In JoVE (1)

Other Publications (71)

Articles by Jaewoo Song in JoVE

Other articles by Jaewoo Song on PubMed

T(5;12)(q13;p13) in Acute Myeloid Leukemia with Preceding Granulocytic Sarcoma

Cancer Genetics and Cytogenetics. Sep, 2007  |  Pubmed ID: 17854675

A 56-year-old woman was brought to the emergency room with gum swelling and pain. Biopsy of the gingiva revealed sheet-like proliferation of myeloperoxidase and CD45-positive large cells, and she was diagnosed with granulocytic sarcoma. Two years later, bone marrow involvement of granulocytic sarcoma was suspected. Her chromosome study repeatedly revealed a 46,XX,t(5;12)(q13;p13) karyotype. Case reports of t(5;12)(q13;p13) are extremely rare in the literature. To our knowledge, this is the first report of t(5;12)(q13;p13) in a patient with acute myelogenous leukemia with preceding granulocytic sarcoma.

A Der(1;15)(q10;q10) is a Rare Nonrandom Whole-arm Translocation in Patients with Acute Lymphoblastic Leukemia

Cancer Genetics and Cytogenetics. Dec, 2007  |  Pubmed ID: 18036400

A rare karyotypic event, der(1;15)(q10;q10), which involves the whole long arms of chromosomes 1 and 15, has been reported in patients with various conditions, including acute myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, and multiple myeloma. Only 27 cases of unbalanced der(1;15)(q10;q10) have been documented in the literature as single or complexed chromosomal abnormalities in hematological malignancies. Here, we describe two cases of acute lymphoblastic leukemia with der(1;15)(q10;q10), and review the previous reports. Although more case studies are needed, we suggest that der(1;15)(q10;q10) should be considered a nonrandom chromosomal abnormality in hematological malignancies including both lymphoid and myeloid neoplasms.

[Evaluation of the Abbott Cell-Dyn Sapphire Hematology Analyzer]

The Korean Journal of Laboratory Medicine. Jun, 2007  |  Pubmed ID: 18094570

The performance of Cell-Dyn Sapphire (Abbott Diagnostic, USA) was compared to the Bayer Advia 2120 (Bayer Diagnostics, USA), Sysmex XE-2100 (Sysmex Corporation, Japan), and reference microscopy.

Investigation of Von Willebrand Factor Gene Mutations in Korean Von Willebrand Disease Patients

The Korean Journal of Laboratory Medicine. Jun, 2007  |  Pubmed ID: 18094571

We intended to find the mutations of von Willebrand factor (VWF) gene as the most important contributing factor of von Willebrand disease (VWD) in Korean patients.

8p11 Myeloproliferative Syndrome Preceded by T(8;9)(p11;q33), CEP110/FGFR1 Fusion Transcript: Morphologic, Molecular, and Cytogenetic Characterization of Myeloid Neoplasms Associated with Eosinophilia and FGFR1 Abnormality

Cancer Genetics and Cytogenetics. Mar, 2008  |  Pubmed ID: 18295660

We report a rare case of t(8;9)(p11;q33) in a patient with 8p11 myeloproliferative syndrome (EMS) that was preceded by centrosomal protein 110kDa (CEP110; previously CEP1)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript. A 36-year-old man was brought to Severance Hospital with a nasopharyngeal mass and eosinophilia. Biopsy of the left tonsil and nasopharynx revealed diffuse infiltration of atypical lymphoid cells, and he was diagnosed with precursor T-cell lymphoma with hypereosinophilic syndrome. Two months later, chromosome study revealed a 46,XY,t(8;9)(p11;q33) karyotype, and the CEP110/FGFR1 fusion transcript was detected by reverse transcription-polymerase chain reaction (RT-PCR) in both this and the previous bone marrow specimen. Timely molecular and cytogenetic tests are of value for diagnosis and treatment of the newly classified "myeloid neoplasms associated with clonal eosinophilic disorders" (according to 2008 World Health Organization criteria).

A Novel Missense MSH2 Gene Mutation in a Patient of a Korean Family with Hereditary Nonpolyposis Colorectal Cancer

Cancer Genetics and Cytogenetics. Apr, 2008  |  Pubmed ID: 18406877

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer-susceptible syndrome that predisposes to the early development of colorectal cancer. Germline mutations in DNA mismatch repair genes, particularly MLH1 and MSH2, are associated with the clinical phenotype of HNPCC. A previously unreported, novel missense mutation in exon 3 of the MSH2 gene (c.380A>T) was identified in the proband and a different missense mutation in exon 3 of MSH2 gene (c.505A>G) was noted in the mother, with a mutual splice mutation in intron 12 of the MSH2 gene in the proband, mother, and younger brother. Here, we report the clinical implications of a novel mutation in a patient with early-onset colorectal cancer and the significance of a common underlying splice site mutation occurring within a family with HNPCC.

Paracentric Inversion-associated T(8;21) Variant in De Novo Acute Myelogenous Leukemia: Characteristic Patterns of Conventional Cytogenetics, FISH, and Multicolor Banding Analysis

Cancer Genetics and Cytogenetics. May, 2008  |  Pubmed ID: 18474302

Acute myelogenous leukemia (AML) with t(8;21)(q22;q22) demonstrates unique clinico-pathologic disease entity in patients with hematologic malignancies. The t(8;21), which results in fusion of the AML1 gene on 21q22 and the ETO gene on 8q22 on a molecular level, is one of the most common nonrandom chromosomal changes, and it is found in about 5-12% of patients with AML. Among these cases, complex variants involving chromosomes 8 and 21, as well as a third or fourth chromosome, account for approximately 6-10% of patients with an AML1/ETO chimeric gene, and about 100 variant cases with AML1/ETO fusion transcript have been reported in the literature. Here, we describe a rare case report of reciprocal paracentric inversion-associated t(8;21) variant in a 28-year old male patient with de novo AML. The abnormal results of conventional cytogenetics and interphase fluorescent in situ hybridization in this patient drove us to perform further studies and a literature review. This report emphasizes the value of "conventional" cytogenetics, as well as "newly developed" molecular cytogenetic methods in the diagnosis of rare complex t(8;21) variant in patients with AML.

Preceding Orbital Granulocytic Sarcoma in an Adult Patient with Acute Myelogenous Leukemia with T(8;21): a Case Study and Review of the Literature

Cancer Genetics and Cytogenetics. Aug, 2008  |  Pubmed ID: 18656695

A 25-year old man with a 30 month history of proptosis and pain of the right eye was referred to Severance Hospital of Yonsei University. Orbital computed tomography (CT) demonstrated a huge mass in the right retrobulbar orbit; an incisional biopsy and orbitotomy were performed for diagnosis and orbital soft tissue decompression. Subsequent histopathology disclosed sheets of mononuclear cells in the orbital mass, and immunohistochemical stains demonstrated positive results for myeloperoxidase and CD43, which supported the diagnosis of granulocytic sarcoma (GS). After his 1-year follow-up, the patient presented with pancytopenia, and an ensuing bone marrow aspiration revealed markedly hypercellular marrow replaced by many large abnormal myeloblasts. The patient was diagnosed with acute myelogenous leukemia with t(8;21) preceded by orbital GS. Orbital GS is primarily a disease of children, and extremely rare in adults. To the best of our knowledge, only four cases of this disease in adults have been reported in the literature. Our case is the first report of preceding orbital GS in an adult patient with a complex karyotype including t(8;21).

