A heparin binding site Arg79Cys missense mutation in the SERPINC1 gene in a Korean patient with hereditary antithrombin deficiency.

We describe a case of heparin binding site Arg79Cys mutation in the gene encoding antithrombin, SERPINC1, in a Korean patient with hereditary antithrombin (AT) deficiency. The patient was a 34-year-old Korean man who presented with deep vein thrombosis (DVT) in his right leg without precipitating factors. On outpatient evaluation, coagulation tests without anticoagulation revealed a decreased AT III activity level at 48%, but normal AT III antigen level at 103%, indicating type II AT deficiency. Family studies revealed that his father (62 years of age) had decreased AT activity (48%) but had normal AT antigen levels (116%), indicating that the proband had a paternally inherited type II AT deficiency. Direct sequencing of the SERPINC1 gene in the patient and his father revealed a heterozygotic missense mutation, a cytosine to thymine substitution at nucleotide position 235 in exon 2 of the SERPINC1 gene (p.Arg79Cys). To our knowledge, this is the first report of Arg79Cys heterozygote mutation in family members with venous thromboembolism.

Oxidative status in iron-deficiency anemia.

Oxidative stress is an imbalance between free radicals and antioxidant molecules that can play an important role in the pathogenesis of iron-deficiency anemia (IDA). The aim of this study was to investigate oxidative status in patients with IDA and alteration of oxidative status after iron treatment. Thirty-three female patients with IDA and 25 healthy controls were included in this study. Oxidant and total antioxidant capacity were determined using free oxygen radicals test and free oxygen radicals defence (Form CR 3000, Callegari, Parma, Italy). Catalase activity was measured by spectrophotometer using a commercially available kit (Bioxytech Catalase-520, OxisResearch, Portland, OR). Oxidant activity in patients with IDA was significantly higher than controls (P<0.05), while total antioxidant and catalase activity were significantly lower (P<0.05). After treatment, oxidant, antioxidant, and catalase activity reached the levels of the control group, and no significant differences were observed among groups (P>0.05). In conclusion, our data indicate that blood reactive oxygen species was lower and total antioxidant and catalase activity were higher after rather than before treatment in patients with IDA. The results of our study support the higher oxidative stress hypothesis in IDA; however, due to the limited number of cases included, more studies may be required to confirm the results.

JAK2 V617F/C618R mutation in a patient with polycythemia vera: a case study and review of the literature.

The acquired Janus kinase 2 (JAK2) V617F mutation shows a high frequency in diverse BCR/ABL-negative chronic myeloproliferative disorders (CMPD), and it is typically associated with polycythemia vera (PV). The frequency of JAK2 V617F mutation is about 90% in patients with PV, 50-60% in patients with essential thrombocythemia (ET), primary myelofibrosis (PMF), and less in patients with other myeloid neoplasms, while extremely rare in lymphoid malignancies. About 20 kinds of novel mutations of JAK2 other than V617F have been reported recently in the literature. Among these mutations, only one case of JAK2 V617F/C618R has been reported in a 67-year-old patient with PV. Here, we report a rare case of JAK2 V617F/C618R in a 41-year-old Korean male patient with review of the relevant literature on JAK2 mutations other than V617F. Although the frequency of JAK2 mutations other than the V617F is very low, this study emphasizes the need for assiduous analysis of the JAK2 gene to characterize new mutations, to determine their frequency, and to improve understanding of the clinical phenotypes as well as prognostic and biologic features associated with these mutations.

Cutaneous leukocytoclastic vasculitis with cervical tuberculous lymphadenitis: a case report and literature review.

Cutaneous leukocytoclastic vasculitis (CLV) is a small-vessel vasculitis localized to the skin. Many possible causes exist for this pathological condition, including drugs, infection, collagen vascular disease, and malignancy. However, Mycobacterium tuberculosis is rarely reported to be associated with CLV. Here, we report a 49-year-old male patient that presented with fever, myalgia, and multiple palpable purpura on both of his legs. The biopsy from the purpura yielded a histologic diagnosis of leukocytoclastic vasculitis. The patient had several enlarged lymph nodes on his right neck, and the biopsy revealed tuberculous lymphadenitis. There were no signs of vasculitis present in the internal organs. After anti-tuberculosis treatment, his fever declined and the skin purpura were completely resolved. Although incidence is rare, tuberculosis should be considered as a possible cause of CLV.

