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Hiroshi Fujiwara

Publications and source records attributed to Hiroshi Fujiwara.

At least 19 recordsLinked to original sources
PubMed2026

Placental Site Trophoblastic Tumor Acquires Immune Functions by Incorporating Host Maternal Genes.

Although it was proposed that cell fusion of cancer cells with leukocytes creates mobile hybrids with a metastatic phenotype, it has been difficult to genetically confirm cell fusion events in human cancer in vivo. Here, we experienced 4 cases of placental site trophoblastic tumor (PSTT) that produced immunoglobulin (Ig). Three cases showed recurrence and responded well to pembrolizumab therapy. Among them, we could analyze temporal changes in the genetic profiles on one case of daughter-derived PSTT, which relapsed after pembrolizumab therapy. In this case, we found that PSTT incorporated the exogenous genes from host maternal cells. The rearrangement patterns of Ig genes and protein expressions sequentially increased. By analyzing single-nucleotide variants, PSTT incorporated daughter-non-inherited maternal alleles (DNIMA), including the Ig lambda and HLA-DQA2 loci. Protein expressions of TLR10 and SIGLEC10 increased during tumor progression concomitantly with DNIMA incorporation. DNIMA mapping indicates the incorporation of exogenous maternal genes was widely distributed through the whole chromosomes, suggesting the involvement of cell fusion in gene transfer mechanisms. These findings indicate that PSTT sequentially incorporated exogenous genes from maternal cells to express immune-related molecules and suggest that cancer cells acquired B cell-related functions, including Ig production by cell fusion with host immune cells.

Humans↗
PubMed2006

Reduced frequency, diversity, and function of human T cell leukemia virus type 1-specific CD8+ T cell in adult T cell leukemia patients.

Human T cell lymphotropic virus type 1 (HTLV-1)-specific CTL are thought to be immune effectors that reduce the risk of adult T cell leukemia (ATL). However, in vivo conditions of anti-HTLV-1 CTL before and after ATL development have yet to be determined. To characterize anti-HTLV-1 CTL in asymptomatic HTLV-1 carriers (AC) and ATL patients, we analyzed the frequency and diversity of HTLV-1-specific CD8+ T cells in PBMC of 35 AC and 32 ATL patients using 16 distinct epitopes of HTLV-1 Tax or Env/HLA tetramers along with intracellular cytolytic effector molecules (IFN-gamma, perforin, and granzyme B). Overall frequency of subjects possessing Tax-specific CD8+ T cells was significantly lower in ATL than AC (53 vs 90%; p = 0.001), whereas the difference in Env-specific CD8+ T cells was not statistically significant. AC possessed Tax11-19/HLA-A*0201-specific tetramer+ cells by 90% and Tax301-309/HLA-A*2402-specific tetramer+ cells by 92%. Some AC recognized more than one epitope. In contrast, ATL recognized only Tax11-19 with HLA-A*0201 and Tax301-309 with HLA-A*2402 at frequencies of 30 and 55%. There were also significant differences in percentage of cells binding Tax11-19/HLA-A*0201 and Tax301-309/HLA-A*2402 tetramers between AC and ATL. Anti-HTLV-1 Tax CD8+ T cells in AC and ATL produced IFN-gamma in response to Tax. In contrast, perforin and granzyme B expression in anti-HTLV-1 CD8+ T cells of ATL was significant lower than that of AC. Frequency of Tax-specific CD8+ T cells in AC was related to proviral load in HLA-A*0201. These results suggest that decreased frequency, diversity, and function of anti-HTLV-1 Tax CD8+ T cell clones may be one of the risks of ATL development.

Adult↗
PubMed2006

Integrin alpha5 is involved in fibronectin-induced human extravillous trophoblast invasion.

To identify the molecules involved in human extravillous trophoblast (EVT) invasion, we raised murine mAbs that react with EVTs and obtained one mAb (CHL3) that inhibited invasion of a human choriocarcinoma-derived cell line, BeWo cells. The N-terminal 22 aminoacid sequence of the CHL3 antigen (150kDa) purified from placental tissue completely matched that of integrin alpha5, which is known to interact with fibronectin. Double immunohistochemical staining and flow cytometry confirmed the reactivity of CHL3 with integrin alpha5 and its expression on the surface of BeWo cells and human EVTs isolated from villous explant cultures. CHL3 mAb inhibited the attachment of human EVTs and BeWo cells to fibronectin-coated dishes, but not to Matrigel dishes. In the Matrigel invasion assay supplemented with or without fibronectin, the invasion of isolated EVTs and BeWo cells was attenuated by treatment with CHL3 without affecting cell proliferation. During invasion assays, the production of matrix metalloproteases 2 and 9 was not changed by CHL3. These findings suggest that interaction with fibronectin through integrin alpha5 plays an important role in human extravillous trophoblast invasion.