Complex T(8;19;21)(q22;p13;q22) As a Sole Abnormality in a Patient with De Novo Acute Myeloid Leukemia

Cancer Genetics and Cytogenetics. Sep, 2008  |  Pubmed ID: 18722881

Tetrasomy 8 in a Patient with Acute Monoblastic Leukemia

The Korean Journal of Laboratory Medicine. Aug, 2008  |  Pubmed ID: 18728374

Trisomy 8 is one of the most frequent numerical chromosomal abnormalities observed in hematological malignancies, whereas tetrasomy 8 is a clonal aberration seen mainly in myeloid disorders such as acute myelod leukemia (AML) and myelodysplastic syndromes. In contrast to trisomy 8, tetrasomy 8 is a rare chromosomal aberration, in that only 17 reported AML cases with isolated tetrasomy 8 have been documented. Interestingly, the majority of reported cases were associated with monocytic-lineage leukemias. According to recent reports, tetrasomy 8 is regarded as a poor prognostic factor, and most patients having this abnormality relapsed and died within 1 yr. Here, we report a patient with acute monoblastic leukemia having tetrasomy 8 and a very aggressive disease course.

Acute Erythroleukemia with Der(1;7)(q10;p10) As a Sole Acquired Abnormality After Treatment with Azathioprine

Cancer Genetics and Cytogenetics. Oct, 2008  |  Pubmed ID: 18786444

Rare Translocations Involving Chromosome Band 8p11 in Myeloid Neoplasms

Cancer Genetics and Cytogenetics. Oct, 2008  |  Pubmed ID: 18940479

[Evaluation of Multiplex PCR Assay Using Dual Priming Oligonucleotide System for Detection Mutation in the Duchenne Muscular Dystrophy Gene]

The Korean Journal of Laboratory Medicine. Oct, 2008  |  Pubmed ID: 18971620

Exon deletions of Duchenne muscular dystrophy (DMD) gene account for most of the alterations found in DMD and Becker muscular dystrophy (BMD). This study was to evaluate the usefulness of dual priming oligonucleotide multiplex PCR (DPO PCR) in detection of exon deletions of DMD gene.

Linear Relationship Between ADAMTS13 Activity and Platelet Dynamics Even Before Severe Thrombocytopenia

Annals of Clinical and Laboratory Science. 2008  |  Pubmed ID: 18988930

Von Willebrand factor (VWF) cleaving metalloprotease, ADAMTS13, known for its causative relation to thrombotic thrombocytopenic purpura (TTP), also decreases to variable degree in other clinical conditions associated with thrombocytopenia, indicating a possible contribution of moderate deficiency of ADAMTS13 to platelet dynamics. We measured ADAMTS13 activity along with VWF activity, collagen binding activity (VWF:CB), and thrombin/antithrombin complex (TAT) in plasma drawn from patients with consumptive coagulopathy, in whom the platelet count was closely followed. ADAMTS13 activity was significantly but variably decreased in the patients, and VWF activity and VWF:CB were markedly increased as expected. The platelet count itself was not correlated with ADAMTS13 activity, VWF activity, or VWF:CB. However, the rate of decline of log-scaled platelet count (DeltaLnPLT/day) correlated well with ADAMTS13 activity and VWF:CB. ADADMTS13 activity showed inverse correlation with VWF:CB. Moreover, the correlation between ADAMTS13 and DeltaLnPLT/day was preserved even after VWF:CB was controlled. Multiple regression analysis showed that ADAMTS13 activity was the sole factor explaining DeltaLnPLT/day among ADAMTS13, VWF:CB, TAT, prothrombin time, d-dimer, and fibrinogen. TAT level and d-dimer as indicators of systemic fibrinolytic activity did not correlate with ADAMTS13 activity. In conclusion, we found that the decrease of ADADMTS13 activity in consumptive coagulopathy has stronger relationship to platelet dynamics than has generally been recognized.

MLL Rearrangement with T(6;11)(q15;q23) As a Sole Abnormality in a Patient with De Novo Acute Myeloid Leukemia: Conventional Cytogenetics, FISH, and Multicolor FISH Analyses for Detection of Rare MLL-related Chromosome Abnormalities

Cancer Genetics and Cytogenetics. Nov, 2008  |  Pubmed ID: 18992643

We report a rare case of acute myeloid leukemia (AML) with t(6;11)(q15;q23) in a 50-year-old female showing a poor prognosis. Bone marrow biopsy revealed markedly hypercellular marrow with infiltrates of myeloblasts, consistent with AML-M2 morphology. The karyotype of this patient was 46,XX,t(6;11)(q15;q23) in all analyzed cells, and the results of fluorescence in situ hybridization (FISH) and multi-color FISH analysis confirmed this unique MLL rearrangement as a sole abnormality. To our knowledge, t(6;11)(q13 approximately q15;q23) is the most rare type of MLL rearrangement involving the long arm of chromosome 6. Only two cases with t(6;11)(q13;q23) and three cases with t(6;11)(q15;q23) have been reported, but detailed clinical or laboratory data were not available. From this report, it is apparent that in a cytogenetic laboratory, the accurate detection of a rare type of MLL rearrangement is very important in the differential diagnosis, prompt treatment, and prediction of prognosis of leukemias.

Trisomy 8 in an Elderly Patient with Acute Lymphoblastic Leukemia As a Sole Abnormality

Cancer Genetics and Cytogenetics. Nov, 2008  |  Pubmed ID: 18992645

Acute Promyelocytic Leukemia Relapsing As Secondary Acute Myelogenous Leukemia with Translocation T(3;21)(q26;q22) and RUNX1-MDS1-EVI1 Fusion Transcript

Cancer Genetics and Cytogenetics. Dec, 2008  |  Pubmed ID: 19027486

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia (AML) that is characterized by peculiar clinical and biologic features, including severe hemorrhagic diathesis, specific recurrent chromosomal aberration, and distinct morphologic features with predominant pathologic promyelocytes. A reciprocal translocation involving chromosomes 15 and 17, t(15;17)(q22;q21), is a characteristic feature of APL that represents approximately 5-8% of AML. The rearranged gene created by this translocation encodes a chimeric protein PML-RARA that is a transcriptional repressor. In contrast to other AML subtypes, APL is particularly sensitive to treatment with all trans-retinoic acid (ATRA) combined with chemotherapy, converting this once fatal leukemia to a highly curable disease. Nonetheless, therapy-related myelodysplastic syndrome-acute myelogenous leukemia (t-MDS/AML) has been reported as a rare complication of chemotherapy in APL. Of 30 APL cases described as t-MDS/AML in the literature, only 1 case relapsed as acute leukemia with t(3;21)(q26;q22). Here we describe a rare case of APL relapsing as secondary AML with t(3;21)(q26;q22) and clinically characterize this patient using the RUNX1 (previously AML1)-MDS1-EVI1 fusion transcript (with follow-up for 55 months), and review the relevant literature.

Acute Promyelocytic Leukemia in Early Pregnancy with Translocation T(15;17) and Variant PML/RARA Fusion Transcripts

Cancer Genetics and Cytogenetics. Jan, 2009  |  Pubmed ID: 19061780

A 32-year-old pregnant woman in the 13th gestational week was brought to Severance Hospital with gum bleeding and easy bruising. Initial laboratory results revealed anemia and thrombocytopenia. In a peripheral blood smear, 81% of leukocytes were large, abnormal promyelocytes. Bone marrow aspiration showed a hypercellular marrow with packed leukemic promyelocytes, and chromosome study revealed a karyotype of 46,XX,t(15;17)(q22;q21)[10]/46,XX[10]. In addition, variant fusion transcripts of PML/RARA were detected in the marrow specimen. The patient was diagnosed with acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin. One month from the patient's initial diagnosis a follow-up bone marrow examination was performed, revealing complete remission (CR). We know of no previous reports of APL during pregnancy associated with variant PML/RARA fusion transcripts. Here, we describe a novel case of APL in a pregnant woman with a t(15;17) translocation and variant fusion transcripts.