Induction of apoptosis by apicidin, a histone deacetylase inhibitor, via the activation of mitochondria-dependent caspase cascades in human Bcr-Abl-positive leukemia cells.

PURPOSE: Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide that exhibits potent antiproliferative activity against various cancer cell lines. The aim of this study was to examine the potential of apicidin to induce apoptosis in human Bcr-Abl-positive leukemia cells and to assess the mechanism of apicidin-induced apoptosis. EXPERIMENTAL DESIGN: Cells were exposed to various concentrations of apicidin for 2-72 h, after which the levels of apoptosis, histone acetylation, mitochondrial damage, caspase activation, and Bcr-Abl expression were assessed. RESULTS: Apicidin induced apoptosis in K562 cells in a concentration- and time-dependent manner. Similarly, apicidin notably induced the apoptosis in the primary leukemic blasts obtained from chronic myelogenous leukemia patients in blast crisis. The acetylated histone H4 levels increased in a concentration-dependent manner in the K562 cells. However, the timing of cell death caused by apicidin did not exactly correlate with the histone deacetylase inhibitory effect. The disruption of the mitochondrial membrane potential, cytochrome c release into the cytosol, and the mitochondrial Bax translocation were notably demonstrated after the apicidin treatment. Apicidin induced the proteolytic cleavage of procaspase-9, -3, -8, and poly(ADP-ribose) polymerase. Pretreatment of the K562 cells with the caspase-3 inhibitor, DEVD-CHO, completely inhibited the apicidin-induced apoptosis, suggesting that apicidin-induced apoptosis was caspase-dependent. The Fas/Fas ligand death receptor pathway was not involved in the apicidin-mediated apoptosis in K562 cells. Pretreatment of the cells with the caspase-9 inhibitor LEHD-fmk abrogated the apicidin- induced cleavage of procaspase-3, -8, and poly(ADP-ribose) polymerase. The p210 Bcr-Abl protein levels were notably decreased after the apicidin treatment, with near complete loss after 48 h. Reverse transcription-PCR assay demonstrated that the Bcr-Abl mRNA level was also remarkably decreased in a time-dependent manner. CONCLUSIONS: These results indicate that apicidin effectively induces the apoptosis of Bcr-Abl-positive leukemia cells through the activation of the mitochondrial pathway-dependent caspase cascades. The down-regulation of Bcr-Abl mRNA might also be one of the mechanisms implicated in the apicidin-mediated apoptosis in the K562 cells. This study provides the rationale to additionally investigate apicidin as a potential therapeutic agent for the drug-resistant Bcr-Abl-positive leukemia cells.

Constitutive phosphorylation of FKHR transcription factor as a prognostic variable in acute myeloid leukemia.

The transcription factor FKHR, which is controlled by Akt-PKB signaling, is involved in regulating cell cycle progression and cell death. In this study, the phosphorylation of FKHR was observed in 45 (73.8%) of 61 patients with acute myeloid leukemia (AML). The phosphorylation of Akt-PKB was found to be significantly associated with phospho-FKHR (P<0.001). Patients with phospho-FKHR had a significantly shorter overall survival than those without (P<0.05). In conclusion, the constitutive phosphorylation of FKHR was observed in the majority of AML, and the detection of phospho-FKHR might provide a new tool for identifying AML patients with an unfavorable outcome.

Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome.

Phosphorylation of PTEN (phosphatase and tensin homologue) affects PTEN protein stability and function. In this study, phosphorylated PTEN (pPTEN) was observed in 45 (73.8%) of 61 cases with acute myeloid leukaemia (AML). Phosphorylation of Akt and its downstream molecules [FKHR; Forkhead (Drosophila) homologue 1; and GSK-3beta; glycogen synthase kinase 3 beta] was significantly associated with pPTEN (P < 0.001). The complete remission rates were not different with respect to pPTEN, but overall survival was significantly shorter in patients with pPTEN (P < 0.05). Constitutive PTEN phosphorylation may add insight into the molecular pathogenesis of AML, and may be a new parameter for an unfavourable outcome.