Shortened telomeres in essential thrombocythemia: clinicopathological and treatment correlations.
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ABSTRACT:
SUBMITTER: Alimam S
PROVIDER: S-EPMC6058796 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
Publications
Shortened telomeres in essential thrombocythemia: clinicopathological and treatment correlations.
Alimam Samah S McLornan Donal P DP Jiang Jie J Radia Deepti D Mufti Ghulam J GJ Harrison Claire N CN
Haematologica 20171130 6
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Project description:Deregulated Janus Kinase 2 (JAK2) activation is central to the pathogenesis of most myeloproliferative neoplasms (MPNs), of which essential thrombocythemia (ET) is the most common entity. Patients with ET are risk-stratified according to their risk of thrombo-hemorrhagic complications. High-risk patients are offered treatments to reduce their platelet count using cytoreductive therapy. The disease course is often long and therapy intolerance is not infrequent. Ruxolitinib, a Janus Kinase (JAK) 1/JAK2 inhibitor, has demonstrated efficacy in patients with both myelofibrosis (MF) and polycythemia vera and is well tolerated. Side effects include predictable cytopenias and an augmented risk of infections. Ruxolitinib has been investigated in a small group of ET patients who were refractory/intolerant to hydroxycarbamide (HC) and demonstrated improvements in both symptoms and splenomegaly. Of note, a proportion of treated patients (13.2%) also had a significant reduction in platelet counts. However, these results require further validation in comparison with conventional therapy. Recently, a randomized-controlled phase 2 study (MAJIC-ET) assessed the role of Ruxolitinib in patients refractory or intolerant to HC. This study revealed that Ruxolitinib demonstrated some clinical efficacy but was only superior in terms of symptom control. In clinical practice, some individuals with ET do exhaust all potential treatment options and there may well be a role for Ruxolitinib in such patients or those with a significant symptom burden. However, in the wider context the goal of therapy with the use of JAK inhibitor therapy in ET needs to be defined carefully and we explore this within this timely review article.
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Project description:Alcohol abuse leads to earlier onset of aging-related diseases, including cancer at multiple sites. Shorter telomere length (TL) in peripheral blood leucocytes (PBLs), a marker of biological aging, has been associated with alcohol-related cancer risks. Whether alcohol abusers exhibit accelerated biological aging, as reflected in PBL-TL, has never been examined. To investigated the effect of alcohol abuse on PBL-TL and its interaction with alcohol metabolic genotypes, we examined 200 drunk-driving traffic offenders diagnosed as alcohol abusers as per the Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR] and enrolled in a probation program, and 257 social drinkers (controls). We assessed alcohol intake using self-reported drink-units/day and conventional alcohol abuse biomarkers (serum γ-glutamyltrasferase [GGT] and mean corpuscular volume of erythrocytes [MCV]). We used multivariable models to compute TL geometric means (GM) adjusted for age, smoking, BMI, diet, job at elevated risk of accident, genotoxic exposures. TL was nearly halved in alcohol abusers compared with controls (GMs 0.42 vs. 0.87 relative T/S ratio; p<0.0001) and decreased in relation with increasing drink-units/day (p-trend=0.003). Individuals drinking >4 drink-units/day had substantially shorter TL than those drinking ≤4 drink-units/day (GMs 0.48 vs. 0.61 T/S, p=0.002). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be abusers (p=0.008), reported higher drink-units/day (p=0.0003), and exhibited shorter TL (p<0.0001). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with TL. The decrease in PBL-TL modulated by the alcohol metabolic genotype ADH1B*1/*1 may represent a novel mechanism potentially related to alcohol carcinogenesis in alcohol abusers.
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Project description:Alcohol abuse leads to earlier onset of aging-related diseases, including cancer at multiple sites. Shorter telomere length (TL) in peripheral blood leucocytes (PBLs), a marker of biological aging, has been associated with alcohol-related cancer risks. Whether alcohol abusers exhibit accelerated biological aging, as reflected in PBL-TL, has never been examined. To investigated the effect of alcohol abuse on PBL-TL and its interaction with alcohol metabolic genotypes, we examined 200 drunk-driving traffic offenders diagnosed as alcohol abusers as per the Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR] and enrolled in a probation program, and 257 social drinkers (controls). We assessed alcohol intake using self-reported drink-units/day and conventional alcohol abuse biomarkers (serum γ-glutamyltrasferase [GGT] and mean corpuscular volume of erythrocytes [MCV]). We used multivariable models to compute TL geometric means (GM) adjusted for age, smoking, BMI, diet, job at elevated risk of accident, genotoxic exposures. TL was nearly halved in alcohol abusers compared with controls (GMs 0.42 vs. 0.87 relative T/S ratio; p<0.0001) and decreased in relation with increasing drink-units/day (p-trend=0.003). Individuals drinking >4 drink-units/day had substantially shorter TL than those drinking ≤4 drink-units/day (GMs 0.48 vs. 0.61 T/S, p=0.002). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be abusers (p=0.008), reported higher drink-units/day (p=0.0003), and exhibited shorter TL (p<0.0001). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with TL. The decrease in PBL-TL modulated by the alcohol metabolic genotype ADH1B*1/*1 may represent a novel mechanism potentially related to alcohol carcinogenesis in alcohol abusers.
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Project description:Essential thrombocythemia (ET) is a myeloproliferative malignancy caused by the excessive proliferation of megakaryocytes in the bone marrow, resulting in the overproduction of peripheral platelets. ET can lead to thrombotic events, such as ischemic stroke (IS), though it is a rare cause of IS. Bilateral medial medullary infarction (BMMI), also known as "Y appearance" infarction due to its distinctive imaging morphology, is a rare clinical subtype of IS which typically has a poor prognosis and a high mortality rate. Herein, we report the case of a 43-year-old male with a history of ET. The patient's platelet count was poorly controlled, and he did not receive regular treatment. After developing symptoms such as dizziness, dysphagia, choking on water, slurred speech, blurred vision, and bilateral limb numbness. Head magnetic resonance imaging revealed a "Y appearance" infarction in the bilateral medial medulla. After admission, the patient was administered intravenous antiplatelet therapy with tirofiban. However, when he was switched to oral aspirin after three days, he experienced decreased muscle strength and worsening symptoms. Therefore, tirofiban was continued for 14 days. Upon discharge, the patient experienced residual limb numbness. His National Institutes of Health Stroke Scale score was 1, Modified Rankin Scale score was 0, and platelet count had decreased to the normal range. During the 9-month follow-up period after discharge, the patient still had only mild limb numbness. Our report presents a special case of "Y appearance" infarction due to ET. Owing to fluctuations in the patient's condition, he received long-term high-dose tirofiban, which ultimately led to a significant improvement in his symptoms.
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