Three New Nonsense Mutations of MLH1 and MSH2 Genes in Korean Families with Hereditary Nonpolyposis Colorectal Cancer

Cancer Genetics and Cytogenetics. Jan, 2009  |  Pubmed ID: 19100506

Hereditary nonpolyposis colorectal cancer (HNPCC) (MIM #114500), also called Lynch syndrome, is an autosomal dominantly inherited cancer syndrome accounting for 1-5% of all colorectal cancer cases. In a study of three Korean families with HNPCC consistent with the revised Bethesda criteria, DNA testing revealed three novel HNPCC germline mutations in two genes: namely, MLH1, with an insertion resulting in a frameshift and a premature stop codon; MSH2, with a deletion at nucleotide 633, exon 3, which results in stop of translation at codon 213; and MSH2, with a deletion at nucleotide 1413, exon 9, resulting in a frameshift and a premature stop codon. In the first two families, there were splice mutations at c.2006-6 thymine to cytosine. The clinical implications of a frameshift mutation are discussed, along with the significance of common underlying splice mutations existing within families with HNPCC.

Acute Promyelocytic Leukemia with Insertion of PML Exon 7a and Partial Deletion of Exon 3 of RARA: a Novel Variant Transcript Related to Aggressive Course and Not Detected with Real-time Polymerase Chain Reaction Analysis

Cancer Genetics and Cytogenetics. Jan, 2009  |  Pubmed ID: 19100514

We report the case of a 38-year-old man with acute promyelocytic leukemia (APL) showing a distinct breakpoint cluster region 2 (bcr2) variant transcript. Findings from bone marrow, cytogenetic, fluorescence in situ hybridization, and qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses were consistent with the diagnosis of APL. Although PCR products of size 841 bp and 984 bp were amplified from bone marrow specimen, the quantitative PCR (RQ-PCR) findings were negative. Given the discrepancy in PCR results, sequencing of PCR products was performed to determine the detailed composition of these fusion transcripts. By cloning and sequencing, we discovered that these two bands were isoforms, in which one exon (exon 5, 144 bp) of the PML gene was spliced out of the smaller products (minor PCR products); one sequence (G) insertion and one base substitution (T-->C) of PML exon 4 generate a stop codon in the smaller fusion transcript. In addition, a search of the Ensembl database revealed that these variant PML/RARA fusion transcripts were composed of exon 7a insertion of the PML gene and partial deletion (46 bp) of exon 3 of the RARA gene, in addition to inserted sequences of intron 7 of PML and genomic sequence ATCT of unknown origin at the fusion junction site. Although the biological significance of most atypical transcripts remains unclear, sequence analysis of these atypical products should be performed, to reveal the composition of such a fusion transcript and elucidate the molecular mechanism.

Biphenotypic Acute Leukemia with B2a2 Fusion Transcript and Trisomy 21

Cancer Genetics and Cytogenetics. Jan, 2009  |  Pubmed ID: 19100520

Therapy-related Myelodysplastic Syndrome with Der(17)t(12;17)(q13;p13) As a New Recurrent Cytogenetic Abnormality After Treatment for Chronic Lymphocytic Leukemia

Leukemia Research. Jul, 2009  |  Pubmed ID: 19155067

A 54-year-old male presented to our hospital for evaluation of peripheral lymphocytosis. He was initially diagnosed with chronic lymphocytic leukemia (CLL) and treated with six cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. Therapy-related myelodysplastic syndrome (t-MDS) was suspected approximately 2 years later; in addition, complex karyotypic abnormalities including 5q deletion, monosomy 7, and der(17)t(12;17)(q13;p13) were found repeatedly in the patient's chromosome studies. The chromosomal abnormality der(17)t(12;17)(q13;p13) is very rare in hematologic malignancies, and has been reported in only two patients with therapy-related acute myeloid leukemia (t-AML). To our knowledge, this is the first report of t-MDS with der(17)t(12;17)(q13;p13) after treatment for CLL. In addition, we suggest that der(17)t(12;17)(q13;p13) should be considered a new recurrent, nonrandom chromosomal abnormality in patients with t-MDS/AML.

JAK2 V617F/C618R Mutation in a Patient with Polycythemia Vera: a Case Study and Review of the Literature

Cancer Genetics and Cytogenetics. Feb, 2009  |  Pubmed ID: 19167611

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.

Non-age Related Y Chromosome Loss in an Elderly Patient with Acute Promyelocytic Leukemia

Leukemia Research. Aug, 2009  |  Pubmed ID: 19195699

Detection of a Novel CBFB/MYH11 Variant Fusion Transcript (K-type) Showing Partial Insertion of Exon 6 of CBFB Gene Using Two Commercially Available Multiplex RT-PCR Kits

Cancer Genetics and Cytogenetics. Mar, 2009  |  Pubmed ID: 19215788

We report on a 20-year-old man with acute myeloid leukemia (AML) showing a distinct novel CBFB/MYH11 variant fusion transcript. Initial results of bone marrow, chromosome, and flow cytometric analyses were not in accordance with the diagnosis of acute myelomonocytic leukemia with eosinophilia (AML-M4Eo) or AML with a CBFB/MYH11 rearrangement. However, results from 2 commercially available multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) tests repeatedly showed an unusual PCR product from his bone marrow specimen. Not only does this case show a partial insertion of exon 6 of the CBFB (ENSG00000067955) gene, but it also involves novel breakpoints within both exon 6 of the CBFB gene and exon 28 (previously exon 7) of the MYH11 (ENSG00000133392) gene, which is regarded as a previously non-reported, new type (K-type) of CBFB/MYH11 fusion transcript. In addition, our study result was in agreement with the recent report of Schnittger et al. that rare fusion transcripts of CBFB/MYH11 are correlated with an atypical cytomorphology and other aberrant characteristics. Therefore, multiplex RT-PCR and sequence analysis of these atypical products should be performed to diagnose atypical AML with CBFB/MYH11 rearrangement, to predict prognosis of these patients as well as to elucidate the molecular mechanism.

A Tandem Triplication, Trp(1)(q21q32), in a Patient with Follicular Lymphoma: a Case Study and Review of the Literature

Cancer Genetics and Cytogenetics. Mar, 2009  |  Pubmed ID: 19215795

A 1q triplication is a rare karyotypic event in hematologic malignancies, with 26 cases of 1q triplication reported in the literature. Although 1q duplication or triplication is present with a high incidence in Burkitt lymphoma and Fanconi anemia, there have been no detailed reports of an association between non-Burkitt type lymphomas and 1q triplication. Presented here is the case of a 69-year-old man with follicular lymphoma (FL) and 1q triplication, with a review of the pertinent literature. The patient was diagnosed with FL with bone marrow involvement; his bone marrow chromosome study revealed 50,XY,trp(1)(q21q32),+3,+add(3)(q21),+7,+9,add(13)(p11.2)[11]/51 approximately 52,idem,+19,+22[8]/46,XY[3]. Review of the Mitelman Database of Chromosome Aberrations in Cancer revealed 7 previous cases of non-Burkitt type lymphoma (including FL) with 1q triplication. On the basis of these eight cases, we conclude that 1q triplication represents a rare secondary genetic event with prognostic significance in patients with FL or other non-Burkitt types of lymphoma. Further studies are needed to investigate these rare 1q triplication in hematologic malignancies.

