Satomi Asai

FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression

Fms-related tyrosine kinase 3-internal tandem duplications (FLT3-ITD) are strongly associated with the refractory nature of acute myeloid leukemia (AML) by the standard combined chemotherapy. FLT3-ITD-expressing murine and human myeloid cell lines, HF6/FLT3-ITD and K562/FLT3-ITD cells, respectively, were developed in order to clarify whether FLT3-ITD is involved in the resistance to cytotoxic agents in AML. Both of these cell lines were specifically resistant to the pyrimidine analogue cytosine arabinoside (ara-C), an essential agent for AML, accompanied by the downregulation of equilibrative nucleoside transporter 1 (ENT1), a transporter responsible for the cellular uptake of ara-C. The ENT1 promoter activity and the cellular uptake of ara-C were reduced in K562/FLT3-ITD cells, and rescued by pretreating the cells with PKC412, a FLT3 inhibitor. In addition, the expression of hypoxia inducible factor 1 alpha subunit (HIF1A) transcripts was upregulated in K562/FLT3-ITD cells, and the induction of HIF-1alpha reduced the promoter activity of ENT1 gene in K562 cells. Taken together, these findings suggest that FLT3-ITD specifically induces ara-C resistance in leukemic cells by the repression of ENT1 expression, possibly through the upregulation of HIF-1alpha, while also partially accounting for the poor prognosis of AML with FLT3-ITD due to resistance to the standard chemotherapy protocols which include ara-C.

Ultrasonographic differentiation between tuberculous lymphadenitis and malignant lymph nodes

To assess the usefulness of ultrasonography in the differential diagnosis of cervical tuberculous lymphadenitis versus malignant lymph nodes.

Performance evaluation of platelet counting by novel fluorescent dye staining in the XN-series automated hematology analyzers.

Conventional automated hematology analyzers have limitations in platelet measurements such as poor accuracy and precision in the low count range and interference by nonplatelet particles. In order to improve it, the newly developed XN‐Series automated hematology analyzers (Sysmex Corporation, Kobe, Japan) have been installed with a new dedicated channel for platelet analysis (PLT‐F), which is based on a fluorescence flow cytometry method with uses of a novel fluorescent dye specifically staining platelets. We evaluated the basic performance of this new PLT‐F channel.

C/EBPalpha and C/EBPvarepsilon induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene.

CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPα and C/EBPɛ. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPα or C/EBPɛ was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPα-ER, but not vice versa, thus suggesting that C/EBPɛ may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPɛ, as well as C/EBPα, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.

Myoepithelial carcinoma in pleomorphic adenoma of salivary gland type, occurring in the mandible of an infant

A rapidly growing mandibular tumor occurred in a 17 month old female infant. Tumor outgrowth showing a periosteal reaction was radiographically seen on the lower surface (base) of the mandible. Under the biopsy diagnosis of osteosarcoma, high‐dose chemotherapy with methotrexate was performed, resulting in little effect. The right hemiman‐dibulectomy specimen disclosed intraosseous infiltrative growth of pleomorphic adenoma of salivary gland type, associated with chondroid stroma and reactive bone formation. The highly proliferative small‐sized cells retained immunohistochemical features of myoepithelial cells, with positive reactivity of cytokeratin, vimentin, S‐100 protein, a‐smooth muscle actin, epithelial membrane antigen, CA15–3, type IV collagen, laminin and p53 protein. No heterotopia of the salivary gland was identified within the bone tissue. The tumor recurred 2 months later. Due to uncontrollable local growth, the patient died 8 months after operation. At autopsy, reactive ossification was closely associated with malignant myoepithelial proliferation. No distant metastasis was noted. This osteosarcoma‐like tumor can be regarded as myoepithelial carcinoma in pleomorphic adenoma, originating from intramandibular heterotopic salivary gland tissue.

An outbreak of blaOXA-51-like- and blaOXA-66-positive Acinetobacter baumannii ST208 in the emergency intensive care unit.