Amino Acid Sequence↗
PubMed2006

Immunosuppressive treatment for mixed connective tissue disease may facilitate the development of adult T cell leukemia/lymphoma in a HTLVI carrier.

A 66-year-old woman who was positive for human T-lymphotropic virus type I (HTLV-I) antibody developed mixed connective tissue disease (MCTD) with interstitial pneumonia, and was successfully treated with corticosteroid. One year later, under maintenance treatment of prednisolone (PSL), she contracted acute type adult Tcell leukemia/lymphoma (ATLL) without flaring of MCTD. MCTD is considered to be as one of the HTL-V-I-related inflammatory diseases, however the development of ATLL during the treatment of HTL-V-I-related MCTD has not been well studied. Here, we review the literature and raise the issue of the mutual interactions between MCTD-causative anti-HTLV-I immune response and anti-ATLL immune response.

Aged↗
PubMed2006

Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients.

We have identified the genes whose expressions are augmented in the blood cells of the patients with systemic lupus erythematosus (SLE) using the 'stepwise subtraction' technique along with microarray analysis. The expression levels of these genes were assessed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) in 31 SLE patients and 30 healthy controls. We found that the transcription levels of following eight genes were significantly increased in SLE patients; interferon (IFN)-alpha-inducible protein 27 (IFI27), IFN-alpha-inducible protein IFI-15K (G1P2), IFN stimulated gene 20 kDa (ISG20), epithelial stromal interaction 1 (EPSTI1), defensin-alpha (DEFA3), amphiregulin (AREG) and two genes of unknown function (BLAST accession nos AL050290 and AY358224 = SLED1). In comparison with idiopathic thrombocytopenic purpura (ITP), an organ-specific autoimmune disease, IFI27, G1P2 and SLED1 were preferentially upregulated in SLE. In contrast, AREG and AL050290 were more highly expressed in ITP than in SLE. We correlated changes in gene expression and clinical/laboratory features of SLE and found that expression of ISG20, EPSTI1 and SLED1 are significantly correlated with lymphocyte counts. Genes linked to IFN are well known to influence SLE, but several other novel genes unrelated to IFN signaling we report here would be useful to understand the pathophysiology of SLE.

Female↗
PubMed2006

Eph-ephrin A system regulates murine blastocyst attachment and spreading.

Although numerous adhesion molecules are expressed on mammalian endometrial epithelial cells, there have not been any studies of a mechanism to prevent premature attachment of the embryo. In this study, we examined the possible involvement of Eph-ephrin interaction, which can induce repulsive forces. In mice, Eph A1, A2, and A4 were expressed on endometrial epithelial cells and ephrin A1-4 on blastocysts. Reverse transcriptase-polymerase chain reaction showed that mRNA expression of ephrin A1-4 on embryos transiently decreased around the implantation period. Immunohistochemistry demonstrated that the expression of Eph A1 on endometrial epithelial cells and ephrin A1 and A3 expression on embryos decreased at implantation sites. Recombinant Eph A1 reacted with cell the surface of ephrin A-bearing trophectoderm cells. Attachment assays using Eph A1-coated dishes showed that blastocyst attachment was reversibly inhibited by Eph A1. These findings suggest an important role of the Eph-ephrin A system in regulating the initial embryo-maternal contact during the cross-talk period that precedes embryo implantation.

Animals↗
PubMed2006

Stevens-Johnson syndrome induced by mizoribine in a patient with systemic lupus erythematosus.

A 32-year-old Japanese woman, who had a treatment history of systemic lupus erythematosus (SLE) with lupus nephritis World Health Organization class IV for 11 months, visited our hospital due to fever, facial erythema, and erosion of the oral cavity on November 10, 2003. Her mucosal erosion and facial skin erythema progressed over the following week, and Stevens-Johnson syndrome was diagnosed due to pathological findings of the skin. Among the administrated drugs, only mizoribine, started 6 months earlier, produced a positive reaction in the drug lymphocyte stimulation test. Increased prednisolone and high dose intravenous gamma-globulin were given successfully. Cyclosporine at 50 mg was administered to control the SLE, followed by an increase to 100 mg on January 7, 2004. She suffered from abdominal pain, blindness, and convulsion on January 9. The magnetic resonance image of her brain prompted a diagnosis of reversible posterior leukoencephalopathy syndrome. After withdrawal of cyclosporine and control of hypertension, symptoms disappeared rapidly. Cyclophosphamide pulse therapy was successfully administrated to control lupus nephritis. This is the first report describing the relationship between Stevens-Johnson syndrome and mizoribine. Although the use of mizoribine is thought to be safe, careful observation is necessary.

Adult↗
PubMed2006

[A case of pulmonary tumor embolism presenting with an initial manifestation of urothelial carcinoma].