BCR/ABL Rearrangement with B3a3 Fusion Transcript in a Case of Childhood Acute Lymphoblastic Leukemia

Cancer Genetics and Cytogenetics. Mar, 2009  |  Pubmed ID: 19215796

The role of BCR/ABL isoforms and their relationship to leukemia phenotype have been of major concern. Atypical BCR/ABL mRNA transcripts lacking exon a2 have been reported in 12 cases of acute lymphoblastic leukemia (ALL) to date; among them, a b3a3 type transcript has been reported only once in the childhood ALL. Reported here is the case of a patient with Philadelphia-positive (Ph(+)) ALL expressing a b3a3 type transcript, a rare type of BCR/ABL mRNA lacking ABL exon a2 sequences. Bone marrow showed a hypercellular marrow with leukemic blasts positive for CD10, CD19, CD79a, and cytoplasmic mu, which is consistent with pre-B ALL. The G-banding and fluorescence in situ hybridization analyses indicated Ph(+). After the patient was diagnosed with ALL-L2, induction chemotherapy was performed and imatinib mesylate was thereafter given as the maintenance therapy. Sequencing analysis showed deletion of ABL a2 in the polymerase chain reaction product, which corresponded to a b3a3 fusion transcript. To our knowledge, this is the second report of an aberrant BCR/ABL product lacking ABL exon a2 in childhood ALL.

Concomitant T(3;3)(q21;q26), Trisomy 19, and E255V Mutation Associated with Imatinib Mesylate Resistance in Chronic Myelogenous Leukemia

Cancer Genetics and Cytogenetics. Apr, 2009  |  Pubmed ID: 19264234

Der(1)t(1;19)(p13;p13.1) in Two Elderly Patients with Myeloid Neoplasms: New Case Reports and Review of the Literature

Leukemia Research. Aug, 2009  |  Pubmed ID: 19345416

Therapy-related Acute Lymphoblastic Leukemia with T(9;22)(q34;q11.2):a Case Study and Review of the Literature

Cancer Genetics and Cytogenetics. May, 2009  |  Pubmed ID: 19389510

Therapy-related acute lymphoblastic leukemia (t-ALL) with t(9;22)(q34;q11.2) is rarely reported as a secondary malignant neoplasm. To our knowledge, only 10 Ph+ t-ALL cases have been reported in the literature. However, 8/10 cases were not reported individually but constituted parts of larger studies reporting cytogenetic abnormalities in secondary leukemia. Snyder et al. first reported Ph+ t-ALL in two patients who had been treated successfully for Ewing sarcoma. We present a novel case of t-ALL with t(9;22) in a patient with primary breast cancer. The interval between diagnosis of breast cancer and the appearance of ALL was 4 years. The patient was treated with partial mastectomy and axillary lymph node dissection followed by six cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy and radiation therapy. Bone metastases were found 3 years after surgery, and she was treated with epirubicin and paclitaxel. This case has the following unique features: BCR/ABL gene rearrangement in t-ALL, and two types of malignant cells (leukemic lymphoblasts and metastatic breast cancer cells) coexisted in the bone marrow.

Three-way Philadelphia Variant T(9;22;14)(q34;q11.2;p11) in Chronic Myeloid Leukemia

Cancer Genetics and Cytogenetics. May, 2009  |  Pubmed ID: 19389511

Concomitant Isochromosome 17q and Trisomy 14 in a Patient with Myelodysplastic Syndrome in Leukemic Transformation

Annals of Clinical and Laboratory Science. 2009  |  Pubmed ID: 19429805

We describe a novel case of simultaneous karyotypic abnormalities of isochromosome 17q and trisomy 14 in a patient with myelodysplastic syndrome (MDS) in leukemic transformation. A 66-yr-old Korean man was admitted to Severance Hospital for evaluation of pancytopenia. On the basis of bone marrow studies at 3 different stages, he was diagnosed with MDS in leukemic transformation. Chromosome karyotyping repeatedly showed the same main clonal abnormalities, including isochromosome 17q and trisomy 14. Isochromosome 17q and trisomy 14 have each been reported as rare, nonrandom recurrent chromosomal abnormalities in patients with MDS showing a poor prognosis. To our knowledge, this is the first report of concurrent i(17)(q10) and trisomy 14 in a patient with MDS in leukemic transformation.

A Novel PHEX Mutation in a Korean Patient with Sporadic Hypophosphatemic Rickets

Annals of Clinical and Laboratory Science. 2009  |  Pubmed ID: 19429806

Mutations including nonsense mutations, missense mutations, splicing-site mutations, insertions, and deletions in phosphate regulating genes on the X-chromosome (PHEX) are known to be responsible for X-linked hypophosphatemic rickets. The PHEX gene encodes an endopeptidase that is involved in phosphate regulation. Herein we present a female patient with sporadic hypophosphatemic rickets harboring a novel deletion mutation (c.1586_1586+1delAG; p.Glu529GlyfsX41) at exon 14 and intron 14 junction, which caused a premature termination at codon 569 and possibly produced a truncated PHEX protein. The laboratory and radiologic findings of the patient are reviewed to correlate the impact of the two-base deletion mutations at the exon-intron junction.

Two Case Reports of 1q Triplication in Myeloproliferative Neoplasms

Cancer Genetics and Cytogenetics. Jun, 2009  |  Pubmed ID: 19446749

Association Between Acute Promyelocytic Leukemia and Ring Chromosome 6

Cancer Genetics and Cytogenetics. Jul, 2009  |  Pubmed ID: 19480938

Chronic Myelomonocytic Leukemia with Der(9)t(1;9)(q11;q34) As a Sole Abnormality

Annals of Clinical and Laboratory Science. 2009  |  Pubmed ID: 19667417

The chromosomal abnormality der(9)t(1;9)(q11;q34) is a rare occurrence in patients with hematologic malignancies. As far as we know, only 3 cases of acute myeloid leukemia, 1 case of polycythemia vera, and 1 case of multiple myeloma with this derivative chromosome have been reported in the literature. Here we report the first case of der(9)t(1;9)(q11;q34) in a patient with chronic myelomonocytic leukemia (CMML). A 45-yr-old man was brought to our hospital for evaluation of pancytopenia and monocytosis. The patient's persistent monocytosis in peripheral blood and his bone marrow findings were consistent with the diagnosis of CMML. Chromosome study results repeatedly showed 46,XY,der(9)t(1;9)(q11;q34). In addition, the BCR/ABL fluorescent in situ hybridization (FISH) pattern of the interphase cells was interpreted as: "nuc ish(ABL, BCR) x 2[292/300]," consistent with the normal signal patterns found in 97% of the nuclei examined. For further evaluation, multi-color FISH (mFISH) analysis was performed and it showed the distinct unbalanced derivative chromosome der(9)t(1;9)(q11;q34) in 5 metaphase cells analyzed. Not only does this show an extraordinary type of trisomy 1q, but it reveals a rare recurrent case of der(9)t(1;9)(q11;q34) in patients with monocytic-lineage leukemia. Further studies are needed to evaluate the prognosis, survival, and treatment response of such patients with der(9)t(1;9)(q11;q34).

Detection of FUS-ERG Chimeric Transcript in Two Cases of Acute Myeloid Leukemia with T(16;21)(p11.2;q22) with Unusual Characteristics

Cancer Genetics and Cytogenetics. Oct, 2009  |  Pubmed ID: 19781443

Reciprocal t(16;21)(p11;q22) is a rare chromosomal abnormality in acute myeloid leukemia (AML). The chimeric transcript FUS-ERG formed by this translocation which causes the replacement of RNA-binding domain of FUS (alias TLS) with the DNA-binding domain of ERG, and this event is thought to be responsible for leukemogenesis. Here we report two cases of AML with t(16;21)(p11.2;q22) showing unusual characteristics, and address the clinical, hematological, and molecular aspects of leukemia with t(16;21), along with a review of the literature.