A series of clinical isolates of drug-resistant (DR) Acinetobacter baumannii with diverse drug susceptibility was detected from eight patients in the emergency intensive care unit of Tokai University Hospital. The initial isolate was obtained in March 2010 (A. baumannii Tokai strain 1); subsequently, seven isolates were obtained from patients (A. baumannii Tokai strains 2–8) and one isolate was obtained from an air-fluidized bed used by five of the patients during the 3 months from August to November 2011. The isolates were classified into three types of antimicrobial drug resistance patterns (RRR, SRR and SSR) according to their susceptibility (S) or resistance (R) to imipenem, amikacin and ciprofloxacin, respectively. Genotyping of these isolates by multilocus sequence typing revealed one sequence type, ST208, whilst that by a DiversiLab analysis revealed two subtypes. All the isolates were positive for blaOXA-51-like and blaOXA-66, as assessed by PCR and DNA sequencing. A. baumannii Tokai strains 1–8 and 10 (RRR, SRR and SSR) had quinolone resistance-associated mutations in gyrA/parC, as revealed by DNA sequencing. The ISAba1 upstream of blaOXA-51-like and aminoglycoside resistance-associated gene, armA, were detected in A. baumannii Tokai strains 1–7 and 10 (RRR and SRR) as assessed by PCR. Among the genes encoding resistance–nodulation–division family pumps (adeB, adeG and adeJ) and outer-membrane porins (oprD and carO), overexpression of adeB and adeJ and suppression of oprD and carO were seen in isolates of A. baumannii Tokai strain 2 (RRR), as assessed by real-time PCR. Thus, the molecular characterization of a series of isolates of DR A. baumannii revealed the outbreak of ST208 and diverse antimicrobial drug susceptibilities, which almost correlated with differential gene alterations responsible for each type of drug resistance.

C/EBPα and C/EBPε induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene

CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPα and C/EBPɛ. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPα or C/EBPɛ was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPα-ER, but not vice versa, thus suggesting that C/EBPɛ may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPɛ, as well as C/EBPα, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.

Fatal fulminant myocarditis associated with novel influenza A (H1N1) infection

A 51-year-old male presented to a local hospital with deteriorating general fatigue. The patient had reportedly been well until 2 days earlier when he began to have general fatigue. Because the blood pressure was as low as 70/40 mmHg, he was transferred to our hospital. Laboratory data showed WBC of 25 …

Localized or Diffuse Lesions of the Submandibular Glands in Immunoglobulin G4-Related Disease in Association With Differential Organ Involvement

OBJECTIVES The purpose of this study was to assess the relationship between the sonographic characteristics of the submandibular glands and organ involvement at the initial presentation in patients with immunoglobulin G4 (IgG4)-related disease. METHODS We conducted a retrospective study that included 15 patients who had bilateral swollen submandibular glands and elevated serum IgG4 levels between January 2005 and December 2010. RESULTS In all 15 patients, sonography revealed the involvement of both sides of the submandibular glands. The sonographic appearance of each gland was classified into two types: localized tumor-forming and diffuse focal types. On the basis of this typing, all 15 patients were classified into two groups: a group with the localized tumor-forming type observed on one or both sides of the glands (n = 10) and a group with the diffuse focal type present on both sides (n = 5). All 10 patients in the former group had lesions in local exocrine organs, such as the lacrimal and parotid glands, with regional lymphadenopathy. In contrast, all 5 patients in the latter group had lesions in abdominal organs, such as autoimmune pancreatitis and sclerosing cholangitis. CONCLUSIONS The sonographic patterns of the submandibular glands in patients with IgG4-related disease can be divided into two types: localized tumor-forming and diffuse focal. The distinctive patient groups defined by the sonographic patterns in both glands were associated with differential organ involvement and thus could be used as indicators of the disease extension and specific organ involvement.

Sonographic Appearance of the Submandibular Glands in Patients With Immunoglobulin G4-Related Disease

Swelling of the salivary glands is often an initial sign of immunoglobulin G4 (IgG4)‐related disease or IgG4‐related sclerosing/autoimmune disease. We encountered 2 patients with IgG4‐related disease who showed swollen submandibular glands with a unique characteristic sonographic pattern. Bilateral submandibular glands of both patients were enlarged with a smooth contour. The internal echo texture indicated multiple hypoechoic foci scattered against a heterogeneous background, which characteristically appeared with a mottled or irregular netlike appearance. A histopathologic examination of a resected section showed multiple foci of dense infiltrated lymphoplasmacytic cells and lymph follicles encircled by fibrous bands. A mottled appearance in the sonographic findings of the submandibular glands suggests the characteristic of IgG4‐related disease and can be helpful in the differential diagnosis at the initial manifestation.