A 64-year-old man presented with fever, chest pain, and bloody sputum. Chest computed tomography showed multiple, irregularly shaped infiltrative shadows in the subpleural regions of both lung fields. Out of the 6 sputum cytology specimens, only one specimen suggested malignancy. Furthermore, no malignant cells were detected in the bronchoalveolar lavage fluid. A video-assisted lung biopsy yielded a diagnosis of pulmonary tumor embolism was made. The primary lesion of this pulmonary metastatic cancer was urothelial carcinoma, which was not detected by contrast-enhanced computed tomography of the abdomen. This case is particularly unusual because it is difficult to establish an ante-mortem diagnosis of pulmonary tumor embolism, and there have been only a few previous reports regarding pulmonary tumor embolism from a urothelial tumor.

Biopsy↗
PubMed2005

Regulation of human extravillous trophoblast function by membrane-bound peptidases.

During human placentation, the invasion of extravillous trophoblasts (EVTs) into maternal decidual tissues, especially toward maternal spiral arteries, is considered an essential process for subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVTs from further invasion have not been well understood. Recently, we found that two cell surface peptidases, dipeptidyl peptidase IV (DPPIV) and carboxypeptidase-M (CP-M,) are differentially expressed on EVTs. DPPIV expression was mainly observed on EVTs that had already ceased invasion. CP-M was detected on migrating EVTs including endovascular trophoblasts in the maternal arteries. The enzymatic inhibition of these peptidases affected the invasive property of choriocarcinoma-derived cell lines, BeWo and JEG3 cells. In addition, a chemokine, RANTES, that is one of the substrates for DPPIV, enhanced invasion of EVTs isolated from primary villous explant culture and its receptor, CCR1, was specifically expressed on migrating EVTs toward maternal arteries. Furthermore, a novel membrane-bound cell surface peptidase, named laeverin, was found to be specifically expressed on EVTs that had almost ceased invasion. These findings suggest that membrane-bound peptidases are important factors regulating EVT invasion during early placentation in humans.

Amino Acid Sequence↗
PubMed2005

The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions.

To study natural killer (NK) cell-mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56(+) cells to inhibit granulocyte macrophage-colony-forming unit (CFU-GM) formation by leukemic CD34(+) cells. In 14 HLA-identical donor-recipient pairs, donor CD56(+) cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% +/- 9% vs 39.5% +/- 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56(+)CD3(-) (natural killer [NK]) and CD56(+)CD3(+)(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34(+) cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain-related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell-mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56(+) cells.

Adult↗
PubMed2005

In vitro induction of myeloid leukemia-specific CD4 and CD8 T cells by CD40 ligand-activated B cells gene modified to express primary granule proteins.

The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3), human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate post-allogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-gamma or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.

Antigen-Presenting Cells↗
PubMed2005

Body composition is related to increase in plasma adiponectin levels rather than training in young obese men.

We assessed the major factors regulating adiponectin levels and the influence of exercise training on adiponectin levels in young obese men (19.2 +/- 1.1 yrs, BMI: 31.1 +/- 4.2, %fat: 27.2 +/- 3.9%). Subjects were separated into three groups (aerobic exercise group [AE: n=7], aerobic and resistance exercise group [AE + RE: n = 7], control group [n = 7]). AE underwent an 8-week training program (three times per week, more than 30 min endurance exercise at ventilatory threshold (VT) intensity). AE + RE went through resistance exercise two or three times per week together with the above endurance exercise for 5 months. Prior to intervention (n = 21), adiponectin levels were significantly correlated with percentage of fat. Stepwise multiple regression analysis revealed that percent body fat was an independent predictor of basal adiponectin levels (r2 = 0.370; P<0.01). After intervention, fat mass, and VT were significantly improved in AE. AE + RE exhibited significant reduction in weight, BMI, percent body fat and fat mass, and had significantly increased VT, VO2max cycling power and torque. Insulin was not changed in both groups. The control group exhibited no significant change in any variables. Although adiponectin levels were unchanged in the three groups, a significant negative correlation between delta fat mass and delta adiponectin levels was observed (n = 21, r = -0.461, P<0.05). In addition, delta percent body fat was an independent predictor of delta adiponectin levels (r2 = 0.327, P<0.05). These findings indicate that for increasing the adiponectin level, improvement of the body composition of young obese men is more important than the way training is performed.

Adaptation, Physiological↗
PubMed2005

Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma.

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-gamma (IFN-gamma) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T-->C SNP, which is in linkage disequilibrium with a synonymous coding 390A-->G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P = 0.004, P(c) = 0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P = 0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

Adolescent↗
PubMed2005

Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries.