A Novel In-frame Deletion in the Factor V C1 Domain Associated with Severe Coagulation Factor V Deficiency in a Korean Family

Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. Mar, 2009  |  Pubmed ID: 19786944

Hereditary coagulation factor V deficiency is a rare bleeding disorder characterized by extremely low levels of functional and immunoreactive factor V in plasma associated with moderate-to-severe bleeding symptoms. The genetic bases of factor V deficiency have been characterized only in a limited number of cases and the majority of causative mutations are truncating mutations providing only limited information about the function of subdomains and of individual residues. Here, we present the first report on a Korean family with inherited factor V deficiency. The proband is a 25-year-old man who showed normal coagulation factor levels except those for factor V antigen and activity (3 and 4%, respectively), and was only suffering from bleeding after tooth extraction. Direct sequencing of the factor V gene disclosed the already known nonsense mutation (R1133X) and a novel in-frame 6-bp deletion (6116-6121delGAACAG, corresponding to the amino-acid deletion N1982-S1983) located in the factor V C1 domain; both mutations were found in the heterozygous state. The structural and functional importance of the in-frame deletion was examined by constructing a molecular model based on the crystal structure of bovine activated factor V that has been inactivated by activated protein C. N1982 and S1983 are located on a loop that is exposed on the surface of the C1 domain, and are in close contact with another loop belonging to the A3 domain. Even though the detailed mechanism of the association of the in-frame deletion of our patient and factor V deficiency needs further investigation, this model suggests the possibility that the N1982-S1983 deletion could destabilize the C1-A3 interaction by preventing the potential formation of hydrogen bonds between K1980 and N1986 of the C1 domain with D1604 of the A3 domain. Also, because N1982 is strongly expected to be N-glycosylated judging from its structural homology to factor VIII, loss of this residue can influence proper folding of factor V, resulting in unstable structure, which is vulnerable to intracellular degradation.

CASP8AP2 is a Novel Partner Gene of MLL Rearrangement with T(6;11)(q15;q23) in Acute Myeloid Leukemia

Cancer Genetics and Cytogenetics. Nov, 2009  |  Pubmed ID: 19837277

Therapy-related Myelodysplastic Syndrome/acute Myeloid Leukemia After Treatment with Temozolomide in a Patient with Glioblastoma Multiforme

Annals of Clinical and Laboratory Science. 2009  |  Pubmed ID: 19880768

Therapy-related myelodysplastic syndrome and acute leukemia after treatment with temozolomide have rarely been described in the literature. Only 10 cases in association with temozolomide have been documented. The cases included anaplastic astrocytoma (4 cases), anaplastic oligodendroglioma (2 cases), low grade astrocytoma (2 cases), low grade oligodendroglioma (1 case), and one case of secondary Philadelphia-positive acute lymphoblastic leukemia in a patient with glioblastoma multiforme. Here we report a novel case of therapy-related myelodysplastic syndrome/acute myeloid leukemia associated with der(1;7)(q10;p10) in a glioblastoma multiforme patient treated with temozolomide. Results of bone marrow morphology, chromosome, and fluorescent in situ hybridization (FISH) analyses, as well as the clinical history, strongly suggest a treatment-related etiology in our case. In past reports, karyotypes in cases of therapy-related myelodysplastic syndrome/acute myeloid leukemia mostly demonstrated abnormalities in chromosomes 5 and 7. However, we report a case of temozolomide-related myelodysplastic syndrome/acute myeloid leukemia with der(1;7)(q10;p10), possibly the first reported case, to the authors' knowledge.

A Novel T(1;12)(q21;q24) in a Patient with Myelodysplastic Syndrome

Annals of Hematology. May, 2010  |  Pubmed ID: 19697027

Three-way Translocation Involving MLL, MLLT1, and a Novel Third Partner, NRXN1, in a Patient with Acute Lymphoblastic Leukemia and T(2;19;11) (p12;p13.3;q23)

Cancer Genetics and Cytogenetics. Feb, 2010  |  Pubmed ID: 20113834

Translocations involving mixed lineage leukemia (MLL) gene at 11q23 are associated with de novo acute leukemia as well as therapy-related acute leukemia. More than 100 different translocations involving MLL have been described in acute leukemia, with more than 60 translocation partner genes characterized on the molecular level. In addition to various simple translocations affecting MLL, there are also complex forms involving three or more chromosomes. Here, we describe a novel three-way translocation of t(2;19;11)(p12;p13.3;q23) in a patient with acute lymphoblastic leukemia (ALL). In this translocation, the distal 19p13.3 joins the proximal 11q23 on der(11), whereas the distal 11q23 is translocated to 2p12. Three-way translocations involving 11q23 are often difficult to detect with cytogenetic means alone. In the present case, however, the chromosomes involved in the three-way translocation were readily identifiable by GTG banding. The MLL-MLLT1 fusion products from the derivative chromosome 11 were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and two splicing variant forms were confirmed by cloning and sequencing. Furthermore, the novel third partner gene, NRXN1, was detected by systematic breakpoint analysis using long-distance inverse-PCR methods (LDI-PCR). The apparent three-way translocation thus identified is noteworthy because few studies have reported complex rearrangements involving 11q23 and 19p13.3 in acute leukemias.

Molecular Cytogenetic Analysis of Korean Patients with Waldenström Macroglobulinemia

Cancer Genetics and Cytogenetics. Mar, 2010  |  Pubmed ID: 20193844

To compare the molecular cytogenetic characteristics between Waldenström macroglobulinemia (WM) and multiple myeloma (MM), we performed interphase fluorescent in situ hybridization (FISH) in Korean patients with WM and MM. Forty patients with WM and 132 patients with MM were enrolled onto the study. FISH was performed with seven different probes: 6q21, 6q23, CEP4, CEP9, immunoglobulin (IgH) breakapart, RB1 gene, and 1q25. Out of 22 WM patients, 4 (18%) had abnormal karyotypes, mainly structural changes on conventional karyotyping. After performing FISH for the available 29 cases, deletions of 6q23 and 6q21 were newly detected in 3 cases (10%). There was no other anomaly, including trisomy 4 in WM. No 6q deletion was observed in MM patients, but RB1 deletion was the most common change (45%), followed by IgH translocation (42%) and gain of 1q (38%). In conclusion, Korean WM patients had a low rate of 6q deletion (10%) and no trisomy 4.

Automated Detection of Malaria-associated Pseudoeosinophilia and Abnormal WBC Scattergram by the Sysmex XE-2100 Hematology Analyzer: a Clinical Study with 1,801 Patients and Real-time Quantitative PCR Analysis in Vivax Malaria-endemic Area

The American Journal of Tropical Medicine and Hygiene. Mar, 2010  |  Pubmed ID: 20207865

Recently, the XE-2100 hematology analyzer was investigated in a rather small patient group; pseudoeosinophilia or abnormal white blood cell (WBC) scattergrams reported by this instrument were considered as significantly valuable diagnostic parameters in detecting vivax malaria. This study was conducted not only to assess the usefulness of pseudoeosinophilia or abnormal WBC scattergram in vivax malaria-endemic areas with large patient groups (N = 1,801) but also to investigate the correlation of parasitemia and platelet count with pseudoeosinophilia and abnormal WBC scattergrams. Of the 1,801 analyzed patients, 413 (22.9%) were found to have malaria by Wright-Giemsa stained blood smears. Overall, either pseudoeosinophilia or abnormal WBC scattergram was detected in 191 of 413 malaria patients and 4 of 1,388 patients without malaria (sensitivity = 46.2%, specificity = 99.7%). We suggest that clinical hematology laboratories using the XE-2100 analyzer should be aware of such specific parameters, even with the absence of a clinical request.

Constitutional Pericentric Inversion 9 in Korean Patients with Chronic Myelogenous Leukemia

The Korean Journal of Laboratory Medicine. Jun, 2010  |  Pubmed ID: 20603579

Although the pericentric inversion of chromosome 9, inv(9)(p11q13), is generally considered a normal variation, it is also associated with solid tumors and several hematologic malignancies such as biphenotypic acute leukemia, ALL, AML, and myeloproliferative neoplasms. However, to the best of our knowledge, there have been no reports that suggest an association between CML and constitutional pericentric inversion of chromosome 9. The purpose of this retrospective study was to investigate the frequency and clinical features of CML patients with concomitant inv(9) and t(9;22)(q34;q11.2) variation at our institution.

