• 2018-07
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  • 2019-04
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  • 2020-01
  • 2020-02
  • A third aim of our investigation was to evaluate


    A third aim of our investigation was to evaluate the impact of the methylation profile of p15, p16, p53, and DAPK, individually or combined, on progression-free and overall survival. We did not find any statistically significant difference in progression-free survival and overall survival in MM cases for any individual studied gene or combination of genes, controlling for age and treatment what is doxycycline hyclate approaches. Our findings are in agreement with the reports of Guillerm et al, who observed that methylation of p15 and p16 was not associated with shorter survival in patients with MM. In contrast, some studies noted that DAPK methylation was related to inferior overall survival and reported that p16 methylation also was associated with a worse prognosis in patients with MM.17, 42
    Conclusions Aberrant methylation of CpG islands in promoter regions of crucial genes involved in what is doxycycline hyclate regulation, apoptosis, and tumor suppression is frequent and early events in plasma cell immortalization, leading to the development of monoclonal gammopathies. However, the relevance of methylation in the clonal evolution from MGUS to MM and the associations between cytogenetic and epigenetic events in this malignant transformation remain unclear. According to our investigation, DAPK methylation may be a marker of disease progression in monoclonal gammopathies. Another unsolved question is the prognostic impact of methylation of individual and combined genes in MM. Although several authors have reported a poor prognosis of p16 and DAPK methylation in patients with MM, this negative impact on outcome was not confirmed in more recent reports, namely, in the current study. To answer all of the questions about the role of epigenetic mechanism during myelomagenesis, a larger study with a longer follow-up and uniform treatment approaches for patients with MM will be necessary.
    Introduction DAP-kinase (DAPK), a Ca2+/calmodulin activated Ser/Thr kinase, was originally identified by Adi Kimchi and co-workers at the Weizmann Institute while screening for genes critical for IFN-γ-induced cell death. DAPK belongs to a family of related death kinases, all of which share significant sequence and functional homology. This family includes two closely related homologues of DAPK (DAPK1): ZIPK [ZIP kinase, also known as Dlk (DAP-like kinase) or DAPK3] and DRP-1 (DAPK-related protein 1, also known as DAPK2). There are two other protein kinases which display homology to DAPK: DRAK-1 and DRAK-2 (DAPK-related apoptosis-inducing protein kinase-1 and -2), although these are more distantly related and have been less well characterized. DAPK is necessary for the regulation or execution of cell death in response to various stimuli, including death receptor activation, cytokines, matrix detachment, ceramide, and others. DAPK is linked to both type I apoptotic and type II autophagic cell death in both caspase-dependent and caspase-independent manners. Shamloo et al. showed that DAPK plays an important role in ischemic rat brain injuries. They characterized the mechanisms of DAPK activation during ischemia and showed that DAPK is dephosphorylated and activated following ischemia in the brain. Based on their findings, Shamloo et al. suggested that DAPK could be a good therapeutic target for treating acute ischemic stroke. Inhibition of DAPK would likely intercept cell death and prevent further damage of ischemic regions in cerebral infarction and other ischemic diseases. Interestingly, Velentza et al. reported that a single intraperitoneal injection of a DAPK non-selective inhibitor, an alkylated 3-amino-6-phenylpyridazine, reduced in vivo brain injury in an animal model when administered 6h after the insult, which is the minimal desired therapeutic time window. Although there have been only a few detailed studies of DAPK as a drug target, it would be useful to have more potent and selective inhibitors against DAPK in order to determine their possible application to unmet needs.