In early pregnancy, human extravillous trophoblasts (EVTs) invade and remodel maternal arteries. We have previously demonstrated that CCR1 is expressed on perivascular/endovascular trophoblasts and that CCR1 ligands promote EVT migration. In this study, we examined the physiologic roles of platelet-derived chemoattractants on EVT invasion. By immunohistochemistry, maternal platelets were localized among endovascular trophoblasts within the lumen of spiral arteries. Extracellular matrices (ECMs) were also detected among endovascular trophoblasts and platelets, suggesting that the platelets in these arteries were activated by ECMs. In vitro, platelets attached to EVTs isolated from human villous explant cultures and expressed P-selectin on the cell surface. Platelets significantly enhanced migration of EVTs without affecting proliferation of EVTs or secretion of MMP-2 or MMP-9. The invasion-enhancing effect of platelet-derived culture medium on EVTs was neutralized by anti-CCR1 antibody. Heat treatment completely abrogated the invasion-promoting effects of platelet-derived culture medium, but charcoal stripping did not. Platelets also induced endovascular trophoblast-like morphologic changes and integrin alpha1 expression in EVTs during 48-hour culture. These findings suggest that maternal platelets activated in the spiral arteries can regulate trophoblastic vascular infiltration and differentiation by releasing various soluble factors.

Arteries↗
PubMed2005

Case of a patient with progressive adult T-cell leukemia/lymphoma treated successfully by reduced-intensity conditioning stem cell transplantation from an HLA-incompatible related donor.

A 61-year-old man with progressive adult T-cell leukemia/lymphoma (ATLL) successfully received reduced-intensity conditioning stem cell transplantation (RIST) without T-cell depletion (TCD) from his HLA-incompatible son, who had negative results for human T-lymphotropic virus type 1 (HTLV-1) (1-locus, 1-allele mismatch in the graft-versus-host [GVH] direction; 2-loci, 1-allele mismatch in the host-versus-graft direction). The preparatory regimen consisted of fludarabine, busulfan, and rabbit antithymocyte globulin. GVH disease (GVHD) prophylaxis consisted of short-term administration of methotrexate, tacrolimus, and methylprednisolone. The patient achieved complete donor chimerism on day 30 after transplantation. On approximately day 50 the patient started to experience steroid-refractory skin GVHD (grade IV), which was successfully managed with basiliximab (anti-CD25 monoclonal antibody) and mycophenolate mofetil (MMF). Serial analysis of HTLV-1 proviral load by quantitative polymerase chain reaction analysis using whole peripheral blood demonstrated undetectable levels from day 90. At the time of this writing the patient had been in complete remission for more than 16 months. The results in this case suggest the potential of non-TCD RIST from an HLA-incompatible relative donor as an alternative source of hematopoietic stem cells even for an elderly patient with advanced ATLL. In addition, basiliximab combined with MMF may be effective for the treatment of steroid-refractory skin GVHD without deteriorating the graft-versus-ATL effect.

B-Lymphocytes↗
PubMed2005

An autopsy case of primary pericardial mesothelioma in arc cutter exposed to asbestos through talc pencils.

An autopsy case of a primary pericardial mesothelioma in a 53-year-old arc cutter is reported. He had often had the chance to inhale dust generated by sharpening the slate pencils composed of talc. He was admitted for heart failure due to pericardial tumor, but later died. The tumor was mainly located on the pericardium with a thickness of about 2.5 cm. Small nodular disseminations were observed in the left parietal pleura. Microscopically, tumor cells were epithelial-like and rich in histochemical demonstrable hyaluronic acid. Findings of immunohistochemical markers revealed keratin (+), EMA (+), calretinin (+), and CEA (-), which were characteristics of mesothelioma of epithelial type. The number of asbestos bodies (AB) in the lung parenchyma was increased (2026 AB/gram dry lung tissue). Subsequent transmission electron microscopic examination equipped with an energy dispersive X-ray analyzer revealed that the fibers identified in the lungs were fibrous talc and actinolite. These findings suggested that this patient had been occupationally exposed to asbestos contaminated in the talc pencils, which induced the development of primary pericardial mesothelioma.

Asbestos, Amphibole↗
PubMed2005

[A case of chronic pleuritis by Paragonimus Westermani infection resistant to standard chemotherapy and cured by three additional cycles of chemotherapy].

A 16-year-old boy had eaten Chinese freshwater crabs soaked in liquor in October 2000, and the left pleural effusion was pointed out on chest X-ray films at a regular medical checkup at school in June 2002. Since his father and friends had suffered from Paragonimiasis Westermani and had been treated in January 2001, the patient agreed to immunoserological examination, and Paragonimiasis Westermani was diagnosed. After drainage of pleural effusion, the patient was treated with praziquantel for three days at a daily dosage of 75 mg/kg, but without effect. The patient received drainage of pleural effusion again, and was treated with praziquantel for 3 days at a daily dosage of 75 mg/kg in a series of three treatments at three week interval. After that, improvement of the disease was achieved.

Adolescent↗