuzumab was only a single dose.
    Telomeres are essential DNA–protein complexes at the ends of eukaryotic chromosomes, which keep the cell\'s genomic stability and integrity. Because conventional DNA polymerases cannot replicate the very ends of linearized DNA, telomeric sequence (TTAGGG repeat arrays) is gradually lost during cell division and aging. For example, normal peripheral blood mononuclear cells loose up to about 100-base pair telomeric sequence per year (). Deregulation of telomere length is associated with various diseases: accelerated telomere shortening exacerbates premature aging in the patients with Werner and Hutchinson–Gilford progeria syndromes, whereas inefficient telomere maintenance in the patients with dyskeratosis congenita causes bone marrow failure. Premalignant hyper-proliferative lesions give rise to shortened telomeres, which are eventually stabilized by telomerase-mediated telomere replenishment in cancer. Accordingly, telomere length is referred to not only as a “mitotic clock”, which counts the number of normal cell division, but also as a biological marker of aging. Recently, telomere length has also been established as a surrogate marker for disease and lifestyle: shortened leukocyte telomeres are associated with a wide range of threat to life, including cardiovascular disease and psychological stresses (). Strictly speaking, however, telomeric TTAGGG repeats are not the caps for stabilizing the chromosome ends. In fact, the farthest end of the double-stranded telomeric DNA consists of a 50–300-nucleotide single-stranded tract, called 3′-overhang or G-tail (guanine-rich strand-tail), which provides a molecular basis for the chromosome end capping. Telomere G-tail folds back to form a protective “t-loop” by means of strand invasion at the double-stranded telomere DNA (). This lariat structure masks the chromosome end from being recognized as damage. Genetic manipulation that disrupts telomere G-tails (, knockout of telomeric repeat-binding factor 2) promptly compromises the end protection, eliciting DNA damage response even if the cells retain long telomeres (). This suggests that G-tail length rather than the total telomere length, more directly contributes to or correlates with pathogenesis. But until recently, whether or not this is the case in the clinical settings has remained elusive. In this issue of , using a highly sensitive and quantitative method, Nezu, Tahara and colleagues quantitated both G-tail and total telomere length of leukocytes in patients with a history of cerebrovascular disease or atypical neurological problems (). Cross-sectional analyses revealed that G-tail length, rather than total telomere length, is associated with endothelial function and severity of age-related white matter changes. Thus, shorter G-tail predicts higher disease risk.