Molecular Characterization of Alternative SET-NUP214 Fusion Transcripts in a Case of Acute Undifferentiated Leukemia

Cancer Genetics and Cytogenetics. Sep, 2010  |  Pubmed ID: 20682390

Cryptic deletions are occasionally reported in hematologic malignancies. The SET-NUP214 fusion gene has been rarely reported in acute myeloid leukemia, acute undifferentiated leukemia, and recurrently in T-cell acute lymphoblastic leukemia. The fusion product is generated by a submicroscopic deletion in the vicinity of 9q34. Herein we present a novel case of acute undifferentiated leukemia with SET-NUP214 rearrangement due to the cryptic deletion of the 9q34 region producing two different types of fusion transcripts by alternative splicing and molecular characterization of the fusion transcripts by fluorescence in situ hybridization, reverse transcriptase-polymerase chain reaction, and array comparative genomic hybridization analyses.

Constitutional Pericentric Inversion 9 and Hematological Disorders: a Korean Tertiary Institution's Experience over Eight Years

Annals of Clinical and Laboratory Science. 2010  |  Pubmed ID: 20689141

Constitutional pericentric inversion of chromosome 9 [inv(9)] occurs in 0.8 to 2% of the normal population and has long been considered a normal variant. It is controversial whether inv(9) is a predisposing factor for acute leukemia (AL). The effect of inv(9) on bone marrow (BM) recovery after stem cell transplantation or chemotherapy is undetermined. Between March 2001 and December 2008, the cytogenetics of 3,809 patients with suspected hematological diseases were reviewed. Of them, 586 patients were diagnosed with AL. Constitutional inv(9) was found in 55 patients with various hematological disorders, including AL and solid tumors. The proportion of inv(9) was similar in patients with AL (8/586, 1.37%) and those without (47/3223, 1.46%; p = 1.0). Of the eight patients with AL and inv(9), one refused treatment and seven had induction chemotherapy. Four of the seven patients achieved prompt hematological recovery, but the other three failed to achieve complete hematological remission. Thus constitutional inv(9) seems not to be related independently to delayed hematological recovery. One recipient of an allogeneic peripheral blood stem cell transplantation, from an unrelated donor with constitutional inv(9), also achieved prompt hematological reconstruction, further suggesting that constitutional inv(9) has no effect on hematopoietic cells. In summary, our data suggest that constitutional inv(9) is a truly random chromosomal aberration with no apparent functional effect on hematological disorders.

An SRY-deleted XXY Female Resulting from a Paternally Inherited T(Y;22)

Annals of Clinical and Laboratory Science. 2010  |  Pubmed ID: 20689145

We report a case of a female with SRY-negative XXYp-. The karyotype by the conventional method revealed chromosome 22 with a short arm enlargement. The enlarged short arm contained a heterochromatic region, which was found by the whole chromosome painting method to be a part of the Y chromosome without the P arm. Chromosome study of the parents revealed that the t(Y;22) chromosome was derived from the patient's father who was phenotypically normal. Although the Y fragment was transmitted in patrilinear fashion in this case, our patient with intact copies of both X chromosomes and the Y chromosome with a deleted p arm is expected to show normal fertility. However, the patient should be closely followed in regard to fertility and the possibility of developing a gonadoblastoma.

Prognostic Significance of Trisomy 6 in an Adult Acute Myeloid Leukemia with T(8;21)

Cancer Genetics and Cytogenetics. Oct, 2010  |  Pubmed ID: 20875878

[Parvovirus B19-induced Pure Red Cell Aplasia in a Liver Transplant Recipient]

The Korean Journal of Laboratory Medicine. Dec, 2010  |  Pubmed ID: 21157144

Parvovirus B19 infection is known to cause chronic anemia in immunocompromised hosts, including organ transplant recipients. We report the first case of liver transplant recipient with parvovirus B19-induced pure red cell aplasia in Korea. A 57-yr-old female patient with hepatocellular carcinoma due to hepatitis C virus received a liver transplantation. Two months later, anemia developed and she received periodic red blood cell transfusions. However, chronic anemia persisted and bone marrow examination was performed 8 months after transplantation. Bone marrow aspiration smears showed markedly reduced erythroid precursors with atypical giant pronormoblasts and nuclear remnants with viral inclusions, and characteristic lantern cells were observed in biopsy sections. In addition, parvovirus B19 DNA PCR was positive. She was diagnosed as parvovirus B19-induced pure red cell aplasia and her anemia was improved following intravenous immunoglobulin therapy.

Diagnosis of Non-overt Disseminated Intravascular Coagulation Made According to the International Society on Thrombosis and Hemostasis Criteria with Some Modifications

The Korean Journal of Hematology. Dec, 2010  |  Pubmed ID: 21253428

An early diagnosis of disseminated intravascular coagulation (DIC) before its progression to an overt stage is necessary for early treatment and positive outcomes. In 2001, the Scientific and Standardization Committee (SCC) of the International Society on Thrombosis and Hemostasis (ISTH) proposed new criteria for the preclinical diagnosis of overt and non-overt DICs. We investigated the clinical usefulness of the modified ISTH criteria for non-overt DIC diagnosis.

Elevated Levels of Activated and Inactivated Thrombin-activatable Fibrinolysis Inhibitor in Patients with Sepsis

The Korean Journal of Hematology. Dec, 2010  |  Pubmed ID: 21253429

In sepsis, large scale inflammatory responses can cause extensive collateral damage to the vasculature, because both coagulation and fibrinolysis are activated unevenly. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in modulating fibrinolysis. Since TAFI can be activated by both thrombin and plasmin, it is thought to be affected in sepsis. Hence, activated and inactivated TAFI (TAFIa/ai) may be used to monitor changes in sepsis.

A Heparin Binding Site Arg79Cys Missense Mutation in the SERPINC1 Gene in a Korean Patient with Hereditary Antithrombin Deficiency

Annals of Clinical and Laboratory Science. 2011  |  Pubmed ID: 21325262

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.

Acute Promyelocytic Leukemia with Trisomy 8 and Del(9)(q22) After Treatment of Cervical Cancer with Concurrent Chemoradiotherapy: a Case Report

Onkologie. 2011  |  Pubmed ID: 21734427

Delta Neutrophil Index: a Promising Diagnostic and Prognostic Marker for Sepsis

Shock (Augusta, Ga.). Mar, 2012  |  Pubmed ID: 22258230

Delta neutrophil index (DN) is the immature granulocyte fraction provided by a blood cell analyzer (ADVIA 2120; Siemens Healthcare Diagnostics, Deerfield, Ill), which is determined by subtracting the fraction of mature polymorphonuclear leukocytes from the sum of myeloperoxidase-reactive cells. The purpose of this study was to define the role of DN in differential diagnosis and prognosis prediction of patients with sepsis. Hospital records of 273 patients were retrospectively collected: 47 with systemic inflammatory response syndrome, 78 with sepsis, 51 with severe sepsis, and 97 control subjects. Delta neutrophil index and C-reactive protein data on the day of the first blood culture were compared among the groups, and 28-day mortality associated with sepsis was assessed. Median values of DN were 0.0% (interquartile range, 0.0%-0.0%) in the control group, 0.8% (0.0%-1.7%) in the systemic inflammatory response syndrome group, 3.4% (1.5%-5.3%) in the sepsis group, and 18.6% (9.3%-24.7%) in the severe sepsis group. Furthermore, there were significant differences among the groups. The receiver operating characteristic curves showed that DN was a better predictor of sepsis than C-reactive protein. The best cutoff value for DN for predicting sepsis was 2.7%. Delta neutrophil index was significantly higher in those who died than in the survivors (median [interquartile range], 11.5% [3.5%-25.0%] vs. 4.7% [2.2%-10.6%], P = 0.008) and was identified to be an independent predictor for 28-day mortality in patients with sepsis by Cox proportional hazards model. Delta neutrophil index may serve as a facile and useful marker for early diagnosis and prognostic assessment of patients with sepsis, as it is included in a routine complete blood count.

