Dysregulation of the nucleo-cytoplasmic transport of proteins plays an important role in carcinogenesis. The nuclear export of proteins depends on the activity of transport proteins, exportins. Exportins belong to the karyopherin β superfamily. Exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), mediates transport of around 220 proteins. In this review, we summarized the development of a new class of antitumor drugs, collectively known as selective inhibitors of nuclear export (SINE). KPT-330 (selinexor) as an oral agent is showing activities in early clinical trials in both solid tumors and hematological malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0078-0) contains supplementary material, which is available to authorized users.
Summary. Background: Warfarin affects the synthesis and function of the matrix Gla-protein, a vitamin K-dependent protein, which is a potent inhibitor of tissue calcification. Objectives: To investigate the incidence of mitral valve calcium (MVC), mitral annular calcium (MAC) and aortic valve calcium (AVC) in patients with non-valvular atrial fibrillation (AF) treated with warfarin vs. no warfarin. Patients and methods: Of 1155 patients, mean age 74 years, with AF, 725 (63%) were treated with warfarin and 430 (37%) without warfarin. The incidence of MVC, MAC and AVC was investigated in these 1155 patients with two-dimensional echocardiograms. Unadjusted logistic regression analysis was conducted to examine the association between the use of warfarin and the incidence of MVC, MAC or AVC. Logistic regression analyses were also conducted to investigate whether the relationship stands after adjustment for confounding risk factors such as age, sex, race, ejection fraction, smoking, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), glomerular filtration rate, calcium, phosphorus, calcium-phosphorus product, alkaline phosphatase, use of aspirin, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. Results: There was a significant association between the use of warfarin and the risk of calcification [unadjusted odds ratio = 1.71, 95% CI = (1.34-2.18)]. The association still stands after adjustment for confounding risk factors. MVC, MAC or AVC was present in 473 of 725 patients (65%) on warfarin vs. 225 of 430 patients (52%) not on warfarin (P < 0.0001). Whether this is a causal relationship remains unknown. Conclusions: Use of warfarin in patients with AF is associated with an increased prevalence of MVC, MAC or AVC.
Vitamin K is required for the activity of various biologically active proteins in our body. Apart from clotting factors, vitamin K–dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest‐specific gene 6 protein, and matrix Gla protein. Glutamic acid residues in matrix Gla protein are γ‐carboxylated by vitamin K–dependent γ‐carboxylase, which enables it to inhibit calcification. Warfarin, being a vitamin K antagonist, inhibits this process, and has been associated with calcification in various animal and human studies. Though no specific guidelines are currently available to prevent or treat this less‐recognized side effect, discontinuing warfarin and using an alternative anticoagulant seems to be a reasonable option. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases. Drugs including statins, alendronate, osteoprotegerin, and vitamin K are currently under study as therapies to prevent or treat warfarin‐associated calcification. Copyright © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.
Azacitidine is a pyrimidine nucleoside analog licensed for treatment of adult patients with myelodysplastic syndrome. Azacitidine acts as an inducer of cell differentiation by causing demethylation and re-expression of genes silenced by hypermethylation. We report a 56-year-old man with myelodysplastic syndrome who developed interstitial lung disease after azacitidine therapy. Open lung biopsy revealed a nonresolving organizing pneumonia pattern and bronchocentric granulomatous pattern suggestive of drug-induced lung injury. Treatment with steroids and discontinuation of azacitidine led to resolution of interstitial lung disease. The Naranjo adverse drug reaction probability scale score indicated that the association between azacitidine and interstitial lung disease was probable. Interstitial lung disease is a serious but uncommon side effect of this relatively safe drug. The mechanism underlying this is still unclear. The patient was subsequently treated with decitabine with no recurrence of interstitial lung disease.
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