CD5-negative Blastoid Variant Mantle Cell Lymphoma with Complex CCND1/IGH and MYC Aberrations

Annals of Laboratory Medicine. Jan, 2012  |  Pubmed ID: 22259787

The coexistence of CCND1/IGH and MYC rearrangements in mantle cell lymphoma (MCL) is a rare finding associated with a very poor prognosis. In this study, a patient with blastoid variant (MCL) is reported. The disease was clinically aggressive and refractory to chemotherapy, and the patient only survived for 1 month following diagnosis. Conventional cytogenetic study, FISH, and multicolor FISH (mFISH) demonstrated the involvement of the BCL1/CCND1 locus in a complex translocation, t(3;11)(q25;p15)t(11;14)(q13;q32). In addition, subclonal abnormalities in the 8q24 region, manifested as a t(8;14)(q24;q32)/MYC rearrangement, were identified. To the best of our knowledge, this is the first MCL case in Korea bearing these complex genomic aberrations.

A Gly1609Arg Missense Mutation in the VWF Gene in a Korean Patient with Von Willebrand Disease Type 2A

Annals of Clinical and Laboratory Science. 2012  |  Pubmed ID: 22371917

We describe a case of a c.4825G>A (p.Gly1609Arg [Gly846Arg]) missense mutation in the gene encoding von Willebrand factor (vWF) in a Korean patient with von Willebrand disease (vWD) type 2A. The proband is a 37-year-old female who suffers from dysmenorrhea and menorrhagia. On laboratory testing, we found a low (0.01) vWF:RCo/Ag ratio, a decrease in high and intermediate molecular weight multimers from plasma, and abnormalities in the collagen binding capacity of plasma vWF, all of which were indicative of vWD type 2. Family studies revealed that her sister, son, and daughter also had a low vWF:RCo/ Ag ratio and a decrease in high molecular weight multimers from plasma. Genetic analyses showed that she and her three family members had the same heterozygous c.4825G>A (p.Gly1609Arg [Gly846Arg]) missense mutation. To our knowledge, this is the first report of the c.4825G>A (p.Gly1609Arg [Gly846Arg]) heterozygote mutation in Korean family members with vWD type 2A.

Fibrinogen Residue γAla341 is Necessary for Calcium Binding and 'A-a' Interactions

Thrombosis and Haemostasis. May, 2012  |  Pubmed ID: 22437918

The fibrinogen γ-module has several important sites relating to fibrinogen function, which include the high affinity calcium binding site, hole 'a' that binds with knob 'A', and the D:D interface. Residue γAla341, which is located in the vicinity of these sites, is altered in three variant fibrinogens: fibrinogen Seoul (γAla341Asp), Tolaga Bay (γAla341Val), and Lyon III (γAla341Thr). In order to investigate the impaired polymerisation of fibrinogens γAla341Asp and γAla341Val to understand the role of γAla341 in fibrin polymerisation and fibrinogen synthesis, we have expressed γAla341Asp and γAla341Val in Chinese hamster ovary (CHO) cells, purified these fibrinogens from the culture media and performed biochemical tests to elucidate their function. Expression in CHO cells was similar for these variants. For both variants the kinetics of thrombin-catalysed FpA release was not different from normal fibrinogen, while FpB release was slower than that of normal. Thrombin-catalysed polymerisation of both variants was dependent on the calcium concentration. At physiologic calcium (1 mM) the variants showed impaired polymerisation with a longer lag period and a slower Vmax than normal fibrinogen. Scanning electron micrographs showed the clots were less organised than normal, having thicker and more twisted fibers, and larger pores. Analysis by SDS-PAGE showed that factor XIIIa-catalysed γ and α chain cross-linking was delayed, and plasmin-catalysed lysis was not reduced by the presence of 5 mM calcium or 5 mM GPRP (Gly-Pro-Arg-Pro). Our data indicate that fibrinogen residue γAla341 is important for the proper conformation of the γ-module, maintaining calcium-binding site and 'A-a' interactions.

Comparison Study of the Rates of Manual Peripheral Blood Smear Review from 3 Automated Hematology Analyzers, Unicel DxH 800, ADVIA 2120i, and XE 2100, Using International Consensus Group Guidelines

Archives of Pathology & Laboratory Medicine. Nov, 2012  |  Pubmed ID: 23106587

In the clinical laboratory, it is important both to reduce the number of peripheral blood slide reviews to save time and money and to avoid reporting false results.

An Engineered Fibrinogen Variant AαQ328,366P Does Not Polymerise Normally, but Retains the Ability to Form α Cross-links

Thrombosis and Haemostasis. Feb, 2013  |  Pubmed ID: 23224113

A fibrin clot is stabilised through the formation of factor XIIIa-catalysed intermolecular ε-lysyl-γ-glutamyl covalent cross-links between α chains to form α polymers and between γ chains to form γ dimers. In a previous study we characterised fibrinogen Seoul II, a heterozygous dysfibrinogen in which a cross-linking acceptor site in Aα chain, Gln328, was replaced with Pro (AαQ328P). Following on the previous study, we investigated whether the alteration of Gln residues Aα328 and Aα366 affects fibrin polymerisation and α chain cross-linking. We have expressed three recombinant fibrinogens: AαQ328P, AαQ366P, and AαQ328,366P in Chinese hamster ovary cells, purified these fibrinogens from the culture media and performed biochemical tests to see how the introduced changes affect fibrin polymerisation and α chain cross-linking. Thrombin-catalysed fibrin polymerisation of all variants was impaired with the double mutation being the most impaired. In contrast, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis showed α polymer formation with all three engineered proteins. This study demonstrates that AαQ328 and AαQ366 are important for normal fibrin clot formation and in the absence of residues AαQ328 and AαQ366, other Gln residues in the α chain can support FXIIIa-catalysed fibrin cross-linking.

Immature Platelet Fraction in Diabetes Mellitus and Metabolic Syndrome

Thrombosis Research. 2013  |  Pubmed ID: 24140451

Dysregulated platelet-endothelial interaction plays a pivotal role in atherothrombotic events in patients with diabetes mellitus (DM). Immature platelet fraction (IPF) is a hematologic parameter of automated hematologic analyzer and is related to platelet size and cytoplasmic RNA contents. It reflects thrombopoiesis and also is often used as the marker of platelet activity.

The Instability of Commercial Control Materials in Quality Control of Mean Corpuscular Volume

Clinica Chimica Acta; International Journal of Clinical Chemistry. Jul, 2014  |  Pubmed ID: 24769249

Mean corpuscular volume (MCV) of stabilized whole blood used for quality control (QC) of hematology analyzers exhibits a tendency to increase during storage. The aim of this study is to evaluate the extent of biases over time with 3 most widely used control materials and to map out a strategy to overcome the data shift of MCV on daily QC practice.

Analytical and Clinical Performance of a New Point of Care LABGEOIB D-dimer Test for Diagnosis of Venous Thromboembolism

Annals of Clinical and Laboratory Science. 2014  |  Pubmed ID: 25117092

LABGEO(IB) D-dimer Test is a newly developed POC D-dimer assay and the first commercially available POC immunoassay instrument that exploits the disk rotation method for extraction of plasma. Citrate plasma was obtained from 201 apparently healthy subjects and 91 patients suspected for VTE, and their D-dimer level was measured by the LABGEO(IB) D-Dimer Test (LABGEO D-dimer) and HemosIL D-dimer test as a comparative method. To examine the effect of blood cells and anticoagulant, paired blood samples anticoagulated by heparin and citrate were obtained from various postoperative patients. The overall diagnostic performance of LABGEO(IB) D-dimer and HemosIL was comparable with similar area under ROC curve (p=0.79). The cut-off levels recommended by manufacturers (LABGEO D-dimer: 0.45 μg/ml fibrinogen equivalent unit (FEU), HemosIL: 0.23 μg/ml D-dimer unit (DDU)) and those yielding highest diagnostic efficiency (LABGEO D-dimer: 1.41 μg/ml FEU; HemosIL: 0.85 μg/ml DDU), were chosen for the evaluation. For LABGEO D-dimer negative predictive value (NPV), positive predictive value (PPV), sensitivity, specificity, and negative likelihood ratio (LR-neg) were 93-100%, 67-89%, 93-100%, 53-89% and 0.00-0.08. For HemosIL D-dimer, NPV, PPV, sensitivity, specificity and LR-neg were 90 - 100%, 76-95%, 89-100%, 70-96% and 0.00-0.12, all comparable to results for LABGEO D-dimer. LABGEO D-dimer test demonstrated acceptable performance when used for the VTE diagnostic work-up.

Comparison of Prothrombin Time Derived from CoaguChek XS and Laboratory Test According to Fibrinogen Level

Journal of Clinical Laboratory Analysis. Jan, 2015  |  Pubmed ID: 24687901

CoaguChek XS is one of the most widely used point-of-care (POC) devices to evaluate prothrombin time for monitoring oral anticoagulant therapy. Unlike laboratory methods, it detects electrical signals produced by thrombin activity to derive the international normalized ratio (INR). Therefore, we hypothesized that laboratory methods and CoaguChek XS could produce different results according to fibrinogen level.

Selective Serotonin Reuptake Inhibitors Facilitate ANO6 (TMEM16F) Current Activation and Phosphatidylserine Exposure

Pflügers Archiv : European Journal of Physiology. Nov, 2015  |  Pubmed ID: 25630304

Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca(2+)-activated Cl(-) channels that generate outward-rectifying ionic currents in response to intracellular Ca(2+) increase. ANO6 is also essential for Ca(2+)-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)--fluoxetine, sertraline, and paroxetine-that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1-7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl(-) current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca(2+)-dependent activation of IANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of IANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca(2+)-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca(2+)-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.

Capillary-scale Direct Measurement of Hemoglobin Concentration of Erythrocytes Using Photothermal Angular Light Scattering

Biosensors & Bioelectronics. Dec, 2015  |  Pubmed ID: 26176206

We present a direct, rapid and chemical-free detection method for hemoglobin concentration ([Hb]), based on photothermal angular light scattering. The iron oxides contained in hemoglobin molecules exhibit high absorption of 532-nm light and generate heat under the illumination of 532-nm light, which subsequently alters the refractive index of blood. We measured this photothermal change in refractive index by employing angular light scattering spectroscopy with the goal of quantifying [Hb] in blood samples. Highly sensitive [Hb] measurement of blood samples was performed by monitoring the shifts in angularly dispersed scattering patterns from the blood-loaded microcapillary tubes. Our system measured [Hb] over the range of 0.35-17.9 g/dL with a detection limit of ~0.12 g/dL. Our sensor was characterized by excellent correlation with a reference hematology analyzer (r>0.96), and yielded a precision of 0.63 g/dL for a blood sample of 9.0 g/dL.

Quantitative Influence of ABO Blood Groups on Factor VIII and Its Ratio to Von Willebrand Factor, Novel Observations from an ARIC Study of 11,673 Subjects

PloS One. 2015  |  Pubmed ID: 26244499

ABO blood groups are known to influence the plasma level of von Willebrand factor (VWF), but little is known about the relationship between ABO and coagulation factor VIII (FVIII). We analyzed the influence of ABO genotypes on VWF antigen, FVIII activity, and their quantitative relationship in 11,673 participants in the Atherosclerosis Risk in Communities (ARIC) study. VWF, FVIII, and FVIII/VWF levels varied significantly among O, A (A1 and A2), B and AB subjects, and the extent of which varied between Americans of European (EA) and African (AA) descent. We validated a strong influence of ABO blood type on VWF levels (15.2%), but also detected a direct ABO influence on FVIII activity (0.6%) and FVIII/VWF ratio (3.8%) after adjustment for VWF. We determined that FVIII activity changed 0.54% for every 1% change in VWF antigen level. This VWF-FVIII relationship differed between subjects with O and B blood types in EA, AA, and in male, but not female subjects. Variations in FVIII activity were primarily detected at low VWF levels. These new quantitative influences on VWF, FVIII and the FVIII/VWF ratio help understand how ABO genotypes differentially influence VWF, FVIII and their ratio, particularly in racial and gender specific manners.

Clinical Utility of Bone Marrow Study in Gaucher Disease: A Case Report of Gaucher Disease Type 3 With Intractable Myoclonic Seizures

Annals of Laboratory Medicine. Mar, 2016  |  Pubmed ID: 26709268

Automated CH50 Liposome-based Immunoassay: Consideration in Dilution and Validation of Reference Interval

Clinical Chemistry and Laboratory Medicine. Oct, 2016  |  Pubmed ID: 27016150

Magnetic Bead-based Nucleic Acid Purification Kit: Clinical Application and Performance Evaluation in Stool Specimens

Journal of Microbiological Methods. May, 2016  |  Pubmed ID: 27030641

Two different methods - the semi-automated magnetic bead-based kit (SK, Stool DNA/RNA Purification kit®) and the manual membrane column-based kit (QS, QIAamp® DNA Stool Mini kit) - for purifying nucleic acids from clinical stool samples were compared and evaluated. The SK kit was more user-friendly than QS due to the reduced manual processing, partial automation, and short turnaround time with half cost. Furthermore, SK produced high yields in both DNA and RNA extractions but poor purity in RNA extraction. In the assessment of rotavirus and Clostridium difficile infection, both kits had equivalent or more sensitive performance compared with the standard method. Although SK showed some interference and inhibition in nucleic acid extraction, the performance, including the repeatability, linearity, analytical sensitivity, and matrix effect, was sufficient for routine clinical use.

Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity

PloS One. 2016  |  Pubmed ID: 27584569

VWF is extensively glycosylated with biantennary core fucosylated glycans. Most N-linked and O-linked glycans on VWF are sialylated. FVIII is also glycosylated, with a glycan structure similar to that of VWF. ST3GAL sialyltransferases catalyze the transfer of sialic acids in the α2,3 linkage to termini of N- and O-glycans. This sialic acid modification is critical for VWF synthesis and activity. We analyzed genetic and phenotypic data from the Atherosclerosis Risk in Communities (ARIC) study for the association of single nucleotide polymorphisms (SNPs) in the ST3GAL4 gene with plasma VWF levels and FVIII activity in 12,117 subjects. We also analyzed ST3GAL4 SNPs found in 2,535 subjects of 26 ethnicities from the 1000 Genomes (1000G) project for ethnic diversity, SNP imputation, and ST3GAL4 haplotypes. We identified 14 and 1,714 ST3GAL4 variants in the ARIC GWAS and 1000G databases respectively, with 46% being ethnically diverse in their allele frequencies. Among the 14 ST3GAL4 SNPs found in ARIC GWAS, the intronic rs2186717, rs7928391, and rs11220465 were associated with VWF levels and with FVIII activity after adjustment for age, BMI, hypertension, diabetes, ever-smoking status, and ABO. This study illustrates the power of next-generation sequencing in the discovery of new genetic variants and a significant ethnic diversity in the ST3GAL4 gene. We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.

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